| 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. |
- Quiceno, Enrique, et al.
(författare)
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Customized Ti6Al4V implants by EBM : design, manufacturing and surface treatments
- 2022
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Ingår i: Proceedings. - 9786289528718 ; , s. 381-388
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Konferensbidrag (refereegranskat)abstract
- Subtractive manufacturing methods such as machining have been conventionally used to produce standard metallic implants for bone replacement in materials such as Co-Cr and Ti-based alloys. The production of a customized implant with complex geometries using conventional machining techniques such as CNC requires specification equipment (5 or 6 axes), where the manufacturing process is difficult, limiting the mass production of customized products. New advanced metal additive manufacturing (AM) methods allow patient-specific implants obtaining, in which the Engineering for Transformation implant geometry can be designed to fit to a specific patient from the information of a CT scan. Besides this flexibility in the design, AM offers a cleaner production with less generation of scrap, low energy consumption and lower CO2 release. Electron Beam Melting (EBM) is one of the most used AM methods in the implant industry. In EBM, an electron beam is used to melt metal powder layer by layer in a vacuum protective environment, following a digital 3D model. Titanium alloys, specifically Ti6Al4V, have been the most widely used biomaterial in biomedical applications of orthopedic implants. In general, implants for biomedical applications require postmanufacturing surface modification to improve their performance, biocompatibility and fixation with the surrounding tissues in the area where they are implanted. Formation of anodic layers is one of the surface modifications that have become essential due to the high demands of implant applications and in order to enhance chemical and mechanical properties of the surface specimen. The most common anodizing developments were performed on Ti6Al4V alloy surfaces manufactured by conventional technologies such as forging and conventional machining. The project explores the feasibility of EBM of metal implants prototypes manufacturing for the Colombian healthcare market. 3D implant models were obtained, and then manufactured using EBM in Ti6Al4V alloy. A PEO process to surface modification with the aim to improve the biocompatibility of the manufactured implants by EMB process were demonstrated.
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| 3. |
- Vargas, Carlos, et al.
(författare)
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The Effect Of Microstructure And Anisotropy Of Different Ti-6al-4v AlloysSubstrates Over Their Surface Modification By Plasma Electrolytic Oxidation
- 2022
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Ingår i: Abstracts E-book.
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Konferensbidrag (refereegranskat)abstract
- Ti-6Al-4V is one of the widely used load-bearing implant materials due to its unique set of combinatorial properties such as biocompatibility and enhanced mechanical properties. However, after being implanted, these biomaterials can trigger difficulties in patients due to infections mainly caused by bacterial adhesion. Their good corrosion performance is mainly explained by the formation of a dense and passive oxide layer on their surface. Nevertheless, this oxide film alone does not have enough surface characteristics like bioactivity, antimicrobial activity, corrosion resistance, osseointegration, roughness, biocompatibility, fatigue, and wear to provide good performance for biomedical applications. For that reason, others surface modifications on these alloys are required. In that direction, the surface modification of plasma electrolytic oxidation (PEO) is of great interest given its low cost and environmentally friendly nature. PEO had been widely studied on Ti-6Al-4V alloys, especially on substrates made by conventional manufacturing like forged. However, currently, most implants are manufactured by additive manufacturing techniques (electron beam melting, selective laser melting) and the effect of PEO on substrates manufactured by these techniques has not been completely studied, especially by the electron beam melting technique. In this work, the morphology, chemical composition, and phase composition of the PEO coatings on substrates manufactured by the EBM technique were analyzed by Scanning Electron Microscopy (SEM) with energy-dispersive x-ray spectroscopy (EDS) and X-ray diffraction (XRD). PEO coatings characteristics like thicknesses, pore sizes, and layer homogeneity along the built direction of the printed part and its transversal direction were measured with the purpose to evaluate the effect of the anisotropic of printed substrates over the PEO layer growth. For comparative analysis, PEO coatings on the forged substrates were evaluated to analyze the effect of different microstructures with respect to substrates manufactured by the EBM technique. According to previous microstructure characterization of substrates, the analysis shows a differential growth of the anodic layer on substrates manufactured by EBM due to the presence of beta and alpha phases in Ti-6Al-4V and the difference in grain size related to the build direction of the printed part and its transversal direction.
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| 4. |
- Perez-Escobar, Oscar A., et al.
(författare)
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The origin and speciation of orchids
- 2024
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Ingår i: NEW PHYTOLOGIST. - 0028-646X .- 1469-8137.
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Tidskriftsartikel (refereegranskat)abstract
- Orchids constitute one of the most spectacular radiations of flowering plants. However, their origin, spread across the globe, and hotspots of speciation remain uncertain due to the lack of an up-to-date phylogeographic analysis. We present a new Orchidaceae phylogeny based on combined high-throughput and Sanger sequencing data, covering all five subfamilies, 17/22 tribes, 40/49 subtribes, 285/736 genera, and c. 7% (1921) of the 29 524 accepted species, and use it to infer geographic range evolution, diversity, and speciation patterns by adding curated geographical distributions from the World Checklist of Vascular Plants. The orchids' most recent common ancestor is inferred to have lived in Late Cretaceous Laurasia. The modern range of Apostasioideae, which comprises two genera with 16 species from India to northern Australia, is interpreted as relictual, similar to that of numerous other groups that went extinct at higher latitudes following the global climate cooling during the Oligocene. Despite their ancient origin, modern orchid species diversity mainly originated over the last 5 Ma, with the highest speciation rates in Panama and Costa Rica. These results alter our understanding of the geographic origin of orchids, previously proposed as Australian, and pinpoint Central America as a region of recent, explosive speciation.
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| 5. |
- Rodriguez-Espigares, Ismael, et al.
(författare)
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GPCRmd uncovers the dynamics of the 3D-GPCRome
- 2020
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Ingår i: Nature Methods. - : Springer Nature. - 1548-7091 .- 1548-7105. ; 17:8, s. 777-787
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Tidskriftsartikel (refereegranskat)abstract
- G-protein-coupled receptors (GPCRs) are involved in numerous physiological processes and are the most frequent targets of approved drugs. The explosion in the number of new three-dimensional (3D) molecular structures of GPCRs (3D-GPCRome) over the last decade has greatly advanced the mechanistic understanding and drug design opportunities for this protein family. Molecular dynamics (MD) simulations have become a widely established technique for exploring the conformational landscape of proteins at an atomic level. However, the analysis and visualization of MD simulations require efficient storage resources and specialized software. Here we present GPCRmd (http://gpcrmd.org/), an online platform that incorporates web-based visualization capabilities as well as a comprehensive and user-friendly analysis toolbox that allows scientists from different disciplines to visualize, analyze and share GPCR MD data. GPCRmd originates from a community-driven effort to create an open, interactive and standardized database of GPCR MD simulations.
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| 6. |
- van der Stel, Wanda, et al.
(författare)
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New Approach Methods (NAMs) Supporting Read-Across : Two Neurotoxicity AOP-based IATA Case Studies
- 2021
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Ingår i: Altex. - : ALTEX Edition. - 1868-596X .- 1868-8551. ; 38:4, s. 615-635
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Tidskriftsartikel (refereegranskat)abstract
- Read-across approaches are considered key in moving away from in vivo animal testing towards addressing data-gaps using new approach methods (NAMs). Ample successful examples are still required to substantiate this strategy. Here we present and discuss the learnings from two OECD IATA endorsed read-across case studies. They involve two classes of pesticides - rotenoids and strobilurins - each having a defined mode-of-action that is assessed for its neurological hazard by means of an AOP-based testing strategy coupled to toxicokinetic simulations of human tissue concentrations. The endpoint in question is potential mitochondrial respiratory chain mediated neurotoxicity, specifically through inhibition of complex I or III. An AOP linking inhibition of mitochondrial respiratory chain complex I to the degeneration of dopaminergic neurons formed the basis for both cases but was deployed in two different regulatory contexts. The two cases also exemplify several different read-across concepts: analogue versus category approach, consolidated versus putative AOP, positive versus negative prediction (i.e., neurotoxicity versus low potential for neurotoxicity), and structural versus biological similarity. We applied a range of NAMs to explore the toxicodynamic properties of the compounds, e.g., in silico docking as well as in vitro assays and readouts - including transcriptomics - in various cell systems, all anchored to the relevant AOPs. Interestingly, although some of the data addressing certain elements of the read-across were associated with high uncertainty, their impact on the overall read-across conclusion remained limited. Coupled to the elaborate regulatory review that the two cases underwent, we propose some generic learnings of AOP-based testing strategies supporting read-across.
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