| 1. |
- Braniste, Viorica, et al.
(författare)
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The gut microbiota influences blood-brain barrier permeability in mice
- 2014
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 6:263, s. 263ra158-
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Tidskriftsartikel (refereegranskat)abstract
- Pivotal to brain development and function is an intact blood-brain barrier (BBB), which acts as a gatekeeper to control the passage and exchange of molecules and nutrients between the circulatory system and the brain parenchyma. The BBB also ensures homeostasis of the central nervous system (CNS). We report that germ-free mice, beginning with intrauterine life, displayed increased BBB permeability compared to pathogen-free mice with a normal gut flora. The increased BBB permeability was maintained in germ-free mice after birth and during adulthood and was associated with reduced expression of the tight junction proteins occludin and claudin-5, which are known to regulate barrier function in endothelial tissues. Exposure of germ-free adult mice to a pathogen-free gut microbiota decreased BBB permeability and up-regulated the expression of tight junction proteins. Our results suggest that gut microbiota-BBB communication is initiated during gestation and propagated throughout life.
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| 2. |
- Cervenka, Simon, et al.
(författare)
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PET Studies of D2-Receptor Binding in Striatal and Extrastriatal Brain Regions : Biochemical Support In Vivo for Separate Dopaminergic Systems in Humans
- 2010
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Ingår i: Synapse. - : Wiley. - 0887-4476 .- 1098-2396. ; 64:6, s. 478-485
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Tidskriftsartikel (refereegranskat)abstract
- Most molecular imaging studies of the dopamine (DA) system performed to date have focused on the striatum, a region receiving dense dopaminergic innervation. In clinical research on the DA D2-receptor, striatal binding has often been regarded as an index of global DA function, based on the underlying assumption of common regulatory mechanisms for receptor expression across brain regions. Recent data has challenged this view, suggesting differences in genetic regulation between striatal and extrastriatal brain regions. The relationship between binding levels in brain regions has, however, not been directly examined in the same sample. In this study, we searched for interregional correlations between DA D2-receptor availability as determined with Positron Emission Tomography in 16 control subjects. The radioligands [C-11]raclopride and [C-11]FLB 457 were used for measurements of D2-receptor binding in striatal and extrastriatal regions, respectively. No correlation was observed between D2-receptor availability in striatum and any of the extrastriatal regions, as assessed using both region of interest- and voxel-based analyses. Instead, the pattern of correlations was consistent with the model of separate dopaminergic systems as has been originally observed in rodents. These preliminary results encourage approaches searching for individual patterns of receptor binding across the whole brain volume in clinical studies on the dopamine system.
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| 3. |
- Guanglin, Kuang, et al.
(författare)
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Theoretical study of the binding profile of an allosteric modulator NS-1738 with a chimera structure of the alpha 7 nicotinic acetylcholine receptor
- 2016
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Ingår i: Physical Chemistry, Chemical Physics - PCCP. - : Royal Society of Chemistry. - 1463-9076 .- 1463-9084. ; 18:40, s. 28003-28009
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Tidskriftsartikel (refereegranskat)abstract
- Potentiation of the function of the alpha 7 nicotinic acetylcholine receptor (alpha 7-nAChR) is believed to provide a possible way for the treatment of cholinergic system dysfunctions such as Alzheimer's disease and schizophrenia. Positive allosteric modulators (PAMs) are able to augment the peak current response of the endogenous agonist of alpha 7-nAChR by binding to some allosteric sites. In this study, the binding profile of a potent type I PAM, NS-1738, with a chimera structure (termed alpha 7-AChBP) constructed from the extracellular domain of alpha 7-nAChR and an acetylcholine binding protein was investigated with molecular docking, molecular dynamics simulation, and free energy calculation methods. We found that NS-1738 could bind to three allosteric sites of alpha 7-AChBP, namely, the top pocket, the vestibule pocket and the agonist sub-pocket. NS-1738 has moderate binding affinities (-6.76 to -9.15 kcal mol(-1)) at each allosteric site. The urea group is critical for binding and can form hydrogen-bond interactions with the protein. The bulky trifluoromethyl group also has a great impact on the binding modes and binding affinities. We believe that our study provides valuable insight into the binding profiles of type I PAMs with alpha 7-nAChR and is helpful for the development of novel PAMs.
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| 4. |
- Murugan, N. Arul, et al.
(författare)
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The Culprit Is in the Cave : The Core Sites Explain the Binding Profiles of Amyloid-Specific Tracers
- 2016
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Ingår i: The Journal of Physical Chemistry Letters. - : American Chemical Society (ACS). - 1948-7185. ; 7:17, s. 3313-3321
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Tidskriftsartikel (refereegranskat)abstract
- The design of molecular probes and tracer molecules with specificity toward amyloid beta (A beta) fibrils is of paramount importance for the selective diagnosis of Alzheimer's disease. This requires a detailed understanding of the binding sites in amyloid targets, their number, and their binding mechanism for various tracer molecules. We adopt an integrated approach including molecular docking, molecular dynamics, and generalized Born-based free energy calculations to investigate site-specific interactions of different amyloid binding molecules. Our study reproduces the experimental results on the relative binding affinity of the tracers and amyloid binders and explains the feature of "multiple binding sites" in amyloid targets as probed by competition binding experiments. A major outcome of this study is that it is the core sites of the Afi fibrils that are responsible for the experimentally reported binding profiles of tracers in amyloid targets rather than the surface sites that received much focus in earlier investigations.
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| 5. |
- Schain, Martin, et al.
(författare)
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Arterial input function derived from pairwise correlations between PET-image voxels
- 2013
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Ingår i: Journal of Cerebral Blood Flow and Metabolism. - : Nature Publishing Group. - 0271-678X .- 1559-7016. ; 33:7, s. 1058-1065
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Tidskriftsartikel (refereegranskat)abstract
- A metabolite corrected arterial input function is a prerequisite for quantification of positron emission tomography (PET) data by compartmental analysis. This quantitative approach is also necessary for radioligands without suitable reference regions in brain. The measurement is laborious and requires cannulation of a peripheral artery, a procedure that can be associated with patient discomfort and potential adverse events. A non invasive procedure for obtaining the arterial input function is thus preferable. In this study, we present a novel method to obtain image-derived input functions (IDIFs). The method is based on calculation of the Pearson correlation coefficient between the time-activity curves of voxel pairs in the PET image to localize voxels displaying blood-like behavior. The method was evaluated using data obtained in human studies with the radioligands [11C]flumazenil and [11C]AZ10419369, and its performance was compared with three previously published methods. The distribution volumes (VT) obtained using IDIFs were compared with those obtained using traditional arterial measurements. Overall, the agreement in VT was good (~3% difference) for input functions obtained using the pairwise correlation approach. This approach performed similarly or even better than the other methods, and could be considered in applied clinical studies. Applications to other radioligands are needed for further verification.
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| 6. |
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| 7. |
- Westerberg, Ida, et al.
(författare)
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Precipitation data in a mountainous catchment in Honduras: quality assessment and spatiotemporal characteristics
- 2010
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Ingår i: Theoretical and Applied Climatology. - : Springer Nature. - 0177-798X .- 1434-4483. ; 101:3-4, s. 381-396
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Tidskriftsartikel (refereegranskat)abstract
- An accurate description of temporal and spatial precipitation variability in Central America is important for local farming, water supply and flood management. Data quality problems and lack of consistent precipitation data impede hydrometeorological analysis in the 7,500 km2 Choluteca River basin in central Honduras, encompassing the capital Tegucigalpa. We used precipitation data from 60 daily and 13 monthly stations in 1913–2006 from five local authorities and NOAA's Global Historical Climatology Network. Quality control routines were developed to tackle the specific data quality problems. The quality-controlled data were characterised spatially and temporally, and compared with regional and larger-scale studies. Two gapfilling methods for daily data and three interpolation methods for monthly and mean annual precipitation were compared. The coefficient-of-correlation-weighting method provided the best results for gap-filling and the universal kriging method for spatial interpolation. In-homogeneity in the time series was the main quality problem, and 22% of the daily precipitation data were too poor to be used. Spatial autocorrelation for monthly precipitation was low during the dry season, and correlation increased markedly when data were temporally aggregated from a daily time scale to 4–5 days. The analysis manifested the high spatial and temporal variability caused by the diverse precipitationgenerating mechanisms and the need for an improved monitoring network.
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| 8. |
- Zhou, Yang, et al.
(författare)
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In silico studies of ASEM analogues targeting alpha 7-nAChR and experimental verification
- 2021
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Ingår i: RSC Advances. - : ROYAL SOC CHEMISTRY. - 2046-2069. ; 11:7, s. 3942-3951
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Tidskriftsartikel (refereegranskat)abstract
- The alpha 7 nicotinic acetylcholine receptor (alpha 7-nAChR) is implicated in a variety of neurodegenerative and neuropsychiatric disorders, such as Alzheimer's disease (AD) and schizophrenia. The progress of these disorders can be studied using positron emission tomography (PET) with radiotracers for alpha 7-nAChR. [F-18]ASEM and [F-18] para-ASEM (also referred to as [F-18]DBT-10) are novel and potent alpha 7-nAChR PET radiotracers which have successfully been used in human subjects and nonhuman primates, though further improvement of them is still a pressing task in the community of neurodegeneration research. In this work, we demonstrate the use of modern in silico techniques to predict the binding modes, binding strengths, and residence times for molecular PET tracers binding to proteins, using ASEM and DBT-10 as a showcase of the predictive and interpretational power of such techniques, in particular free energy perturbation theory. The corresponding compounds were synthesized and further tested by in vitro binding experiment for validation. Encouragingly, our in silico modeling can correctly predict the binding affinities of the ASEM analogues. The structure-activity relationships for the ortho- and para-substitutions are well explained at the atomistic level and provide structure-based guiding for the future development of PET tracers for alpha 7-nAChR. A discussion is presented on the complementary use of in silico rational methods based on atomic and electronic principles for in vitro characterization of PET tracers.
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