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| 5. |
- Aalbers, J., et al.
(författare)
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A next-generation liquid xenon observatory for dark matter and neutrino physics
- 2023
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Ingår i: Journal of Physics G: Nuclear and Particle Physics. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 50:1
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Forskningsöversikt (refereegranskat)abstract
- The nature of dark matter and properties of neutrinos are among the most pressing issues in contemporary particle physics. The dual-phase xenon time-projection chamber is the leading technology to cover the available parameter space for weakly interacting massive particles, while featuring extensive sensitivity to many alternative dark matter candidates. These detectors can also study neutrinos through neutrinoless double-beta decay and through a variety of astrophysical sources. A next-generation xenon-based detector will therefore be a true multi-purpose observatory to significantly advance particle physics, nuclear physics, astrophysics, solar physics, and cosmology. This review article presents the science cases for such a detector.
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| 9. |
- Guerreiro, R., et al.
(författare)
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Heritability and genetic variance of dementia with Lewy bodies
- 2019
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 127, s. 492-501
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Tidskriftsartikel (refereegranskat)abstract
- Recent large-scale genetic studies have allowed for the first glimpse of the effects of common genetic variability in dementia with Lewy bodies (DLB), identifying risk variants with appreciable effect sizes. However, it is currently well established that a substantial portion of the genetic heritable component of complex traits is not captured by genome-wide significant SNPs. To overcome this issue, we have estimated the proportion of phenotypic variance explained by genetic variability (SNP heritability) in DLB using a method that is unbiased by allele frequency or linkage disequilibrium properties of the underlying variants. This shows that the heritability of DLB is nearly twice as high as previous estimates based on common variants only (31% vs 59.9%). We also determine the amount of phenotypic variance in DLB that can be explained by recent polygenic risk scores from either Parkinson's disease (PD) or Alzheimer's disease (AD), and show that, despite being highly significant, they explain a low amount of variance. Additionally, to identify pleiotropic events that might improve our understanding of the disease, we performed genetic correlation analyses of DLB with over 200 diseases and biomedically relevant traits. Our data shows that DLB has a positive correlation with education phenotypes, which is opposite to what occurs in AD. Overall, our data suggests that novel genetic risk factors for DLB should be identified by larger GWAS and these are likely to be independent from known AD and PD risk variants. © 2019 Elsevier Inc.
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| 10. |
- Guerreiro, R., et al.
(författare)
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Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study
- 2018
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Ingår i: Lancet Neurology. - 1474-4422. ; 17:1, s. 64-74
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Tidskriftsartikel (refereegranskat)abstract
- Background Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson's disease, and Alzheimer's disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. Findings This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2.40, 95% CI 2.14-2.70; p=1.05 x 10-48), SNCA (rs7681440; OR 0.73, 0.66-0.81; p=6.39 x 10(-10)), and GBA (rs35749011; OR 2.55, 1.88-3.46; p=1.78 x 10(-9)). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1.51, 1.27-1.79; p=2.32 x 10(-6)); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. Interpretation Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease.
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| 12. |
- Orme, T., et al.
(författare)
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Analysis of neurodegenerative disease-causing genes in dementia with Lewy bodies
- 2020
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Ingår i: Acta neuropathologica communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.
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| 16. |
- Bras, H., et al.
(författare)
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An investigation of local actions of ionophoretically applied DOPA in the spinal cord
- 1988
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Ingår i: Experimental Brain Research. - 0014-4819 .- 1432-1106. ; 71, s. 447-449
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Tidskriftsartikel (refereegranskat)abstract
- Methyl-L-DOPA (L-beta-3,4-dihydroxyphenylalanine methyl ester, hydrochloride) was applied ionophoretically to investigate its effects on neurones at various locations in the cat spinal cord. Its actions were tested on monosynaptic field potentials evoked from group I and group II muscle afferents in midlumbar segments. Methyl-L-DOPA has been found to depress field potentials evoked from group II afferents in the ventral horn and in the intermediate zone but not in the dorsal horn, nor field potentials evoked from group I afferents. Its effects were the same as those of systemically applied L-DOPA (L-beta-3,4-dihydroxyphenylalanine), although weaker. © 1998 Springer-Verlag.
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| 17. |
- Bras, H., et al.
(författare)
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Demonstration of initial axon collaterals of cells of origin of the ventral spinocerebellar tract in the cat
- 1988
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Ingår i: Journal of Comparative Neurology. - : Wiley. - 0021-9967 .- 1096-9861. ; 273, s. 584-592
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Tidskriftsartikel (refereegranskat)abstract
- Neurones of origin of the ventral spinocerebellar tract were stained with intracellularly applied horseradish peroxidase to investigate whether they give off any initial axon collaterals. The neurones were located in the fourth and fifth lumbar segments and were identified by their antidromic activation following stimulation in the contralateral superior cerebellar peduncle. Nine of the 23 neurones with well‐stained axons were found to give off axon collaterals soon after the axons crossed the midline. The collaterals entered the contralateral ventral horn and branched within lamina VII and the dorsal part of lamina VIII. Collaterals were found arising only from neurones located in the middle of lamina VII and from axons which took a mediorostral direction. In all of these neurones excitatory postsynaptic potentials were evoked from group Ia afferents of at least some nerves, in addition to such potentials from Ib or unidentified group I afferents, and inhibitory postsynaptic potentials were evoked from group I and II afferents. The area of terminal branching of the collaterals suggests that they may supply contralateral ventral spinocerebellar neurones with information from muscles and/or mediate crossed reflexes from group I afferents. Copyright © 1988 Alan R. Liss, Inc.
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| 18. |
- Bras, H., et al.
(författare)
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Morphology of midlumbar interneurones relaying information from group II muscle afferents in the cat spinal cord
- 1989
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Ingår i: Journal of Comparative Neurology. - : Wiley. - 0021-9967 .- 1096-9861. ; 290, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- The morphology of midlumbar interneurones with peripheral input from group II muscle afferents was analysed after intracellular injection of horseradish peroxidase (HRP). Twenty‐three interneurones were stained intrasomatically and five others intra‐axonally. The majority (10 of 13) of interneurones located in lamina VII (intermediate zone and ventral horn interneurones) were found to project ipsilaterally. They had medium‐sized somata and dendrites projecting radially over a distance of more than 1 mm. All of these neurones had axons that projected caudally within the ventral part of the lateral funiculus or in the lateral part of the ventral funiculus, although four had in addition an ascending secondary axonal branch. Numerous axon collaterals were given off from these axons, both before and after they left the grey matter. The collaterals arborized within laminae VII, VIII, and IX, where they covered the area of several motor nuclei. Intra‐axonal labelling of five neurones with similar input and axon trajectories revealed several axon collaterals given off between the cell body and the terminal projection areas in L7 or S1 segments. Only three of the labelled interneurones located in lamina VII and displaying the same kind of input had axons with different destinations; their axons crossed to the opposite side of the spinal cord and ascended within the contralateral ventral funiculus. These were large neurones with extensive dendritic trees, which had fairly thick axons with initial axon collaterals that branched primarily ipsilaterally (within laminae V‐VIII). Interneurones located in lamina V and in the bordering parts of laminae IV and VI (dorsal horn interneurones; n = 10) constituted a very nonhomogenous population. They projected either ipsilaterally or contralaterally and had either ascending or descending axons running in either the lateral or ventral funiculi. Generally, dorsal horn interneurones had cell bodies smaller than those of intermediate zone and ventral horn interneurones, and their dendrites extended less extensively and less uniformly around the soma. Their initial axon collaterals branched primarily in the dorsal horn, or in lamina VII, but not in or close to the motor nuclei. Our results support the conclusions of previous physiological studies that the intermediate zone and ventral horn midlumbar interneurones with group II input and that project to motor nuclei have collateral actions on other interneurones in the L4‐L6 segments, and that dorsal horn interneurones do not project to motoneurones, but have as their targets other interneurones or ascending cells. On the other hand, we have not found any projections of L4 interneurones with input from either group I or group I1 muscle afferents, to Clarke's column, in contrast to the projections of interneurones in reflex pathways from tendon organs from more caudal segments. Copyright © 1989 Alan R. Liss, Inc.
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| 19. |
- Fernades, M., et al.
(författare)
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Carbon footprint of tourism sector in Portugal : Calculator self-validation
- 2022
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Ingår i: Journal of Tourism and Development. - : Universidade de Aveiro. - 1645-9261. ; 39, s. 475-491
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Tidskriftsartikel (refereegranskat)abstract
- | In this work, a Carbon Footprint (CF) calculator developed by authors to the tourism sector in Portugal, was validated. The CF calculator self-validation was based on the comparison of the results obtained with two tools available online (Carbon Footprint Ltd-CFL and Climate Care-CC) and with a Life Cycle Assessment (LCA) performed using the SimaPro PhD software. The calculator is based in the CO2e (carbon dioxide equivalent) emissions of 6 components: electricity, water, laundry, fuels, waste and food. These tools were applied to a 3 stars Hotel, located in Viseu region (Portugal) with 50 guestsrooms and an occupied area of 1500m2. CF results attained with calculator developed were slightly higher than CFL and lower than CC results, as it has a different emission from electricity componentFor LCA two scenarios were considered, Scenario 1 (same assumptions as CF calculator) and Scenario 2 (assumptions based on LCA methodology) a higher emission was obtained of more than 23975.7 kgCO2e/year and 72680 kgCO2e/year, respectively. For both scenarios the difference was caused by electricity consumption component and additional by fuel consumption in Scenario 2. The emission factors chosen used for each component were the main responsible for these differences. Self-validation process demonstrated that the CO2e emissions from the different tools were very similar when the same assumptions were considered, so the calculator is consistent.
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| 20. |
- Gising, Johan, 1981-, et al.
(författare)
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The Discovery of New Inhibitors of Insulin-Regulated Aminopeptidase by a High-Throughput Screening of 400,000 Drug-like Compounds
- 2024
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 25:7
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Tidskriftsartikel (refereegranskat)abstract
- With the ambition to identify novel chemical starting points that can be further optimized into small drug-like inhibitors of insulin-regulated aminopeptidase (IRAP) and serve as potential future cognitive enhancers in the clinic, we conducted an ultra-high-throughput screening campaign of a chemically diverse compound library of approximately 400,000 drug-like small molecules. Three biochemical and one biophysical assays were developed to enable large-scale screening and hit triaging. The screening funnel, designed to be compatible with high-density microplates, was established with two enzyme inhibition assays employing either fluorescent or absorbance readouts. As IRAP is a zinc-dependent enzyme, the remaining active compounds were further evaluated in the primary assay, albeit with the addition of zinc ions. Rescreening with zinc confirmed the inhibitory activity for most compounds, emphasizing a zinc-independent mechanism of action. Additionally, target engagement was confirmed using a complementary biophysical thermal shift assay where compounds causing positive/negative thermal shifts were considered genuine binders. Triaging based on biochemical activity, target engagement, and drug-likeness resulted in the selection of 50 qualified hits, of which the IC50 of 32 compounds was below 3.5 µM. Despite hydroxamic acid dominance, diverse chemotypes with biochemical activity and target engagement were discovered, including non-hydroxamic acid compounds. The most potent compound (QHL1) was resynthesized with a confirmed inhibitory IC50 of 320 nM. Amongst these compounds, 20 new compound structure classes were identified, providing many new starting points for the development of unique IRAP inhibitors. Detailed characterization and optimization of lead compounds, considering both hydroxamic acids and other diverse structures, are in progress for further exploration.
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| 21. |
- Lacher, Larissa, et al.
(författare)
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The Puy de Dôme ICe Nucleation Intercomparison Campaign (PICNIC): comparison between online and offline methods in ambient air
- 2024
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Ingår i: ATMOSPHERIC CHEMISTRY AND PHYSICS. - 1680-7316 .- 1680-7324. ; 24:4, s. 2651-2678
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Tidskriftsartikel (refereegranskat)abstract
- Ice crystal formation in mixed-phase clouds is initiated by specific aerosol particles, termed ice-nucleating particles (INPs). Only a tiny fraction of all aerosol particles are INPs, providing a challenge for contemporary INP measurement techniques. Models have shown that the presence of INPs in clouds can impact their radiative properties and induce precipitation formation. However, for a qualified implementation of INPs in models, measurement techniques able to accurately detect the temperature-dependent INP concentration are needed. Here we present measurements of INP concentrations in ambient air under conditions relevant to mixed-phase clouds from a total of 10 INP methods over 2 weeks in October 2018 at the Puy de Dome observatory in central France. A special focus in this intercomparison campaign was placed on having overlapping sampling periods. Although a variety of different measurement principles were used, the majority of the data show INP concentrations within a factor of 5 of one another, demonstrating the suitability of the instruments to derive model-relevant INP data.Lower values of comparability are likely due to instrument-specific features such as aerosol lamina spreading in continuous-flow diffusion chambers, demonstrating the need to account for such phenomena when interpreting INP concentration data from online instruments. Moreover, consistently higher INP concentrations were observed from aerosol filters collected on the rooftop at the Puy de Dome station without the use of an aerosol inlet.
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| 22. |
- Lane, C. A., et al.
(författare)
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Study protocol: Insight 46-a neuroscience sub-study of the MRC National Survey of Health and Development
- 2017
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Ingår i: Bmc Neurology. - : Springer Science and Business Media LLC. - 1471-2377. ; 17
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Tidskriftsartikel (refereegranskat)abstract
- Background: Increasing age is the biggest risk factor for dementia, of which Alzheimer's disease is the commonest cause. The pathological changes underpinning Alzheimer's disease are thought to develop at least a decade prior to the onset of symptoms. Molecular positron emission tomography and multi-modal magnetic resonance imaging allow key pathological processes underpinning cognitive impairment -including a-amyloid depostion, vascular disease, network breakdown and atrophy -to be assessed repeatedly and non-invasively. This enables potential determinants of dementia to be delineated earlier, and therefore opens a pre-symptomatic window where intervention may prevent the onset of cognitive symptoms. Methods/design: This paper outlines the clinical, cognitive and imaging protocol of "Insight 46", a neuroscience sub-study of the MRC National Survey of Health and Development. This is one of the oldest British birth cohort studies and has followed 5362 individuals since their birth in England, Scotland and Wales during one week in March 1946. These individuals have been tracked in 24 waves of data collection incorporating a wide range of health and functional measures, including repeat measures of cognitive function. Now aged 71 years, a small fraction have overt dementia, but estimates suggest that similar to 1/3 of individuals in this age group may be in the preclinical stages of Alzheimer's disease. Insight 46 is recruiting 500 study members selected at random from those who attended a clinical visit at 60-64 years and on whom relevant lifecourse data are available. We describe the sub-study design and protocol which involves a prospective two time-point (0, 24 month) data collection covering clinical, neuropsychological, beta-amyloid positron emission tomography and magnetic resonance imaging, biomarker and genetic information. Data collection started in 2015 (age 69) and aims to be completed in 2019 (age 73). Discussion: Through the integration of data on the socioeconomic environment and on physical, psychological and cognitive function from 0 to 69 years, coupled with genetics, structural and molecular imaging, and intensive cognitive and neurological phenotyping, Insight 46 aims to identify lifetime factors which influence brain health and cognitive ageing, with particular focus on Alzheimer's disease and cerebrovascular disease. This will provide an evidence base for the rational design of disease-modifying trials.
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| 23. |
- Manyuhina, Oksana, et al.
(författare)
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Doubly periodic instability pattern in a smectic-A liquid crystal
- 2013
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Ingår i: Physical Review E. Statistical, Nonlinear, and Soft Matter Physics. - : American Physical Society. - 1539-3755 .- 1550-2376. ; 87:5, s. 050501-
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Tidskriftsartikel (refereegranskat)abstract
- We report the observation of a doubly periodic surface defect pattern in the liquid crystal 8CB, formed during the nematic-smectic-A phase transition. The pattern results from the antagonistic alignment of the 8CB molecules, which is homeotropic at the surface and planar in the bulk of the sample cell. Within the continuum Landau-de Gennes theory of smectic liquid crystals, we find that the long period (approximate to 10 mu m) of the pattern is given by the balance between the surface anchoring and the elastic energy of curvature wall defects. The short period (approximate to 10 mu m) we attribute to a saddle-splay distortion, leading to a nonzero Gaussian curvature and causing the curvature walls to break up.
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| 24. |
- Torres-Garcia, Laura, et al.
(författare)
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Monitoring the interactions between alpha-synuclein and Tau in vitro and in vivo using bimolecular fluorescence complementation
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson’s disease (PD) and Alzheimer’s disease (AD) are characterized by pathological accumulation and aggregation of different amyloidogenic proteins, α-synuclein (aSyn) in PD, and amyloid-β (Aβ) and Tau in AD. Strikingly, few PD and AD patients’ brains exhibit pure pathology with most cases presenting mixed types of protein deposits in the brain. Bimolecular fluorescence complementation (BiFC) is a technique based on the complementation of two halves of a fluorescent protein, which allows direct visualization of protein–protein interactions. In the present study, we assessed the ability of aSyn and Tau to interact with each other. For in vitro evaluation, HEK293 and human neuroblastoma cells were used, while in vivo studies were performed by AAV6 injection in the substantia nigra pars compacta (SNpc) of mice and rats. We observed that the co-expression of aSyn and Tau led to the emergence of fluorescence, reflecting the interaction of the proteins in cell lines, as well as in mouse and rat SNpc. Thus, our data indicates that aSyn and Tau are able to interact with each other in a biologically relevant context, and that the BiFC assay is an effective tool for studying aSyn-Tau interactions in vitro and in different rodent models in vivo.
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