| 1. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 2. |
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| 3. |
- Lord, Anna, 1979-, et al.
(författare)
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Arctic Aβ selectively increases diffuse deposition of wild type Aβ in APP transgenic mice with the Swedish mutation
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Studies of familial Alzheimer´s disease (AD) suggest that misfolding and aggregation of amyloid-β (Aβ) peptides initiate the pathogenesis, which causes dementia. The Arctic amyloid precursor protein (APP) mutation results in AD, and Arctic Aβ is more prone to form Aβ protofibrils. Here we show that the number of diffuse Aβ deposits, but not amyloid plaques, is increased if tg-ArcSwe mice synthesizing a low level of Arctic Aβ are crossed with plaque-depositing tg-Swe mice. The diffuse deposits in bitransgenic mice, which contain mainly wild type Aβ42, accumulate in regions both with and without transgene expression. The selective increase of a single type of parenchymal Aβ deposit suggest that different pathways of Aβ aggregation lead to the formation of diffuse and compact Aβ deposits in the brain. The raise in diffuse deposits is most likely due to direct physical interactions between Arctic and wild type Aβ42, and not to altered APP processing in young bitransgenic mice. A mixture of Arctic and wild type Aβ42 facilitates the formation of prefibrillar and fibrillar Aβ assemblies, but inhibits the further elongation of Aβ fibrils in vitro. Our findings might have implications to the pathogenesis of patients who are heterozygous for the Arctic mutation. It also further illustrates how Aβ neuropathology can be manipulated in vivo in a manner reminiscent to prion disorders.
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| 4. |
- Möller, Bengt, et al.
(författare)
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Lead Levels Determined in Swedish Permanent Teeth by Particle-Induced X-Ray Emission
- 1982
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Ingår i: Scandinavian Journal of Work, Environment and Health. - 0355-3140. ; 8:4, s. 267-272
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Tidskriftsartikel (refereegranskat)abstract
- The determination of lead in permanent teeth is a useful measure of past exposure in early childhood since these teeth are mineralized in early childhood. Particle-induced X-ray emission (PIXE) analysis has been shown to be a method with good applicability for the contamination-free analysis of elements heavier than calcium in dental hard tissues. The method is rapid and nondestructive. The purpose of this study, which used the PIXE technique, was to survey the average level of lead in the coronal dentin of permanent bicuspid teeth collected in three places representing Swedish urban and rural areas. In addition teeth from the New York City area were analyzed. The material comprised 165 teeth from Sweden and, for comparison, 14 teeth from New York City. The median value of lead in the Swedish teeth was 2.9 micrograms/g, a value indicating an insignificant influence from the environment in comparison to the New York teeth, for which the median value was 9.2 micrograms/g. There was however a statistically significant difference in the lead concentration of teeth from large and small Swedish cities; this finding may reflect different automobile traffic intensity.
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| 5. |
- Nilsson, K. Peter R., et al.
(författare)
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Imaging distinct conformational states of amyloid-beta fibrils in Alzheimer's disease using novel luminescent probes
- 2007
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Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 2:8, s. 553-560
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Tidskriftsartikel (refereegranskat)abstract
- Using luminescent conjugated polyelectrolyte probes (LCPs), we demonstrate the possibility to distinguish amyloid-β 1–42 peptide (Aβ1–42) fibril conformations, by analyzing in vitro generated amyloid fibrils of Aβ1–42 formed under quiescent and agitated conditions. LCPs were then shown to resolve such conformational heterogeneity of amyloid deposits in vivo. A diversity of amyloid deposits depending upon morphology and anatomic location was illustrated with LCPs in frozen ex vivo brain sections from a transgenic mouse model (tg-APP swe) of Alzheimer’s disease. Comparative LCP fluorescence showed that compact-core plaques of amyloid β precursor protein transgenic mice were composed of rigid dense amyloid. A more abundant form of amyloid plaque displayed morphology of a compact center with a protruding diffuse exterior. Surprisingly, the compact center of these plaques showed disordered conformations of the fibrils, and the exterior was composed of rigid amyloid protruding from the disordered center. This type of plaque appears to grow from more loosely assembled regions toward solidified amyloid tentacles. This work demonstrates how application of LCPs can prove helpful to monitor aggregate structure of in vivo formed amyloid deposits such as architecture, maturity, and origin.
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| 6. |
- Nilsson, Peter, et al.
(författare)
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Imaging distinct conformational states of amyloid-β fibrils in Alzheimer's disease using novel luminescent probes
- 2007
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Ingår i: ACS Chemical Biology. - : American Chemical Society (ACS). - 1554-8929 .- 1554-8937. ; 2:8, s. 553-560
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Tidskriftsartikel (refereegranskat)abstract
- Using luminescent conjugated polyelectrolyte probes (LCPs), we demonstrate the possibility to distinguish amyloid-β 1-42 peptide (Aβ1-42) fibril conformations, by analyzing in vitro generated amyloid fibrils of Aβ1-42 formed under quiescent and agitated conditions. LCPs were then shown to resolve such conformational heterogeneity of amyloid deposits in vivo. A diversity of amyloid deposits depending upon morphology and anatomic location was illustrated with LCPs in frozen ex vivo brain sections from a transgenic mouse model (tg-APPswe) of Alzheimer's disease. Comparative LCP fluorescence showed that compact-core plaques of amyloid β precursor protein transgenic mice were composed of rigid dense amyloid. A more abundant form of amyloid plaque displayed morphology of a compact center with a protruding diffuse exterior. Surprisingly, the compact center of these plaques showed disordered conformations of the fibrils, and the exterior was composed of rigid amyloid protruding from the disordered center. This type of plaque appears to grow from more loosely assembled regions toward solidified amyloid tentacles. This work demonstrates how application of LCPs can prove helpful to monitor aggregate structure of in vivo formed amyloid deposits such as architecture, maturity, and origin.
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| 7. |
- Philipson, Ola, et al.
(författare)
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A highly insoluble state of Abeta similar to that of Alzheimer's disease brain is found in Arctic APP transgenic mice.
- 2009
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Ingår i: Neurobiology of aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 30:9, s. 1393-405
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid-beta (Abeta) is a major drug target in Alzheimer's disease. Here, we demonstrate that deposited Abeta is SDS insoluble in tgAPP-ArcSwe, a transgenic mouse model harboring the Arctic (E693G) and Swedish (KM670/671NL) APP mutations. Formic acid was needed to extract the majority of deposited Abeta in both tgAPP-ArcSwe and Alzheimer's disease brain, but not in a commonly used type of mouse model with the Swedish mutation alone. Interestingly, the insoluble state of Arctic Abeta was determined early on and did not gradually evolve with time. In tgAPP-ArcSwe, Abeta plaques displayed a patchy morphology with bundles of Abeta fibrils, whereas amyloid cores in tgAPP-Swe were circular with radiating fibrils. Amyloid was more densely stacked in tgAPP-ArcSwe, as demonstrated with a conformation sensitive probe. A reduced increase in plasma Abeta was observed following acute administration of an Abeta antibody in tgAPP-ArcSwe, results that might imply reduced brain to plasma Abeta efflux. TgAPP-ArcSwe, with its insoluble state of deposited Abeta, could serve as a complementary model to better predict the outcome of clinical trials.
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| 8. |
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| 9. |
- Wehlin, Anna, 1994-
(författare)
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Structural and Functional Studies on Evolutionary Repurposing of H-box/NC-proteins : From Host Factor to Virus Protein
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The Picornaviridae are a large family of biomedically important viruses causing diseases such as the common cold, hepatitis A and polio in humans and foot-and-mouth disease in cattle. These diseases have great impact on people’s everyday life and cause economical losses all around the world. To date, no antiviral treatments are available. In attempts to identify potential drug targets for novel antiviral therapies, a human protein was identified as a common host factor for several enteroviruses, a genus within the picornavirus family. This host factor, PLAAT3, facilitates genome transfer from the virus particle into the cytoplasm early in the viral lifecycle prior to virus clearance by autophagy. PLAAT3 is part of a human phospholipid-modifying enzyme family of five members, PLAAT1-5, which all have a conserved H-box/NC-motif forming the active site of these enzymes as well as a hydrophobic C-terminal region that is critical for enzymatic function. This H-box/ NC-motif is also found in the 2A locus of some picornaviruses, suggesting that these viruses might have acquired the protein through horizontal gene transfer to become independent of the human host factor.This thesis focuses on understanding the structural mechanism allowing picornavirus infection. Therefore, two members of the PLAAT-family were studied together with viral 2A proteins sharing the H-box/NC-motif.PLAAT3 was studied with the aim to elucidate its molecular mechanism underpinning its role as a host factor enabling genome transfer. PLAAT3 is composed of a globular N-terminal domain (NTD), whose structure has previously been determined, followed by a 30 amino acid long hydrophobic region (CTR). The catalytic site is located within the NTD, but the hydrophobic CTR is essential both for the catalytic activity as well as cellular localization of PLAAT3.PLAAT4 shares 50% sequence identity with PLAAT3 and exhibits a similar structure with a globular NTD followed by a hydrophobic tail. However, PLAAT4 shows a different activity pattern and displays enzymatic activity even in the absence of the CTR. By comparing the structural properties of PLAAT3 and PLAAT4 more can be understood of the structural characteristics enabling biological functions.The viral 2A proteins studied in this thesis originate from different picornavirus genera but all share the conserved H-box/NC-motif with the PLAAT-family. By investigating the structure and function of representative 2AH/NC proteins from different branches of the phylogenetic tree we aim to identify different steps of evolutionary repurposing to help us understand their role(s) in the viral lifecycle and determine the molecular mechanism allowing them to by-pass PLAAT3 as a host factor.
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| 10. |
- Abrahamsson, Maria, et al.
(författare)
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A 3.0 mu s room temperature excited state lifetime of a bistridentate Ru-II-polypyridine complex for rod-like molecular arrays
- 2006
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 128:39, s. 12616-12617
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Tidskriftsartikel (refereegranskat)abstract
- A bistridentate RuII-polypyridine complex [Ru(bqp)2]2+ (bqp = 2,6-bis(8'-quinolinyl)pyridine) has been prepared, which has a coordination geometry much closer to a perfect octahedron than the typical Ru(terpyridine)2-type complex. Thus, the complex displays a 3.0 mus lifetime of the lowest excited metal-to-ligand charge transfer (3MLCT) state at room temperature. This is, to the best of our knowledge, the longest MLCT state lifetime reported for a RuII-polypyridyl complex at room temperature. The structure allows for the future construction of rod-like, isomer-free molecular arrays by substitution of donor and acceptor moieties on the central pyridine units. This makes it a promising photosensitizer for applications in molecular devices for artificial photosynthesis and molecular electronics.
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