Equipamiento para análisis masivo de expresión génica global aplicado a problemas de biomedicina

Project Title

Partner Organisations

Facultad de Medicina Clínica Alemana Universidad del Desarrollo

Internal ID

EQM190110

Principal Investigator

CALDERON GIADROSIC, JUAN FRANCISCO

Start Date

2019

Publications

Now showing 1 - 10 of 11

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Genetics of spontaneous cervical and coronary artery dissections
(2023)
Isabel Rada
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CALDERON GIADROSIC, JUAN FRANCISCO
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Gonzalo Martínez
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MUÑOZ VENTURELLI, PAULA ANDREA
<jats:sec><jats:title>Objectives</jats:title><jats:p>Spontaneous cervical artery dissections (SCeAD) and coronary artery dissections (SCoAD) are major causes of neurovascular and cardiovascular morbidity in young adults. Although multiple aspects of their etiology are still unknown, most consensuses are focused on the presence of constitutional genetic aspects and environmental triggers. Since recent evidence of genetic contribution points to a possible overlap between these conditions, we aimed to describe current information on SCeAD and SCoAD genetics and their potential shared pathological aspects.</jats:p></jats:sec><jats:sec><jats:title>Materials and methods</jats:title><jats:p>A narrative review is presented. Publications in English and Spanish were queried using database search. The articles were evaluated by one team member in terms of inclusion criteria. After collecting, the articles were categorized based on scientific content.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Given that patients with SCeAD and SCoAD rarely present connective tissue disorders, other genetic loci are probably responsible for the increased susceptibility in some individuals. The common variant rs9349379 at <jats:italic>PHACTR1</jats:italic> gene is associated with predisposition to pathologies of the arterial wall, likely mediated by variations in Endothelin-1 (ET-1) levels. The risk of arterial dissection may be increased for those who carry the rs9349379(A) allele, associated with lower expression levels of ET-1; however, the local effect of this vasomotor imbalance remains unclear. Sex differences seen in SCeAD and SCoAD support a role for sex hormones that could modulate risk, tilting the delicate balance and forcing vasodilator actions to prevail over vasoconstriction due to a reduction in ET-1 expression.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>New evidence points to a common gene variation that could explain dissection in both the cervical and coronary vasculatures. To further confirm the risk conferred by the rs9349379 variant, genome wide association studies are warranted, hopefully in larger and ethnically diverse populations.</jats:p></jats:sec>
14Scopus© Citations 4
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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
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David A. Priestman
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Macarena Las Las Heras
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Boris Rebolledo-Jaramillo
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Valeria Olguín
<jats:p>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.</jats:p>
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Extracellular Cysteines Are Critical to Form Functional Cx46 Hemichannels
(2022)
Ainoa Fernández-Olivares
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Eduardo Durán-Jara
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Daniel A. Verdugo
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Mariana C. Fiori
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Guillermo A. Altenberg
<jats:p>Connexin (Cxs) hemichannels participate in several physiological and pathological processes, but the molecular mechanisms that control their gating remain elusive. We aimed at determining the role of extracellular cysteines (Cys) in the gating and function of Cx46 hemichannels. We studied Cx46 and mutated all of its extracellular Cys to alanine (Ala) (one at a time) and studied the effects of the Cys mutations on Cx46 expression, localization, and hemichannel activity. Wild-type Cx46 and Cys mutants were expressed at comparable levels, with similar cellular localization. However, functional experiments showed that hemichannels formed by the Cys mutants did not open either in response to membrane depolarization or removal of extracellular divalent cations. Molecular-dynamics simulations showed that Cys mutants may show a possible alteration in the electrostatic potential of the hemichannel pore and an altered disposition of important residues that could contribute to the selectivity and voltage dependency in the hemichannels. Replacement of extracellular Cys resulted in “permanently closed hemichannels”, which is congruent with the inhibition of the Cx46 hemichannel by lipid peroxides, through the oxidation of extracellular Cys. These results point to the modification of extracellular Cys as potential targets for the treatment of Cx46-hemichannel associated pathologies, such as cataracts and cancer, and may shed light into the gating mechanisms of other Cx hemichannels.</jats:p>
Scopus© Citations 6 2
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Connexin46 in the nucleus of cancer cells: a possible role as transcription modulator
(Springer Science and Business Media LLC, 2025-03-27)
Ainoa Fernández-Olivares
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Viviana P Orellana
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Jesús Llanquinao
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NUÑEZ VASQUEZ, GONZALO ESTEBAN
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Pablo Pérez-Moreno
Scopus© Citations 1 10
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Genomic modifiers of neurological resilience in a Niemann‐Pick C family
(Wiley, 2025-06-12)
Macarena Las Heras
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Benjamín Szenfeld
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Valeria Olguín
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Juan Carlos Rubilar
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CALDERON GIADROSIC, JUAN FRANCISCO
Niemann-Pick type C (NPC) disease, caused by NPC1 or NPC2 variants, disrupts cholesterol and glycolipid trafficking, leading to diverse clinical manifestations. To understand the genetic basis of neurological resilience, we analyzed an NPC family with variable phenotypes, identifying loss-of-function variants in CCDC115, SLC4A5, DEPDC5, ETFDH, SNRNP200, and DOCK1 that co-segregated with milder neurological involvement. Using yeast models, we successfully predicted NPC-like severity based on orthologous gene variants. RNA-seq revealed a positive correlation between mitochondrial transcripts and cellular fitness. Modeling NPC in yeast lacking the SLC4A5 ortholog, bor1, enhanced cellular fitness, improved mitochondrial function, and reduced sterol accumulation. Our findings identify potential modifiers and biomarkers of NPC severity, highlighting mitochondrial pathways and SLC4A5 as a therapeutic target.
6
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Eco-epidemiology of rodent-associated trombiculid mites and infection with Orientia spp. in Southern Chile
(2023)
María Carolina Silva de la Fuente
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Caricia Pérez
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Constanza Martínez-Valdebenito
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Pérez Ball, Ruth
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VIAL COX, MARIA CECILIA
<jats:sec id="sec001"> <jats:title>Background</jats:title> <jats:p>Scrub typhus is a potentially severe infection caused by bacteria of the genus <jats:italic>Orientia</jats:italic>, endemic in Asia-Pacific and recently discovered in southern Chile. The presented study aimed to determine the prevalence and species richness of rodent-associated trombiculid mites and their infection with <jats:italic>Orientia</jats:italic> spp. in different areas of two regions in southern Chile.</jats:p> </jats:sec> <jats:sec id="sec002"> <jats:title>Methodology/Principal findings</jats:title> <jats:p>During summer 2020, trombiculid mites were collected from rodents captured in three areas in southern Chile known to be endemic for scrub typhus (Cochamó and Chiloé Island in the Los Lagos Region and Tortel in the Aysén Region). A total of 132 rodents belonging to five species were captured using Sherman-like traps; 89.4% were infested with trombiculids. Mite specimens were morphologically identified and subsequently tested by <jats:italic>Orientia</jats:italic>-specific qPCR. Six mite species were identified. Among chigger-infested rodents, 33.9% carried <jats:italic>Orientia</jats:italic>-positive mites; this rate was higher in Tortel (63.8%) than in Cochamó (45.0%) and Chiloé Island (2.0%). The analysis of individual mites (n = 901) revealed that 31.2% of <jats:italic>Herpetacarus antarctica</jats:italic> samples (n = 202) were positive for <jats:italic>Orientia</jats:italic> DNA; the prevalence was 7.0% in <jats:italic>Paratrombicula neuquenensis</jats:italic> (n = 213), 6.9% in <jats:italic>Herpetacarus eloisae</jats:italic> (n = 144), 3.6% in <jats:italic>Argentinacarus expansus</jats:italic> (n = 55), and 0% in <jats:italic>Paratrombicula goffi</jats:italic> (n = 110) and <jats:italic>Quadraseta chiloensis</jats:italic> (n = 177). The southernmost site (Tortel) showed the highest rates of trombiculid infestation, trombiculid load, and <jats:italic>Orientia</jats:italic> infection in the captured rodents.</jats:p> </jats:sec> <jats:sec id="sec003"> <jats:title>Conclusions/Significance</jats:title> <jats:p>Our study provides new insights into the trombiculid fauna and prevalence of <jats:italic>Orientia</jats:italic> in mites collected from wild rodents in southern Chile. <jats:italic>Orientia</jats:italic> DNA was detected in four of the six mite species. Rates of infestation, mite loads, and <jats:italic>Orientia</jats:italic> prevalences differed geographically and were highest in the Aysén Region. Our data improve our knowledge on possible vectors of scrub typhus and their distribution in Chile.</jats:p> </jats:sec>
1Scopus© Citations 9 2
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Exome Sequencing Identifies Genetic Variants Associated with Extreme Manifestations of the Cardiovascular Phenotype in Marfan Syndrome
(2022)
Yanireth Jimenez
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Cesar Paulsen
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Eduardo Turner
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Sebastian Iturra
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Oscar Cuevas
<jats:p>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.</jats:p>
37Scopus© Citations 4
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CRISPR/Cas13-Based Platforms for a Potential Next-Generation Diagnosis of Colorectal Cancer through Exosomes Micro-RNA Detection: A Review
(2021)
Benjamín Durán-Vinet
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Karla Araya-Castro
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CALDERON GIADROSIC, JUAN FRANCISCO
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Luis Vergara
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Helga Weber
<jats:p>Colorectal cancer (CRC) is the third most prevalent cancer with the second highest mortality rate worldwide. CRC is a heterogenous disease with multiple risk factors associated, including obesity, smoking, and use of alcohol. Of total CRC cases, 60% are diagnosed in late stages, where survival can drop to about 10%. CRC screening programs are based primarily on colonoscopy, yet this approach is invasive and has low patient adherence. Therefore, there is a strong incentive for developing molecular-based methods that are minimally invasive and have higher patient adherence. Recent reports have highlighted the importance of extracellular vesicles (EVs), specifically exosomes, as intercellular communication vehicles with a broad cargo, including micro-RNAs (miRNAs). These have been syndicated as robust candidates for diagnosis, primarily for their known activities in cancer cells, including immunoevasion, tumor progression, and angiogenesis, whereas miRNAs are dysregulated by cancer cells and delivered by cancer-derived exosomes (CEx). Quantitative polymerase chain reaction (qPCR) has shown good results detecting specific cancer-derived exosome micro-RNAs (CEx-miRNAs) associated with CRC, but qPCR also has several challenges, including portability and sensitivity/specificity issues regarding experiment design and sample quality. CRISPR/Cas-based platforms have been presented as cost-effective, ultrasensitive, specific, and robust clinical detection tools in the presence of potential inhibitors and capable of delivering quantitative and qualitative real-time data for enhanced decision-making to healthcare teams. Thereby, CRISPR/Cas13-based technologies have become a potential strategy for early CRC diagnosis detecting CEx-miRNAs. Moreover, CRISPR/Cas13-based platforms’ ease of use, scalability, and portability also showcase them as a potential point-of-care (POC) technology for CRC early diagnosis. This study presents two potential CRISPR/Cas13-based methodologies with a proposed panel consisting of four CEx-miRNAs, including miR-126, miR-1290, miR-23a, and miR-940, to streamline novel applications which may deliver a potential early diagnosis and prognosis of CRC.</jats:p>
7Scopus© Citations 22
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Methadone directly impairs central nervous system cells in vitro
(2024)
Cristian De Gregorio
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Javiera Gallardo
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BERRIOS CARCAMO, PABLO ANDRES
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Álex Handy
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Daniela Santapau
Scopus© Citations 2 3
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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
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Rachel M Smith
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Ashley Styczynski
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Felipe Sánchez
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Lea Maureira
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p> </jats:sec>
Scopus© Citations 10 2

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