Browsing by Author "Verdugo, Ricardo A."

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    Clinical and pulmonary function analysis in long-COVID revealed that long-term pulmonary dysfunction is associated with vascular inflammation pathways and metabolic syndrome
    (FRONTIERS MEDIA SA, 2023) Sanhueza, Sergio; Vidal, Mabel A.; Hernandez, Mauricio A.; Henriquez-Beltran, Mario E.; Cabrera, Camilo; Quiroga, Romina; Antilef, Barbara E.; Aguilar, Kevin P.; Castillo, Daniela A.; Llerena, Faryd J.; Figueroa, Marco Fraga; Nazal, Mauricio; Castro, Eritson; Lagos, Paola; Moreno, Alexa; Lastra, Jaime J.; Gajardo, Jorge; Garces, Pamela; Riffo, Benilde; Buchert, Jorge; Sanhueza, Rocio; Ormazaba, Valeska; Saldivia, Pablo; Vargas, Cristian; Nourdin, Guillermo; Koch, Elard; Zuniga, Felipe A.; Lamperti, Liliana; Bustos, Paula; Guzman-Gutierrez, Enrique; Tapia, Claudio A.; Ferrada, Luciano; Cerda, Gustavo; Woehlbier, Ute; Riquelme, Marcelo; Yuseff, Maria Isabel; Ramirez, Braulio A. Munoz; Lombardi, Giovanna; De Gonzalo-Calvo, David; Salomon, Carlos; Verdugo, Ricardo A.; Quinones, Luis A.; Colombo, Alicia; Barria, Maria I.; Labarca, Gonzalo; Nova-Lamperti, Estefania
    Introduction: Long-term pulmonary dysfunction (L-TPD) is one of the most critical manifestations of long-COVID. This lung affection has been associated with disease severity during the acute phase and the presence of previous comorbidities, however, the clinical manifestations, the concomitant consequences and the molecular pathways supporting this clinical condition remain unknown. The aim of this study was to identify and characterize L-TPD in patients with long-COVID and elucidate the main pathways and long-term consequences attributed to this condition by analyzing clinical parameters and functional tests supported by machine learning and serum proteome profiling. Methods: Patients with L-TPD were classified according to the results of their computer-tomography (CT) scan and diffusing capacity of the lungs for carbon monoxide adjusted for hemoglobin (DLCOc) tests at 4 and 12-months post-infection. Results: Regarding the acute phase, our data showed that L-TPD was favored in elderly patients with hypertension or insulin resistance, supported by pathways associated with vascular inflammation and chemotaxis of phagocytes, according to computer proteomics. Then, at 4-months post-infection, clinical and functional tests revealed that L-TPD patients exhibited a restrictive lung condition, impaired aerobic capacity and reduced muscular strength. At this time point, high circulating levels of platelets and CXCL9, and an inhibited FCgamma-receptor-mediated-phagocytosis due to reduced Fc gamma RIII (CD16) expression in CD14+ monocytes was observed in patients with L-TPD. Finally, 1-year post infection, patients with L-TPD worsened metabolic syndrome and augmented body mass index in comparison with other patient groups. Discussion: Overall, our data demonstrated that CT scan and DLCOc identified patients with L-TPD after COVID-19. This condition was associated with vascular inflammation and impair phagocytosis of virus-antibody immune complexes by reduced Fc gamma RIII expression. In addition, we conclude that COVID-19 survivors required a personalized follow-up and adequate intervention to reduce long-term sequelae and the appearance of further metabolic diseases.
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    Early-life nutrition interacts with developmental genes to shape the brain and sleep behavior in Drosophila melanogaster
    (2023) Olivares, Gonzalo H.; Nunez-Villegas, Franco; Candia, Noemi; Orostica, Karen; Gonzalez-Ramirez, M. Constanza; Vega-Macaya, Franco; Zuniga, Nolberto; Molina, Cristian; Oliva, Carlos; Mackay, Trudy F. C.; Verdugo, Ricardo A.; Olguin, Patricio
    The mechanisms by which the genotype interacts with nutrition during development to contribute to the variation of complex behaviors and brain morphology of adults are not well understood. Here we use the Drosophila Genetic Reference Panel to identify genes and pathways underlying these interactions in sleep behavior and mushroom body morphology. We show that early-life nutritional restriction effects on sleep behavior and brain morphology depends on the genotype. We mapped genes associated with sleep sensitivity to early-life nutrition, which were enriched for protein-protein interactions responsible for translation, endocytosis regulation, ubiquitination, lipid metabolism, and neural development. By manipulating the expression of candidate genes in the mushroom bodies (MBs) and all neurons, we confirm that genes regulating neural development, translation and insulin signaling contribute to the variable response of sleep and brain morphology to early-life nutrition. We show that the interaction between differential expression of candidate genes with nutritional restriction in early life resides in the MBs or other neurons and that these effects are sex-specific. Natural variations in genes that control the systemic response to nutrition and brain development and function interact with early-life nutrition in different types of neurons to contribute to the variation of brain morphology and adult sleep behavior.
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    Inflammatory profiles in Chilean Mapuche and non-Mapuche women with gallstones at risk of developing gallbladder cancer
    (2021) Jackson, Sarah S.; Van De Wyngard, Vanessa; Pfeiffer, Ruth M.; Cook, Paz; Hildesheim, Allan; Pinto, Ligia A.; Jackson, Sharon H.; Choi, Kelvin; Verdugo, Ricardo A.; Cuevas, Mara; Yanez, Cristian; Tobar-Calfucoy, Eduardo; Retamales-Ortega, Rocio; Araya, Juan Carlos; Ferreccio, Catterina; Koshiol, Jill
    Chile has high incidence rates of gallbladder cancer globally, particularly among Amerindian women, who also have a high prevalence of gallstones. We examined differences in inflammatory biomarkers between Mapuche and non-Mapuche women from the Chile Biliary Longitudinal Study, a cohort of women with ultrasound-detected gallstones. We randomly selected 200 Mapuche women frequency matched to non-Mapuche women on age and statin use Inflammatory biomarkers were analyzed using a multiplex assay and linear regression to assess associations of a priori markers (CCL20, CXCL10, IL-6, and IL-8) with ethnicity. Novel biomarkers were analyzed using exploratory factor analysis (EFA) and sufficient dimension reduction (SDR) to identify correlated marker groups, followed by linear regression to examine their association with ethnicity. The mean values of IL-8 were higher in Mapuche than non-Mapuche women (P=0.04), while CCL20, CXCL10, and IL-6 did not differ significantly by ethnicity. EFA revealed two marker groups associated with ethnicity (P=0.03 and P<0.001). SDR analysis confirmed correlation between the biomarkers and ethnicity. We found higher IL-8 levels among Mapuche than non-Mapuche women. Novel inflammatory biomarkers were correlated with ethnicity and should be studied further for their role in gallbladder disease. These findings may elucidate underlying ethnic disparities in gallstones and carcinogenesis among Amerindians.
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    Paths and timings of the peopling of Polynesia inferred from genomic networks
    (2021) Ioannidis, Alexander G.; Blanco Portillo, Javier; Sandoval, Karla; Hagelberg, Erika; Barberena Jonas, Carmina; Hill, Adrian V. S.; Rodriguez Rodriguez, Juan Esteban; Fox, Keolu; Robson, Kathryn; Haoa Cardinali, Sonia; Quinto Cortes, Consuelo D.; Miquel Poblete, Juan Francisco; Auckland, Kathryn; Parks, Tom; Sofro, Abdul Salam M.; Ávila Arcos, Maria C.; Sockell, Alexandra; Homburger, Julian R.; Eng, Celeste; Huntsman, Scott; Burchard, Esteban G.; Gignoux, Christopher R.; Verdugo, Ricardo A.; Moraga, Mauricio; Bustamante, Carlos D.; Mentzer, Alexander J.; Moreno Estrada, Andrés
    Polynesia was settled in a series of extraordinary voyages across an ocean spanning one third of the Earth(1), but the sequences of islands settled remain unknown and their timings disputed. Currently, several centuries separate the dates suggested by different archaeological surveys(2-4). Here, using genome-wide data from merely 430 modern individuals from 21 key Pacific island populations and novel ancestry-specific computational analyses, we unravel the detailed genetic history of this vast, dispersed island network. Our reconstruction of the branching Polynesian migration sequence reveals a serial founder expansion, characterized by directional loss of variants, that originated in Samoa and spread first through the Cook Islands (Rarotonga), then to the Society (Totaiete ma) Islands (11th century), the western Austral (Tuha'a Pae) Islands and Tuamotu Archipelago (12th century), and finally to the widely separated, but genetically connected, megalithic statue-building cultures of the Marquesas (Te Henua 'Enana) Islands in the north, Raivavae in the south, and Easter Island (Rapa Nui), the easternmost of the Polynesian islands, settled in approximately ad 1200 via Mangareva.
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    The Association between Fasting Glucose and Sugar Sweetened Beverages Intake Is Greater in Latin Americans with a High Polygenic Risk Score for Type 2 Diabetes Mellitus
    (2022) Lopez-Portillo, Maria Lourdes; Huidobro, Andrea; Tobar-Calfucoy, Eduardo; Yanez, Cristian; Retamales-Ortega, Rocio; Garrido-Tapia, Macarena; Acevedo, Johanna; Paredes, Fabio; Cid-Ossandon, Vicente; Ferreccio, Catterina; Verdugo, Ricardo A.
    Chile is one of the largest consumers of sugar-sweetened beverages (SSB) world-wide. However, it is unknown whether the effects from this highly industrialized food will mimic those reported in industrialized countries or whether they will be modified by local lifestyle or population genetics. Our goal is to evaluate the interaction effect between SSB intake and T2D susceptibility on fasting glucose. We calculated a weighted genetic risk score (GRSw) based on 16 T2D risk SNPs in 2828 non-diabetic participants of the MAUCO cohort. SSB intake was categorized in four levels using a food frequency questionnaire. Log-fasting glucose was regressed on SSB and GRSw tertiles while accounting for socio-demography, lifestyle, obesity, and Amerindian ancestry. Fasting glucose increased systematically per unit of GRSw (beta = 0.02 +/- 0.006, p = 0.00002) and by SSB intake (beta[cat4] = 0.04 +/- 0.01, p = 0.0001), showing a significant interaction, where the strongest effect was observed in the highest GRSw-tertile and in the highest SSB consumption category (beta = 0.05 +/- 0.02, p = 0.02). SNP-wise, SSB interacted with additive effects of rs7903146 (TCF7L2) (beta = 0.05 +/- 0.01, p = 0.002) and with the G/G genotype of rs10830963 (MTNRB1B) (beta = 0.19 +/- 0.05, p = 0.001). Conclusions: The association between SSB intake and fasting glucose in the Chilean population without diabetes is modified by T2D genetic susceptibility.
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    Validation of an NGS Panel Designed for Detection of Actionable Mutations in Tumors Common in Latin America
    (2021) Salvo, Mauricio; Gonzalez-Feliu, Evelin; Toro, Jessica; Gallegos, Ivan; Maureira, Ignacio; Miranda-Gonzalez, Nicolas; Barajas, Olga; Bustamante, Eva; Ahumada, Monica; Colombo, Alicia; Armisen, Ricardo; Villaman, Camilo; Ibanez, Carolina; Bravo, Maria Loreto; Sanhueza, Veronica; Spencer, M. Loreto; de Toro, Gonzalo; Morales, Erik; Bizama, Carolina; Garcia, Patricia; Carrasco, Ana Maria; Gutierrez, Lorena; Bermejo, Justo Lorenzo; Verdugo, Ricardo A.; Marcelain, Katherine
    Next-generation sequencing (NGS) is progressively being used in clinical practice. However, several barriers preclude using this technology for precision oncology in most Latin American countries. To overcome some of these barriers, we have designed a 25-gene panel that contains predictive biomarkers for most current and near-future available therapies in Chile and Latin America. Library preparation was optimized to account for low DNA integrity observed in formalin-fixed paraffin-embedded tissue. The workflow includes an automated bioinformatic pipeline that accounts for the underrepresentation of Latin Americans in genome databases. The panel detected small insertions, deletions, and single nucleotide variants down to allelic frequencies of 0.05 with high sensitivity, specificity, and reproducibility. The workflow was validated in 272 clinical samples from several solid tumor types, including gallbladder (GBC). More than 50 biomarkers were detected in these samples, mainly in BRCA1/2, KRAS, and PIK3CA genes. In GBC, biomarkers for PARP, EGFR, PIK3CA, mTOR, and Hedgehog signaling inhibitors were found. Thus, this small NGS panel is an accurate and sensitive method that may constitute a more cost-efficient alternative to multiple non-NGS assays and costly, large NGS panels. This kind of streamlined assay with automated bioinformatics analysis may facilitate the implementation of precision medicine in Latin America.