Bronfenbrenner, U., & Morris, P. (1998). The ecology of developmental processes. In W. Damon (Series Ed.) & R. M. Lerner (Vol.Ed.), Handbook of child psychology: Vol. 1. Theoretical models of human development (5th ed., pp. 993-1028). New York: Wiley.
A standard quality control was performed on variants and samples from all datasets individually. The samples were then imputed with the TOPMed reference panel57,58. The Haplotype Reference Consortium (HRC) panel59 was also used for some datasets (Supplementary Table 2). For the UKBB, we used the provided imputed data generated from a combination of the 1000 Genomes, HRC and UK10K reference panels (Supplementary Note).
Tests of the association between clinical or proxy-ADD status and autosomal genetic variants were conducted separately in each dataset by using logistic regression and an additive genetic model, as implemented in SNPTEST 2.5.4-beta3 (ref. 60) or PLINK v1.90 (ref. 4). However, a logistic mixed model (as implemented in SAIGE v0.36.4 (ref. 61)) was considered for the UKBB data. We analyzed the genotype probabilities in SNPTEST (using the newml method) and dosages in PLINK and SAIGE. Analyses were adjusted for PCs and genotyping centers, when necessary (Supplementary Table 2). For the UKBB dataset, only variants with a MAF above 0.01% and a minor allele count (MAC) above 3 were analyzed, and effect sizes and standard errors were corrected by a factor of two, because proxy cases were analyzed7. This approach is appropriate for variants with a moderate-to-high frequency and a small effect size. For all datasets, we filtered out duplicated variants and variants with (1) missing data on the effect size, standard error or P value; (2) an absolute effect size above 5; (3) an imputation quality below 0.3; and (4) a value below 20 for the product of the MAC and the imputation quality (MAC-info score). For datasets not imputed with the TOPMed reference panel, we also excluded (1) variants for which conversion of position or alleles from the GRCh37 assembly to the GRCh38 assembly was not possible or problematic or (2) variants with very large difference of frequency between the TOPMed reference panel and the reference panels used to perform imputation.
We computed a gene prioritization score for each candidate gene as the weighted sum of the evidence identified in the seven domains. We specified a weight for each type of evidence, as detailed in Supplementary Table 19. For the molecular QTL-GWAS integration domains, we gave more weight to replicated hits (i.e., evidence in several datasets) than to single hits. We also gave more weight to hits observed in brain (the bulk brain and microglia datasets) than to hits observed in other tissues/cell types (LCLs, monocytes, macrophages and blood). To avoid score inflation, several specific rules were applied: (1) for the results of sQTL- and mQTL-based analyses, multiple splice junctions or CpGs annotated for the same genes were aggregated prior to weighting due to correlated data; (2) if we observed a fine-mapped eTWAS association for a gene, its other significant (but not fine-mapped) eTWAS associations were not considered; (3) for genes having several significant CpGs (prior to aggregation) in MetaMeth analyses, the associated CpGs with a low (
Current treatments for COPD do not address the pathogenic role of EVs in promoting emphysema and ECM remodeling, highlighting the need for in vivo models of EV-induced emphysema. Therefore, to provide a way to expand on our discoveries regarding neutrophil-derived EVs and further explore discrete disease-related mechanisms, we developed a mouse-to-mouse EV transfer model. In this study, using an in vivo model of LPS-driven PMN activation and inflammation, we comprehensively studied the characteristics and pathogenicity of the neutrophil-derived EVs associated with the tissue trauma. Our study provides a preclinical in vivo model that allows expansion of the role of airway EVs in the pathogenesis of acute and chronic lung disease, and could provide a platform for novel understanding of disease and therapeutic testing.
LPS-derived EVs induce lung damage and emphysema. To determine whether LPS-derived EVs are pathogenic and, if so, the optimal conditions under which to model airway damage mediated by EVs, we delivered saline- and LPS-derived EVs i.t. for 1 week at a single dose or over 3 doses 2 days apart (Supplemental Figure 4). Airway damage was quantified by alveolar enlargement (mean linear intercepts [Lm]). The dosing strategies resulted in similar levels of alveolar enlargement after 1 week in the LPS EV group when compared with the saline EV control group, with LPS-derived EVs inducing significantly more damage. Therefore, to minimize the invasiveness of the procedure, the regimen selected for the remainder of the study was 1 dose of EVs followed by tissue analysis 1 week later.
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Meanwhile, Maria Desamparada Iturbide Gutierrez \"Maria Forsaken\" (Maité Perroni) is now a young woman who is ready to leave the orphanage where she grew up. On her way she befriends and moves in with Linda Sorting (Dorismar) and Nati Duval (Susana Diazayas). Maria's aspirations to be a great model lead her to the most famous designer of the moment, Victoria. But far from being a friendly boss, Victoria treats her with contempt and arrogance, especially since Maria is compared to a younger version of Victoria. Maria does not let Victoria's negative attitude affect her work, and it is in the workplace where she meets Max. Max and Maria fall in love, but their love is rejected by Victoria, and she plots with Max's ex-girlfriend and fashion model Jimena de Alba (Dominika Paleta) to separate the two. Together they hatch a plot in which Max mistakenly ends up believing that he impregnated Jimena with his child, and is forced to marry her.
Meanwhile, Maria is really pregnant with Max's child, but keeps her pregnancy a secret. She sacrifices her love and happiness so that Max can fulfill his mother's wishes to marry Jimena. She seeks solace from Juan Pablo, who is now a respected priest, and, unknown to her, is also her real father. Her identity is revealed to him in a secret confession from his mother Bernarda; he is therefore unable to reveal himself, as he is bound by the laws of confession. Padilla and El Alacran (Sergio Acosta) burn Maria's neighborhood's home and now they have to move. Bernarda owns the place where they live now. Maria also finds support in Jimena's renown photographer Alonso del Angel (Mark Tacher). He helps Maria through her pregnancy, and eventually aids her return to the modeling world. He falls in love with Maria, though Maria cannot reciprocate his love as she continues to love Max. Victoria deals with her hidden past by focusing on her fashion label; her husband feels increasingly isolated from her and consoles himself with another woman, Maria's friend and roommate, Linda. However, Osvaldo also hides secrets from his past; while everyone believes Max's biological mother Leonela Montenegro (Mónica Ayos) is dead, she is, in fact, alive, and in jail. Osvaldo is hated by his supposed \"friend\" Guillermo Quintana (Guillermo García Cantú), out of jealousy for both the relationship he once had with Leonela, and for Osvaldo's fame and fortune. He sets out on a path to destroy Osvaldo and his family, and begins by impregnating Jimena, and goes along with the plot to pass the child as Max's.
Max eventually finds out that Jimena's child isn't really his, but Guillermo's, which destroys his marriage. Max ends up maintaining custody of the child since he deems Jimena unfit to take care of him. He also learns that Maria is pregnant with his real son, and they are reunited. Jimena unites with Bernarda to destroy Sandoval's family; Bernarda buys full control of Victoria's failing fashion label, and enlists Jimena as her star model. Osvaldo is shot by his ex-wife Leonela, but he survives. Victoria's happiness continues to disintegrate as she discovers her husband's infidelity, the fact that his first wife Leonela is still alive, and that she has breast cancer. Bernarda, also abducts Maria's son, which also hurts Victoria as he is her grandchild; mother and daughter bond over this mutual pain, though not understanding why the bond is so deep. El Alacran was killed by Bernarda and then Rodolfo was killed in a shootout by the police officers.
Meanwhile, Bernarda plans to get rid of Maria and sets her abduction. Victoria runs to her aid but it falls on a lure and also pitched for it with Maria is kidnapped in an abandoned warehouse. Max and Osvaldo, with Alonso, Fernanda and father anxiously awaiting Juan Pablo at the home of Victoria's call demanding the ransom the kidnappers of the two. Victoria is suffering by believing the illusion that one shot killed her daughter. The kidnappers are captured by federal agents after attempting to set a trap and collect the ransom money, while Victoria is released in a wasteland on the outskirts of Mexico City. Victoria discovers the deception and runs to rescue her daughter Maria, still sequestered in the abandoned warehouse.
Casa Victoria and Casa Bernarda face in a fashion contest. The winner of the night turns out to be Casa Victoria, with Maria as the flagship model of the moment. But the happiness of Victoria last only a moment, when Maria's nose begins to bleed and she loses consciousness. Maria is taken to hospital, where Dr. Heriberto Rios Bernal (César Évora) tells Victoria that Maria has Phase 1 disease and acquired the same virus that killed Alonso and must remain isolated to prevent future infections. Victoria goes mad with grief and Bernarda took the opportunity to take