| 2151. |
- Limbocker, Ryan, et al.
(författare)
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Trodusquemine enhances Aβ42 aggregation but suppresses its toxicity by displacing oligomers from cell membranes
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Transient oligomeric species formed during the aggregation process of the 42-residue form of the amyloid-β peptide (Aβ42) are key pathogenic agents in Alzheimer’s disease (AD). To investigate the relationship between Aβ42 aggregation and its cytotoxicity and the influence of a potential drug on both phenomena, we have studied the effects of trodusquemine. This aminosterol enhances the rate of aggregation by promoting monomer-dependent secondary nucleation, but significantly reduces the toxicity of the resulting oligomers to neuroblastoma cells by inhibiting their binding to the cellular membranes. When administered to a C. elegans model of AD, we again observe an increase in aggregate formation alongside the suppression of Aβ42-induced toxicity. In addition to oligomer displacement, the reduced toxicity could also point towards an increased rate of conversion of oligomers to less toxic fibrils. The ability of a small molecule to reduce the toxicity of oligomeric species represents a potential therapeutic strategy against AD.
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| 2152. |
- Lin, Weihua, et al.
(författare)
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Physical mechanism on exciton-plasmon coupling revealed by femtosecond pump-probe transient absorption spectroscopy.
- 2017
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Ingår i: Materials Today Physics. - : Elsevier BV. - 2542-5293. ; 3, s. 33-40
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Tidskriftsartikel (refereegranskat)abstract
- The unclear mechanism of exciton-plasmon coupling interaction in monolayer MoS2-Ag nanoparticles hybrid, as a longstanding target in molecular nanotechnology and catalysis, is systemically investigated with transmission spectra and femtosecond pump-probe transient absorption spectroscopy in this paper. The properties of exciton in monolayer MoS2 are strongly enhanced due to the local surface plasmon resonance (LSPR) induced by Ag nanoparticles, and manifested by obvious changes in transmission spectra. Furthermore, we discuss the dynamic processes of exciton-plasmon coupling interaction with the femtosecond transient absorption spectroscopy, which indicates that there are three lifetimes, Auger scattering, electron-electron interaction and electron-phonon interaction, and illustrate the reason of the enlarged lifetime in hybrid system. Meanwhile, the intensity of A excitonic state in femtosecond transient absorption spectroscopy is significantly enhanced by LSPR, instead of excitonic state B. In conclusion, our study can promote the deeper understanding and illustrate the unique merits of the exciton-plasmon coupling interaction in the monolayer MoS2-Ag nanoparticles hybrid system.
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| 2153. |
- Lin, Zhipeng, et al.
(författare)
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Electrocatalyzed direct arene alkenylations without directing groups for selective late-stage drug diversification
- 2023
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Ingår i: Nature Communications. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Electrochemistry has emerged as an increasingly viable tool in molecular synthesis. Here the authors realize electrocatalyzed C-H activations, with the aid of data science and artificial intelligence, towards selective alkenylations for late-stage drug diversifications. Electrooxidation has emerged as an increasingly viable platform in molecular syntheses that can avoid stoichiometric chemical redox agents. Despite major progress in electrochemical C-H activations, these arene functionalizations generally require directing groups to enable the C-H activation. The installation and removal of these directing groups call for additional synthesis steps, which jeopardizes the inherent efficacy of the electrochemical C-H activation approach, leading to undesired waste with reduced step and atom economy. In sharp contrast, herein we present palladium-electrochemical C-H olefinations of simple arenes devoid of exogenous directing groups. The robust electrocatalysis protocol proved amenable to a wide range of both electron-rich and electron-deficient arenes under exceedingly mild reaction conditions, avoiding chemical oxidants. This study points to an interesting approach of two electrochemical transformations for the success of outstanding levels of position-selectivities in direct olefinations of electron-rich anisoles. A physical organic parameter-based machine learning model was developed to predict position-selectivity in electrochemical C-H olefinations. Furthermore, late-stage functionalizations set the stage for the direct C-H olefinations of structurally complex pharmaceutically relevant compounds, thereby avoiding protection and directing group manipulations.
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| 2154. |
- Lin, Zesen, et al.
(författare)
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The Age Dependence of Mid-infrared Emission around Young Star Clusters
- 2020
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 896:1
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Tidskriftsartikel (refereegranskat)abstract
- Using the star cluster catalogs from the Hubble Space Telescope program Legacy Extragalactic UV survey (LEGUS) and 8 mu m images from the IRAC camera on the Spitzer Space Telescope for five galaxies within 5 Mpc, we investigate how the 8 mu m dust luminosity correlates with the stellar age on the 30-50 pc scale of star-forming regions. We construct a sample of 97 regions centered at local peaks of 8 mu m emission, each containing one or more young star cluster candidates from the LEGUS catalogs. We find a tight anticorrelation with a Pearson correlation coefficient ofr = -0.84 0.05 between the mass-normalized dust-only 8 mu m luminosity and the age of stellar clusters younger than 1 Gyr; the 8 mu m luminosity decreases with increasing age of the stellar population. Simple assumptions on a combination of stellar and dust emission models reproduce the observed trend. We also explore how the scatter of the observed trend depends on assumptions of stellar metallicity, polycyclic aromatic hydrocarbon (PAH) abundance, fraction of stellar light absorbed by dust, and instantaneous versus continuous star formation models. We find that variations in stellar metallicity have little effect on the scatter, while PAH abundance and the fraction of dust-absorbed light bracket the full range of the data. We also find that the trend is better explained by continuous star formation, rather than instantaneous burst models. We ascribe this result to the presence of multiple star clusters with different ages in many of the regions. Upper limits of the dust-only 8 mu m emission as a function of age are provided.
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| 2155. |
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| 2156. |
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| 2157. |
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| 2158. |
- Lindström, Sara, et al.
(författare)
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Systematic replication study of reported genetic associations in prostate cancer : Strong support for genetic variation in the androgen pathway
- 2006
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Ingår i: The Prostate. - Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. Umea Univ, Dept Radiat Sci Oncol, Umea, Sweden. Wake Forest Univ, Sch Med, Ctr Human Genome, Winston Salem, NC USA. Karolinska Inst, Ctr Genome & Bioinformat, Stockholm, Sweden. Univ Leicester, Dept Genet, Leicester, Leics, England. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD USA. Karolinska Inst, CLINTEC, Ctr Oncol, Stockholm, Sweden. : WILEY-LISS. - 0270-4137 .- 1097-0045. ; 66:16, s. 1729-1743
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND. Association studies have become a common and popular method to identify genetic variants predisposing to complex diseases. Despite considerable efforts and initial promising findings, the field of prostate cancer genetics is characterized by inconclusive reports and no prostate cancer gene has yet been established. METHODS. We performed a literature review and identified 79 different polymorphisms reported to influence prostate cancer risk. Of these, 46 were selected and tested for association in a large Swedish population-based case-control prostate cancer population. RESULTS. We observed significant (P < 0.05) confirmation for six polymorphisms located in five different genes. Three of them coded for key enzymes in the androgen biosynthesis and response pathway; the CAG repeat in the androgen receptor (AR) gene (P = 0.03), one SNP in the CYP17 gene (P = 0.04), two SNPs in the SRD5A2 gene (P = 0.02 and 0.02, respectively), a deletion of the GSTT1. gene (P = 0.006), and one SNP in the MSR1 gene, IVS5-59C > A, (P = 0.009). CONCLUSIONS. Notwithstanding the difficulties to replicate findings in genetic association studies, our results strongly support the importance of androgen pathway genes in prostate cancer etiology.
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| 2159. |
- Linninge, C., et al.
(författare)
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Lactobacillus fermentum and Lactobacillus plantarum increased gut microbiota diversity and functionality, and mitigated Enterobacteriaceae, in a mouse model
- 2019
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Ingår i: Beneficial microbes. - : WAGENINGEN ACADEMIC PUBLISHERS. - 1876-2883 .- 1876-2891. ; 10:4, s. 413-424
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Tidskriftsartikel (refereegranskat)abstract
- Probiotics should bring ‘balance’ to the intestinal microbiota by stimulating beneficial bacteria, whilst mitigating adverse ones. Balance can also be interpreted as high alpha-diversity. Contrary, Escherichia coli is often regarded as an adverse component of the resident intestinal microbiota. The aim of the present study was to implement a mouse model for in vivo screening of Lactobacillus-strains for ability to increase gut-microbiota diversity and to mitigate E. coli. Mice were divided into six groups, two dietary control-groups and four groups administered strains of Lactobacillus fermentum and/or Lactobacillus plantarum. All animals were pre-treated with antibiotics, and E. coli in order to equalise the microbiota from the start. After 7 weeks of Lactobacillus administration, the animals were sacrificed: DNA was extracted from caecum tissue, and the microbiota composition was analysed with terminal restriction fragment length polymorphism (T-RFLP) and 16S rRNA gene sequencing. The diversity of the caecal microbiota decreased when the dietary carbohydrate source was limited to corn starch. Conversely, the diversity was restored by Lactobacillus-supplements. The tested combinations of two Lactobacillus strains exerted different influences, not only on the taxonomic level, but also on the inferred microbiome functions. The mixture of L. fermentum GOS47 and L. fermentum GOS1 showed potential for anti-inflammatory activity and short chain fatty acid production. On the other hand, co-administration of L. fermentum GOS57 and L. plantarum GOS42 significantly decreased the viable count of Enterobacteriaceae. These results warrant further investigation of the tested strains as candidates for probiotics. Furthermore, the findings demonstrated that the current experimental animal model is suitable for in vivo studies of the effect of bacterial supplements on the gut-microbiota.
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| 2160. |
- Linse, Sara, et al.
(författare)
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Kinetic fingerprints differentiate the mechanisms of action of anti-Aβ antibodies
- 2020
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Ingår i: Nature Structural and Molecular Biology. - : Springer Science and Business Media LLC. - 1545-9993 .- 1545-9985. ; 27:12, s. 1125-1133
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Tidskriftsartikel (refereegranskat)abstract
- The amyloid cascade hypothesis, according to which the self-assembly of amyloid-β peptide (Aβ) is a causative process in Alzheimer’s disease, has driven many therapeutic efforts for the past 20 years. Failures of clinical trials investigating Aβ-targeted therapies have been interpreted as evidence against this hypothesis, irrespective of the characteristics and mechanisms of action of the therapeutic agents, which are highly challenging to assess. Here, we combine kinetic analyses with quantitative binding measurements to address the mechanism of action of four clinical stage anti-Aβ antibodies, aducanumab, gantenerumab, bapineuzumab and solanezumab. We quantify the influence of these antibodies on the aggregation kinetics and on the production of oligomeric aggregates and link these effects to the affinity and stoichiometry of each antibody for monomeric and fibrillar forms of Aβ. Our results reveal that, uniquely among these four antibodies, aducanumab dramatically reduces the flux of Aβ oligomers.
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