| 1. |
- Cruz, Raquel, et al.
(författare)
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Novel genes and sex differences in COVID-19 severity
- 2022
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 31:22, s. 3789-3806
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Tidskriftsartikel (refereegranskat)abstract
- Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.
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| 2. |
- Lampinen, Jussi, et al.
(författare)
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Acceptance of near-natural greenspace management relates to ecological and socio-cultural assigned values among European urbanites
- 2021
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Ingår i: Basic and Applied Ecology. - : Elsevier BV. - 1439-1791 .- 1618-0089. ; 50, s. 119-131
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Tidskriftsartikel (refereegranskat)abstract
- Grasslands are widespread elements of urban greenspace providing recreational, psychological and aesthetic benefits to city residents. Two urban grassland types of contrasting management dominate urban greenspaces: frequently mown, species-poor short-cut lawns and less intensively managed, near-natural tall-grass meadows. The higher conservation value of tall-grass meadows makes management interventions such as converting short-cut lawns into tall-grass meadows a promising tool for urban biodiversity conservation. The societal success of such interventions, however, depends on identifying the values urban residents assign to different types of urban grasslands, and how these values translate to attitudes towards greenspace management. Using 2027 questionnaires across 19 European cities, we identify the assigned values that correlate with people's personal greenspace use and their preferences for different types of urban grasslands to determine how these values relate to the agreement with a scenario of converting 50% of their cities' short-cut lawns into tall-grass meadows. We found that most people assigned nature-related values, such as wildness, to tall-grass meadows and utility-related values, such as recreation, to short-cut lawns. Positive value associations of wildness and species richness with tall-grass meadows, and social and nature related greenspace activities, positively correlated with agreeing to convert short-cut lawns into tall-grass meadows. Conversely, disapproval of lawn conversion correlated with positive value associations of cleanliness and recreation potential with short-cut lawns. Here, people using greenspaces for nature-related activities were outstandingly positive about lawn conversion. The results show that the plurality of values assigned to different types of urban grasslands should be considered in urban greenspace planning. For example, tall-grass meadows could be managed to also accommodate the values associated with short-cut lawns, such as tidiness and recreation potential, to support their societal acceptance.
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| 3. |
- Alay, Özgü, et al.
(författare)
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Monitoring and Analytics (Release B)
- 2021
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Rapport (refereegranskat)abstract
- This document describes the design and implementation of the 5GENESIS Monitoring & Analytics (M&A) framework in its Release B, developed within Task T3.3 of the project work plan. M&A Release B leverages and extends M&A Release A, which has been documented in the previous Deliverable D3.5 [1]. In particular, we present new features and enhancements introduced in this new Release compared to the Release A. We also report some examples of usage of the M&A framework, in order to showcase its integrated in the 5GENESIS Reference Architecture.
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| 4. |
- Benesperi, Iacopo, et al.
(författare)
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Dynamic dimer copper coordination redox shuttles
- 2022
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Ingår i: Chem. - : Elsevier. - 2451-9308 .- 2451-9294. ; 8:2, s. 439-449
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Tidskriftsartikel (refereegranskat)abstract
- Summary Conventional redox mediators based on metal coordination complexes undergo electron transfer through the change in oxidation state of the metal center. However, electron transfer kinetics are offset toward preferred oxidation states when preorganized ligands constrain the reorganization of the coordination sphere. In contrast, we report here on dimeric copper(II/I) redox couples, wherein the extent of oxidation/reduction of two metal centers dictates the dynamic formation of dimer and monomer complexes: the dimeric (Cu(I))2 transitions to monomers of Cu(II). The bis(thiazole/pyrrole)-bipyridine tetradentate ligands stabilize both oxidation states of the unique redox systems. The dynamic dimer redox mediators offer a viable two-electron redox mechanism to develop efficient hybrid solar cells through inhibited recombination and rapid charge transport. Density functional theory calculations reveal inner reorganization energies for single-electron transfer as low as 0.27 eV, marking the dimeric complexes superior redox systems over single complexes as liquid and potentially solid-state electrolytes.
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| 5. |
- Casas Garcia, Belén, et al.
(författare)
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Integrated experimental-computational analysis of a HepaRG liver-islet microphysiological system for human-centric diabetes research
- 2022
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 17:10
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Tidskriftsartikel (refereegranskat)abstract
- Microphysiological systems (MPS) are powerful tools for emulating human physiology and replicating disease progression in vitro. MPS could be better predictors of human outcome than current animal models, but mechanistic interpretation and in vivo extrapolation of the experimental results remain significant challenges. Here, we address these challenges using an integrated experimental-computational approach. This approach allows for in silico representation and predictions of glucose metabolism in a previously reported MPS with two organ compartments (liver and pancreas) connected in a closed loop with circulating medium. We developed a computational model describing glucose metabolism over 15 days of culture in the MPS. The model was calibrated on an experiment-specific basis using data from seven experiments, where HepaRG single-liver or liver-islet cultures were exposed to both normal and hyperglycemic conditions resembling high blood glucose levels in diabetes. The calibrated models reproduced the fast (i.e. hourly) variations in glucose and insulin observed in the MPS experiments, as well as the long-term (i.e. over weeks) decline in both glucose tolerance and insulin secretion. We also investigated the behaviour of the system under hypoglycemia by simulating this condition in silico, and the model could correctly predict the glucose and insulin responses measured in new MPS experiments. Last, we used the computational model to translate the experimental results to humans, showing good agreement with published data of the glucose response to a meal in healthy subjects. The integrated experimental-computational framework opens new avenues for future investigations toward disease mechanisms and the development of new therapies for metabolic disorders.
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| 6. |
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| 7. |
- Demichev, Vadim, et al.
(författare)
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A time-resolved proteomic and prognostic map of COVID-19
- 2021
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Ingår i: Cell Systems. - : Elsevier BV. - 2405-4712 .- 2405-4720. ; 12:8, s. 780-794.e7
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Tidskriftsartikel (refereegranskat)abstract
- COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.
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| 8. |
- Ferrara, Maria Cristina, et al.
(författare)
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Sustained improvement of intrinsic capacity in community-dwelling older adults : The plus AGIL Barcelona multidomain program
- 2023
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Ingår i: Journal of Internal Medicine. - 0954-6820 .- 1365-2796. ; 294:6, s. 730-742
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDifferent programs promote healthy ageing through the optimization of intrinsic capacity. However, a major challenge is to assess their sustained effects over time. +AGIL Barcelona, a consolidated multidomain program, aims to optimize older adults' intrinsic capacity through a coordinated approach among primary care, geriatrics and community resources, in agreement with the integrated care for older people (ICOPE) guidelines. We aimed to evaluate the +AGIL Barcelona longitudinal effect on older adults' physical performance. MethodsAll +AGIL Barcelona consecutive participants since 2016 were enrolled. After a comprehensive geriatric assessment, a tailored, multidisciplinary intervention aligned with the ICOPE guidelines is offered. It includes a 10-week boost multicomponent exercise program, nutritional and sleep-hygiene counselling, revision and optimization of pharmacological treatments and screening for cognitive impairment, depression and loneliness. Changes in physical performance after 3 and 6 months were assessed using mixed models including baseline frailty degree, time and all potential significant confounders. ResultsWe included 194 participants in the analysis (mean age = 81.6 [standard deviation = 5.8], 68% women). An independent, clinically and statistically significant improvement in physical performance (Short Physical Performance Battery [SPPB] test, combining gait speed, strength and balance) was found at 3 months (SPPB mean change: 1.4; 95% CI: 1.1-1.6) and 6 months (SPPB mean change: 1.1; 95% CI 0.8-1.5). Equivalent results were observed for all the SPPB sub-tests. ConclusionsA coordinated, multidisciplinary and integrated program can benefit older adults' intrinsic capacity. The participants' empowerment and the connection with the available community resources are critical points for a successful intervention.
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| 9. |
- García-Vázquez, Víctor, et al.
(författare)
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An Expedient Method for the Umpolung Coupling of Enols with Heteronucleophiles
- 2022
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Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 28:44
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Tidskriftsartikel (refereegranskat)abstract
- In this paper, we present an unprecedented and general umpolung protocol that allows the functionalization of silyl enol ethers and of 1,3-dicarbonyl compounds with a large range of heteroatom nucleophiles, including carboxylic acids, alcohols, primary and secondary amines, azide, thiols, and also anionic carbamates derived from CO2. The scope of the reaction also extends to carbon-based nucleophiles. The reaction relies on the use of 1-bromo-3,3-dimethyl-1,3-dihydro-1λ3[d][1,2]iodaoxole, which provides a key α-brominated carbonyl intermediate. The reaction mechanism has been studied experimentally and by DFT, and we propose formation of an unusual enolonium intermediate with a halogen-bonded bromide.
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| 10. |
- García-Vázquez, Víctor, 1993-
(författare)
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Selective Transformations of Allylic Compounds and Enol Derivatives : Synthesis of Fluorinated and Nitrogenated Scaffolds
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this thesis, new synthetic methods to give access to molecules having fluorinated scaffolds and other polar functional groups have been developed. The methods give access to highly valuable organic compounds that may serve as building blocks in the synthesis of functionalized drug candidates. In particular, the present thesis describes four new protocols for the synthesis of such compounds starting from allylic substrates and enol derivatives, using metal- or organocatalysts.In the introductory chapter (Chapter 1), the importance and the different approaches to catalysis are discussed. The structural features and reactivity of allylic substrates are presented, followed by an extensive description of the use of CO2 as a building block in organic synthesis. In the final part of this chapter, the structure and common reactive pathways of hypervalent iodine(III) reagents are described.In the second part (Chapter 2), a palladium-catalyzed allylic substitution method is designed to obtain 3-fluoropiperidines from 1,3-dicarbonyl compounds and allylic carbamates. The final products are further functionalized in a chemo- and diastereoselective manner. Additionally, the enantioselective version of this reaction is studied using chiral phosphoramidite ligands.In the third chapter, an umpolung methodology for CO2 fixation is explored in the coupling of silyl enol ethers with amines and CO2 mediated by hypervalent iodine(III) reagents. The mechanism of this transformation is examined using DFT calculations and experimental results. Moreover, this protocol is extended to 1,3-dicarbonyl compounds, yielding α-carbamate-β-ketocarbonyl compounds.The final part of this thesis (Chapter IV and V) describes the base-catalyzed stereospecific isomerization of allylic halides and amines. Catalytic amounts of a simple guanidine type base (TBD), are able to transfer the chirality during the isomerization reaction of chiral allylic substrates. In the case of allylic amines, the synthetic utility of the chiral enamine/imine intermediates derived from the isomerization reaction is extensively explored, designing a one-pot protocol for the stereospecific and diastereoselective synthesis of chiral γ-trifluoromethylated aliphatic amines with two non-consecutive stereogenic centers.
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