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Project Title
"Fortalecimiento y desarrollo de la investigación biomédica mediante la adquisición de un cluster computacional"
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Internal ID
EQM150093
Principal Investigator
LUIS EDGARDO LEON PAREDES
Status
TERMINADO
Start Date
15 December 2015
End Date
17 June 2015
Investigators
Nancy Perez

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Now showing 1 - 7 of 7
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Epidermolysis Bullosa Simplex with KLHL24 Mutations Is Associated with Dilated Cardiomyopathy

2019 , Agnes Schwieger-Briel , FUENTES BUSTOS, MARIA IGNACIA , Daniele Castiglia , Antonio Barbato , Matthias Greutmann , Juna Leppert , Sabine Duchatelet , Alain Hovnanian , Sofia Burattini , M. Joao Yubero , Rodrigo Ibañez-Arenas , Boris Rebolledo-Jaramillo , Christoph Gräni , Hagen Ott , Martin Theiler , Lisa Weibel , Amy S. Paller , Giovanna Zambruno , Judith Fischer , Francis Palisson , Cristina Has

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Identification of genetic modifiers of murine hepatic β-glucocerebrosidase activity

2021 , Anyelo Durán , Boris Rebolledo-Jaramillo , Valeria Olguin , Marcelo Rojas-Herrera , Macarena Las Heras , CALDERON GIADROSIC, JUAN FRANCISCO , Silvana Zanlungo , David A. Priestman , Frances M. Platt , KLEIN POSTERNACK, ANDRES DAVID

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High Burden of Intestinal Colonization With Antimicrobial-Resistant Bacteria in Chile: An Antibiotic Resistance in Communities and Hospitals (ARCH) Study

2023 , ARAOS BRALIC, RAFAEL IGNACIO , Rachel M Smith , Ashley Styczynski , Felipe Sánchez , Lea Maureira , ACEVEDO ROMO, JOHANNA PATRICIA , Catalina Paredes , Maite González , RIVAS JIMENEZ, LINA MARIA , Maria Spencer-Sandino , Anne Peters , Ayesha Khan , Dino Sepulveda , Loreto Rojas Wettig , María Luisa Rioseco , Pedro Usedo , Pamela Rojas Soto , Laura Andrea Huidobro , Catterina Ferreccio , Benjamin J Park , Eduardo Undurraga , Erika M C D’Agata , Alejandro Jara , MUNITA SEPULVEDA, JOSE MANUEL

Abstract Background Antimicrobial resistance is a global threat, heavily impacting low- and middle-income countries. This study estimated antimicrobial-resistant gram-negative bacteria (GNB) fecal colonization prevalence in hospitalized and community-dwelling adults in Chile before the coronavirus disease 2019 pandemic. Methods From December 2018 to May 2019, we enrolled hospitalized adults in 4 public hospitals and community dwellers from central Chile, who provided fecal specimens and epidemiological information. Samples were plated onto MacConkey agar with ciprofloxacin or ceftazidime added. All recovered morphotypes were identified and characterized according to the following phenotypes: fluoroquinolone-resistant (FQR), extended-spectrum cephalosporin-resistant (ESCR), carbapenem-resistant (CR), or multidrug-resistant (MDR; as per Centers for Disease Control and Prevention criteria) GNB. Categories were not mutually exclusive. Results A total of 775 hospitalized adults and 357 community dwellers were enrolled. Among hospitalized subjects, the prevalence of colonization with FQR, ESCR, CR, or MDR-GNB was 46.4% (95% confidence interval [CI], 42.9–50.0), 41.2% (95% CI, 37.7–44.6), 14.5% (95% CI, 12.0–16.9), and 26.3% (95% CI, 23.2–29.4). In the community, the prevalence of FQR, ESCR, CR, and MDR-GNB colonization was 39.5% (95% CI, 34.4–44.6), 28.9% (95% CI, 24.2–33.6), 5.6% (95% CI, 3.2–8.0), and 4.8% (95% CI, 2.6–7.0), respectively. Conclusions A high burden of antimicrobial-resistant GNB colonization was observed in this sample of hospitalized and community-dwelling adults, suggesting that the community is a relevant source of antibiotic resistance. Efforts are needed to understand the relatedness between resistant strains circulating in the community and hospitals.

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Exome Sequencing Identifies Genetic Variants Associated with Extreme Manifestations of the Cardiovascular Phenotype in Marfan Syndrome

2022 , Yanireth Jimenez , Cesar Paulsen , Eduardo Turner , Sebastian Iturra , Oscar Cuevas , Guillermo Lay-son , REPETTO LISBOA, MARIA GABRIELA , Marcelo Rojas , CALDERON GIADROSIC, JUAN FRANCISCO

Marfan Syndrome (MFS) is an autosomal dominant condition caused by variants in the fibrillin-1 (FBN1) gene. Cardinal features of MFS include ectopia lentis (EL), musculoskeletal features and aortic root aneurysm and dissection. Although dissection of the ascending aorta is the main cause of mortality in MFS, the clinical course differs considerably in age of onset and severity, even among individuals who share the same causative variant, suggesting the existence of additional genetic variants that modify the severity of the cardiovascular phenotype in MFS. We recruited MFS patients and classified them into severe (n = 8) or mild aortic phenotype (n = 14) according to age of presentation of the first aorta-related incident. We used Exome Sequencing to identify the genetic variants associated with the severity of aortic manifestations and we performed linkage analysis where suitable. We found five genes associated with severe aortic phenotype and three genes that could be protective for this phenotype in MFS. These genes regulate components of the extracellular matrix, TGFβ pathway and other signaling pathways that are involved in the maintenance of the ECM or angiogenesis. Further studies will be required to understand the functional effect of these variants and explore novel, personalized risk management and, potentially, therapies for these patients.

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A Mouse Systems Genetics Approach Reveals Common and Uncommon Genetic Modifiers of Hepatic Lysosomal Enzyme Activities and Glycosphingolipids

2023 , Anyelo Durán , David A. Priestman , Macarena Las Las Heras , Boris Rebolledo-Jaramillo , Valeria Olguín , CALDERON GIADROSIC, JUAN FRANCISCO , Silvana Zanlungo , Jaime Gutiérrez , Frances M. Platt , Andrés D. Klein

Identification of genetic modulators of lysosomal enzyme activities and glycosphingolipids (GSLs) may facilitate the development of therapeutics for diseases in which they participate, including Lysosomal Storage Disorders (LSDs). To this end, we used a systems genetics approach: we measured 11 hepatic lysosomal enzymes and many of their natural substrates (GSLs), followed by modifier gene mapping by GWAS and transcriptomics associations in a panel of inbred strains. Unexpectedly, most GSLs showed no association between their levels and the enzyme activity that catabolizes them. Genomic mapping identified 30 shared predicted modifier genes between the enzymes and GSLs, which are clustered in three pathways and are associated with other diseases. Surprisingly, they are regulated by ten common transcription factors, and their majority by miRNA-340p. In conclusion, we have identified novel regulators of GSL metabolism, which may serve as therapeutic targets for LSDs and may suggest the involvement of GSL metabolism in other pathologies.

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Reliable and accurate prediction of basic pK$$_a$$ values in nitrogen compounds: the pK$$_a$$ shift in supramolecular systems as a case study

2023 , Jackson J. Alcázar , Alessandra C. Misad Saide , Paola R. Campodónico

AbstractThis article presents a quantitative structure–activity relationship (QSAR) approach for predicting the acid dissociation constant (pK$$_a$$ a ) of nitrogenous compounds, including those within supramolecular complexes based on cucurbiturils. The model combines low-cost quantum mechanical calculations with QSAR methodology and linear regressions to achieve accurate predictions for a broad range of nitrogen-containing compounds. The model was developed using a diverse dataset of 130 nitrogenous compounds and exhibits excellent predictive performance, with a high coefficient of determination (R$$^2$$ 2 ) of 0.9905, low standard error (s) of 0.3066, and high Fisher statistic (F) of 2142. The model outperforms existing methods, such as Chemaxon software and previous studies, in terms of accuracy and its ability to handle heterogeneous datasets. External validation on pharmaceutical ingredients, dyes, and supramolecular complexes based on cucurbiturils confirms the reliability of the model. To enhance usability, a script-like tool has been developed, providing a streamlined process for users to access the model. This study represents a significant advancement in pK$$_a$$ a prediction, offering valuable insights for drug design and supramolecular system optimization. Graphical Abstract

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Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

2021 , Elisa Balboa , Tamara Marín , Juan Esteban Oyarzún , Pablo S. Contreras , Robert Hardt , Thea van den Bosch , Alejandra R. Alvarez , Boris Rebolledo-Jaramillo , Andres D. Klein , Dominic Winter , Silvana Zanlungo

Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1−/− mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.

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