Publications by authors named "Oscar Sanchez"

62 Publications

Examination of the Efficacy and Cross-Reactivity of a Novel Polyclonal Antibody Targeting the Disintegrin Domain in SVMPs to Neutralize Snake Venom.

Toxins (Basel) 2021 03 31;13(4). Epub 2021 Mar 31.

National Natural Toxins Research Center (NNTRC), Texas A&M University-Kingsville, MSC 224, 975 West Avenue B, Kingsville, TX 78363, USA.

Snake envenomation can result in hemorrhage, local necrosis, swelling, and if not treated properly can lead to adverse systemic effects such as coagulopathy, nephrotoxicity, neurotoxicity, and cardiotoxicity, which can result in death. As such, snake venom metalloproteinases (SVMPs) and disintegrins are two toxic components that contribute to hemorrhage and interfere with the hemostatic system. Administration of a commercial antivenom is the common antidote to treat snake envenomation, but the high-cost, lack of efficacy, side effects, and limited availability, necessitates the development of new strategies and approaches for therapeutic treatments. Herein, we describe the neutralization ability of anti-disintegrin polyclonal antibody on the activities of isolated disintegrins, P-II/P-III SVMPs, and crude venoms. Our results show disintegrin activity on platelet aggregation in whole blood and the migration of the SK-Mel-28 cells that can be neutralized with anti-disintegrin polyclonal antibody. We characterized a SVMP and found that anti-disintegrin was also able to inhibit its activity in an in vitro proteolytic assay. Moreover, we found that anti-disintegrin could neutralize the proteolytic and hemorrhagic activities from crude venom. Our results suggest that anti-disintegrin polyclonal antibodies have the potential for a targeted approach to neutralize SVMPs in the treatment of snakebite envenomations.
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http://dx.doi.org/10.3390/toxins13040254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066378PMC
March 2021

Emergency CABG for a migrated stent in a COVID-19 positive patient.

J Card Surg 2021 Mar 25. Epub 2021 Mar 25.

Division of Cardiovascular Surgery, Fundación Clínica Shaio, Bogotá, Colombia.

Percutaneous coronary interventions (PCI) have become a standard of treatment worldwide. Despite high safety rates, iatrogenic complications caused by stent dislodgements do exist in 0.21% of cases and most require emergency coronary artery by-pass grafting (CABG). Here we present a case of a coronavirus disease 2019 positive 40-year-old male patient presenting with STEMI due to thrombotic lesions in his left coronary trunk. The patient is taken to PCI and stent placement. Stent dislodgement results in the need for emergency CABG and stent removal. Informed consent and ethics approval were obtained.
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http://dx.doi.org/10.1111/jocs.15523DOI Listing
March 2021

Valorisation of rejected unripe plantain fruits of Musa AAB Simmonds: from nutritional characterisation to the conceptual process design for prebiotic production.

Food Funct 2021 Apr 11;12(7):3009-3021. Epub 2021 Mar 11.

Research Group on Food and Agro-industry, Department of Engineering, Universidad de Caldas, Calle 65 No. 26-10, 170004, Manizales, Colombia.

The increasing consumption of plantain fruits with specific quality standards generates high agricultural waste. This work aimed at valorising the rejected unripe pulp of Dominico-Hartón plantain fruits (Musa AAB Simmonds). The pulp was characterised physico-chemically, thermally and functionally. The data gathered experimentally and collected from different databases were used to design a production process of isomalto-oligosaccharides (IMO) syrup. The plantain flour contains high levels of starch (87 ± 2%) and amylose (31.2 ± 0.8%). The flour showed stability at high temperatures (pasting temperature of 79.26 ± 0.02 °C), allowing its use in high temperature processes. In vitro gastrointestinal digestion of the plantain flour showed that when cooked, the glycemic index of the flour increased from 47.7 ± 2.2 to 84.2 ± 1.8, while its resistant starch content only slightly decreased from 71.7 ± 1% to 52.6 ± 2%, suggesting that this type of flour preserves high content of dietary fibre after digestion. The conceptual process design showed that 24.48 g of IMO are theoretically obtained from 53.24 g of plantain flour maltose. These results suggest that the rejected plantain pulp holds high potential as an ingredient for the production of prebiotic compounds such as IMO.
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http://dx.doi.org/10.1039/d0fo03379kDOI Listing
April 2021

Evaluation of HIV-1 derived lentiviral vectors as transductors of Mucopolysaccharidosis type IV a fibroblasts.

Gene 2021 May 23;780:145527. Epub 2021 Feb 23.

Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá, D.C, Colombia. Electronic address:

Mucopolysaccharidosis type IVA (MPS IVA) is a lysosomal storage disease produced by the deficiency of the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme, leading to glycosaminoglycans (GAGs) accumulation. Since currently available treatments remain limited and unspecific, novel therapeutic approaches are essential for the disease treatment. In an attempt to reduce treatment limitations, gene therapy rises as a more effective and specific alternative. We present in this study the delivery assessment of GALNS and sulfatase-modifying factor 1 (SUMF1) genes via HIV-1 derived lentiviral vectors into fibroblasts from MPS IVA patients. After transduction, we determined GALNS enzymatic activity, lysosomal mass change, and autophagy pathway impairment. Additionally, we computationally assessed the effect of mutations over the enzyme-substrate interaction and phenotypic effects. The results showed that the co-transduction of MPS IVA fibroblasts with GALNS and SUMF1 cDNAs led to a significant increase in GALNS enzyme activity and a reduction of lysosomal mass. We show that patient-specific differences in cellular response are directly associated with the set of mutations on each patient. Lastly, we present new evidence supporting autophagy impairment in MPS IVA due to the presence and changes in autophagy proteins in treated MPS IVA fibroblasts. Our results offer new evidence that demonstrate the potential of lentiviral vectors as a strategy to correct GALNS deficiency.
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http://dx.doi.org/10.1016/j.gene.2021.145527DOI Listing
May 2021

To which world regions does the valence-dominance model of social perception apply?

Nat Hum Behav 2021 01 4;5(1):159-169. Epub 2021 Jan 4.

School of Psychological, Social and Behavioural Sciences, Coventry University, Coventry, UK.

Over the past 10 years, Oosterhof and Todorov's valence-dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. In this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov's methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov's original analysis strategy, the valence-dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence-dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 5 November 2018. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.7611443.v1 .
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http://dx.doi.org/10.1038/s41562-020-01007-2DOI Listing
January 2021

Pre-differentiation exposure to low-dose of atrazine results in persistent phenotypic changes in human neuronal cell lines.

Environ Pollut 2021 Feb 23;271:116379. Epub 2020 Dec 23.

Davidson School of Chemical Engineering, Purdue University, West Lafayette, IN, 47907, USA; Purdue University Center for Cancer Research, West Lafayette, IN, 47907, USA. Electronic address:

Exposures to organic pesticides, particularly during a developmental window, have been associated with various neurodegenerative diseases later in life. Atrazine (ATZ), one of the most used pesticides in the U.S., is suspected to be associated with increased neurodegeneration later in life but few studies assessed the neurotoxicity of developmental ATZ exposure using human neuronal cells. Here, we exposed human SH-SY5Y cells to 0.3, 3, and 30 ppb of ATZ prior to differentiating them into dopaminergic-like neurons in ATZ-free medium to mimic developmental exposure. The differentiated neurons exhibit altered neurite outgrowth and SNCA pathology depending on the ATZ treatment doses. Epigenome changes, such as decreases in 5mC (for 0.3 ppb only), H3K9me3, and H3K27me3 were observed immediately after exposure. These alterations persist in a compensatory manner in differentiated neurons. Specifically, we observed significant reductions in 5mC and H3K9me3, as well as, an increase in H3K27me3 in ATZ-exposed cells after differentiation, suggesting substantial chromatin rearrangements after developmental ATZ exposure. Transcriptional changes of relevant epigenetic enzymes were also quantified but found to only partially explain the observed epigenome alteration. Our results thus collectively suggest that exposure to low-dose of ATZ prior to differentiation can result in long-lasting changes in epigenome and increase risks of SNCA-related Parkinson's Disease.
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http://dx.doi.org/10.1016/j.envpol.2020.116379DOI Listing
February 2021

Biological activities of a new crotamine-like peptide from Crotalus oreganus helleri on C2C12 and CHO cell lines, and ultrastructural changes on motor endplate and striated muscle.

Toxicon 2020 Dec 13;188:95-107. Epub 2020 Oct 13.

National Natural Toxins Research Center (NNTRC), Texas A&M University-Kingsville, Kingsville, TX, USA; Department of Chemistry, Texas A&M University-Kingsville, Kingsville, TX, USA. Electronic address:

Crotamine and crotamine-like peptides are non-enzymatic polypeptides, belonging to the family of myotoxins, which are found in high concentration in the venom of the Crotalus genus. Helleramine was isolated and purified from the venom of the Southern Pacific rattlesnake, Crotalus oreganus helleri. This peptide had a similar, but unique, identity to crotamine and crotamine-like proteins isolated from other rattlesnakes species. The variability of crotamine-like protein amino acid sequences may allow different toxic effects on biological targets or optimize the action against the same target of different prey. Helleramine was capable of increasing intracellular Ca in Chinese Hamster Ovary (CHO) cell line. It inhibited cell migration as well as cell viability (IC = 11.44 μM) of C2C12, immortalized skeletal myoblasts, in a concentration dependent manner, and promoted early apoptosis and cell death under our experimental conditions. Skeletal muscle harvested from mice 24 h after helleramine injection showed contracted myofibrils and profound vacuolization that enlarged the subsarcolemmal space, along with loss of plasmatic and basal membrane integrity. The effects of helleramine provide further insights and evidence of myotoxic activities of crotamine-like peptides and their possible role in crotalid envenomings.
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http://dx.doi.org/10.1016/j.toxicon.2020.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720416PMC
December 2020

Low dose lead exposure induces alterations on heterochromatin hallmarks persisting through SH-SY5Y cell differentiation.

Chemosphere 2021 Feb 1;264(Pt 1):128486. Epub 2020 Oct 1.

Davidson School of Chemical Engineering, Purdue University, West Lafayette, IN, 47907, USA; Purdue University Center for Cancer Research, West Lafayette, IN, 47907, USA. Electronic address:

Lead (Pb) is a commonly found heavy metal due to its historical applications. Recent studies have associated early-life Pb exposure with the onset of various neurodegenerative disease. The molecular mechanisms of Pb conferring long-term neurotoxicity, however, is yet to be elucidated. In this study, we explored the persistency of alteration in epigenetic marks that arise from exposure to low dose of Pb using a combination of image-based and gene expression analysis. Using SH-SY5Y as a model cell line, we observed significant alterations in global 5-methycytosine (5 mC) and histone 3 lysine 27 tri-methylation (H3K27me3) and histone 3 lysine 9 tri-methylation (H3K9me3) levels in a dose-dependent manner immediately after Pb exposure. The changes are partially associated with alterations in epigenetic enzyme expression levels. Long term culturing (14 days) after cease of exposure revealed persistent changes in 5 mC, partial recovery in H3K9me3 and overcompensation in H3K27me3 levels. The observed alterations in H3K9me3 and H3K27me3 are reversed after neuronal differentiation, while reduction in 5 mC levels are amplified with significant changes in patterns as identified via texture clustering analysis. Moreover, correlation analysis demonstrates a strong positive correlation between trends of 5 mC alteration after differentiation and neuronal morphology. Collectively, our results suggest that exposure to low dose of Pb prior to differentiation can result in persistent epigenome alterations that can potentially be responsible for the observed phenotypic changes. Our work reveals that Pb induced changes in epigenetic repressive marks can persist through neuron differentiation, which provides a plausible mechanism underlying long-term neurotoxicity associated with developmental Pb-exposure.
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http://dx.doi.org/10.1016/j.chemosphere.2020.128486DOI Listing
February 2021

Bromocriptine as a Novel Pharmacological Chaperone for Mucopolysaccharidosis IV A.

ACS Med Chem Lett 2020 Jul 24;11(7):1377-1385. Epub 2020 Jun 24.

Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Bogotá D.C. 110231, Colombia.

Mucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disease caused by mutations in the gene encoding for the enzyme -acetylgalactosamine-6-sulfate sulfatase (GALNS), leading to lysosomal accumulation of keratan sulfate (KS) and chondroitin-6-sulfate. In this study, we identified and characterized bromocriptine (BC) as a novel PC for MPS IVA. BC was identified through virtual screening and predicted to be docked within the active cavity of GALNS in a similar conformation to that observed for KS. BC interacted with similar residues to those predicted for natural GALNS substrates. inhibitory assay showed that BC at 50 μM reduced GALNS activity up to 30%. However, the activity of hrGALNS produced in HEK293 cells was increased up to 1.48-fold. BC increased GALNS activity and reduced lysosomal mass in MPS IVA fibroblasts in a mutation-dependent manner. Overall, these results show the potential of BC as a novel PC for MPS IVA and contribute to the consolidation of PCs as a potential therapy for this disease.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356376PMC
July 2020

Lysosomal storage diseases: current therapies and future alternatives.

J Mol Med (Berl) 2020 07 11;98(7):931-946. Epub 2020 Jun 11.

Institute for the Study of Inborn Errors of Metabolism, Faculty of Science, Pontificia Universidad Javeriana, Cra. 7 No. 43-82 Building 54, Room 305A, Bogotá D.C, 110231, Colombia.

Lysosomal storage disorders (LSDs) are a group of monogenic diseases characterized by progressive accumulation of undegraded substrates into the lysosome, due to mutations in genes that encode for proteins involved in normal lysosomal function. In recent years, several approaches have been explored to find effective and successful therapies, including enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, hematopoietic stem cell transplantation, and gene therapy. In the case of gene therapy, genome editing technologies have opened new horizons to accelerate the development of novel treatment alternatives for LSD patients. In this review, we discuss the current therapies for this group of disorders and present a detailed description of major genome editing technologies, as well as the most recent advances in the treatment of LSDs. We will further highlight the challenges and current bioethical debates of genome editing.
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http://dx.doi.org/10.1007/s00109-020-01935-6DOI Listing
July 2020

Role of Connexins 30, 36, and 43 in Brain Tumors, Neurodegenerative Diseases, and Neuroprotection.

Cells 2020 03 31;9(4). Epub 2020 Mar 31.

Department of Nutrition and Biochemistry, Pontificia Universidad Javeriana, 110911 Bogota, Colombia.

Gap junction (GJ) channels and their connexins (Cxs) are complex proteins that have essential functions in cell communication processes in the central nervous system (CNS). Neurons, astrocytes, oligodendrocytes, and microglial cells express an extraordinary repertory of Cxs that are important for cell to cell communication and diffusion of metabolites, ions, neurotransmitters, and gliotransmitters. GJs and Cxs not only contribute to the normal function of the CNS but also the pathological progress of several diseases, such as cancer and neurodegenerative diseases. Besides, they have important roles in mediating neuroprotection by internal or external molecules. However, regulation of Cx expression by epigenetic mechanisms has not been fully elucidated. In this review, we provide an overview of the known mechanisms that regulate the expression of the most abundant Cxs in the central nervous system, Cx30, Cx36, and Cx43, and their role in brain cancer, CNS disorders, and neuroprotection. Initially, we focus on describing the Cx gene structure and how this is regulated by epigenetic mechanisms. Then, the posttranslational modifications that mediate the activity and stability of Cxs are reviewed. Finally, the role of GJs and Cxs in glioblastoma, Alzheimer's, Parkinson's, and Huntington's diseases, and neuroprotection are analyzed with the aim of shedding light in the possibility of using Cx regulators as potential therapeutic molecules.
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http://dx.doi.org/10.3390/cells9040846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226843PMC
March 2020

Self-reported Health is Related to Body Height and Waist Circumference in Rural Indigenous and Urbanised Latin-American Populations.

Sci Rep 2020 03 9;10(1):4391. Epub 2020 Mar 9.

Neuroecology Lab, Faculty of Psychology, National Autonomous University of Mexico, Mexico City, Mexico.

Body height is a life-history component. It involves important costs for its expression and maintenance, which may originate trade-offs on other costly components such as reproduction or immunity. Although previous evidence has supported the idea that human height could be a sexually selected trait, the explanatory mechanisms that underlie this selection are poorly understood. Despite extensive studies on the association between height and attractiveness, the role of immunity in linking this relation is scarcely studied, particularly in non-Western populations. Here, we tested whether human height is related to health measured by self-perception, and relevant nutritional and health anthropometric indicators in three Latin-American populations that widely differ in socioeconomic and ecological conditions: two urbanised populations from Bogota (Colombia) and Mexico City (Mexico), and one isolated indigenous population (Me'Phaa, Mexico). Results showed that self-reported health is best predicted by an interaction between height and waist circumference: the presumed benefits of being taller are waist-dependent, and affect taller people more than shorter individuals. If health and genetic quality cues play an important role in human mate-choice, and height and waist interact to signal health, its evolutionary consequences, including cognitive and behavioural effects, should be addressed in future research.
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http://dx.doi.org/10.1038/s41598-020-61289-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062753PMC
March 2020

Profiling epigenetic changes in human cell line induced by atrazine exposure.

Environ Pollut 2020 Mar 13;258:113712. Epub 2019 Dec 13.

Davidson School of Chemical Engineering, Purdue University, West Lafayette, IN, 47907, USA. Electronic address:

How environmental chemicals can affect and exert their toxic effect at a molecular level has gained significant interest in recent years, not only for understanding their immediate health implications over exposed individuals, but also for their subsequent progeny. Atrazine (ATZ) is a commonly used herbicide in the U.S. and a long-suspected endocrine disrupting chemical. The molecular mechanism conferring long-term adverse health outcomes, however, remain elusive. Here, we explored changes in epigenetic marks that arise after exposure to ATZ at selected doses using image-based analysis coupled with data clustering. Significant decreases in methylated CpG (CpG) and histone 3 lysine 9 tri-methylated (H3K9me3) were observed in the selected human cell line with a clear spatial preference. Treating cells with ATZ leads to the loss of a subpopulation of cells with high CpG levels as identified in our clustering and histogram analysis. A similar trend was observed in H3K9me3 potentially attributing to the cross-talking between CpG and H3K9me3. Changes in CpG are likely to be associated with alterations in epigenetic enzyme expression levels regulating CpG and persist after the removal of ATZ source which collectively provide a plausible mechanism for long-term ATZ-induced toxicity.
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http://dx.doi.org/10.1016/j.envpol.2019.113712DOI Listing
March 2020

Independent parameters of left atrium function in hypertensive heart disease.

Echocardiography 2019 12 22;36(12):2195-2201. Epub 2019 Nov 22.

Cardiology Department, Antiguo Hospital Civil de Guadalajara Fray Antonio Alcalde, Guadalajara, México.

Background: The left atrium reservoir function has an important role in the global cardiac performance and is determined by multiple cardiac and extra-cardiac factors. A new parameter is introduced, the independent strain, which quantifies left atrium reservoir phase deformation during isovolumetric relaxation.

Aims: Is evaluated whether independent strain can identify intrinsic atrial myocardial damage in hypertension.

Material And Methods: Prospective observational study in which echocardiography was done to 50 hypertensive patients and 80 healthy volunteers. Myocardial deformation was evaluated with two-dimensional speckle tracking and left atrium volumes were calculated whit 3D-echocardiography.

Results: In hypertensive patients, the indexed left atrium volume was greater than in the control group (34 ± 7.8 vs 24 ± 4.9 mL/m ); strain of pump (-5.7 ± 2.4% vs -17±3.5%) and reservoir phases (34 ± 9% vs 48 ± 10%) were worst. The minimum left atrium volume was higher (26 ± 10 vs 15 ± 8 mL) and left atrium independent strain was lower in hypertensive patients (4.0% vs 6.5%, P = .001). Left atrium independent strain only correlated with minimum left atrium volume (r = -.31, P = .048).

Discussion: The left ventricle longitudinal performance has an important contributing role in the left atrium reservoir function; despite this finding, the independent strain was unrelated to left ventricle longitudinal function.

Conclusion: Independent strain can identify atrial myocyte contractile dysfunction in hypertension given the relative absence of hemodynamic loads during this period. Additionally, quantification of left atrium minimum volume suggests indirectly the presence of atrial myocyte contractile dysfunction.
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http://dx.doi.org/10.1111/echo.14542DOI Listing
December 2019

Monitoring Histone Methylation (H3K9me3) Changes in Live Cells.

ACS Omega 2019 Aug 1;4(8):13250-13259. Epub 2019 Aug 1.

Davidson School of Chemical Engineering, Purdue University, 480 Stadium Mall Drive, West Lafayette 47907, Indiana, United States.

H3K9me3 (methylation of lysine 9 of histone H3) is an epigenetic modification that acts as a repressor mark. Several diseases, including cancers and neurological disorders, have been associated with aberrant changes in H3K9me3 levels. Different tools have been developed to enable detection and quantification of H3K9me3 levels in cells. Most techniques, however, lack live cell compatibility. To address this concern, we have engineered recombinant protein sensors for probing H3K9me3 in situ. A heterodimeric sensor containing a chromodomain and chromo shadow domain from HP1a was found to be optimal in recognizing H3K9me3 and exhibited similar spatial resolution to commercial antibodies. Our sensor offers similar quantitative accuracy in characterizing changes in H3K9me3 compared to antibodies but claims single cell resolution. The sensor was applied to evaluate changes in H3K9me3 responding to environmental chemical atrazine (ATZ). ATZ was found to result in significant reductions in H3K9me3 levels after 24 h of exposure. Its impact on the distribution of H3K9me3 among cell populations was also assessed and found to be distinctive. We foresee the application of our sensors in multiple toxicity and drug-screening applications.
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http://dx.doi.org/10.1021/acsomega.9b01413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705211PMC
August 2019

Spatial and temporal patterns and the socioeconomic impacts of landslides in the tropical and mountainous Colombian Andes.

Disasters 2020 Jul 14;44(3):596-618. Epub 2020 Jan 14.

Master's Student, Departamento de Geociencias y Medio Ambiente, Facultad de Minas, Universidad Nacional de Colombia, Colombia.

Landslides are a natural hazard that presents a major threat to human life and infrastructure. Although they are a very common phenomenon in Colombia, there is a lack of analysis that entails national and comprehensive spatial, temporal, and socioeconomic evaluations of such events based on historical records. This study provides a detailed assessment of the spatial and temporal patterns and the socioeconomic impacts associated with landslides that occurred in the country between 1900 and 2018. Two national landslide databases were consulted and this information was complemented by local and regional landslide catalogues. A total of 30,730 landslides were recorded in the 118-year period. Rainfall is the most common trigger of landslides, responsible for 92 per cent of those registered, but most fatalities (68 per cent) are due to landslides caused by volcanic activity and earthquakes. An 'fN curve' revealed a very high frequency of small and moderate fatal landslides in the time frame.
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http://dx.doi.org/10.1111/disa.12391DOI Listing
July 2020

Parameter estimation of a meal glucose-insulin model for TIDM patients from therapy historical data.

IET Syst Biol 2019 02;13(1):8-15

FIME, Universidad Autónoma de Nuevo León, Av. Universidad S/N, Ciudad Universitaria, 66455 San Nicolás de los Garza, Nuevo León, N.L., México.

The effect of meal on blood glucose concentration is a key issue in diabetes mellitus because its estimation could be very useful in therapy decisions. In the case of type 1 diabetes mellitus (T1DM), the therapy based on automatic insulin delivery requires a closed-loop control system to maintain euglycaemia even in the postprandial state. Thus, the mathematical modelling of glucose metabolism is relevant to predict the metabolic state of a patient. Moreover, the eating habits are characteristic of each person, so it is of interest that the mathematical models of meal intake allow to personalise the glycaemic state of the patient using therapy historical data, that is, daily measurements of glucose and records of carbohydrate intake and insulin supply. Thus, here, a model of glucose metabolism that includes the effects of meal is analysed in order to establish criteria for data-based personalisation. The analysis includes the sensitivity and identifiability of the parameters, and the parameter estimation problem was resolved via two algorithms: particle swarm optimisation and evonorm. The results show that the mathematical model can be a useful tool to estimate the glycaemic status of a patient and personalise it according to her/his historical data.
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http://dx.doi.org/10.1049/iet-syb.2018.5038DOI Listing
February 2019

Analysis of the transcriptional logic governing differential spatial expression in Hh target genes.

PLoS One 2019 7;14(1):e0209349. Epub 2019 Jan 7.

Applied Mathematics Department, University of Granada, Granada, Spain.

This work provides theoretical tools to analyse the transcriptional effects of certain biochemical mechanisms (i.e. affinity and cooperativity) that have been proposed in previous literature to explain the proper spatial expression of Hedgehog target genes involved in Drosophila development. Specifically we have focused on the expression of decapentaplegic, wingless, stripe and patched. The transcription of these genes is believed to be controlled by enhancer modules able to interpret opposing gradients of the activator and repressor forms of the transcription factor Cubitus interruptus (Ci). This study is based on a thermodynamic approach, which provides expression rates for these genes. These expression rates are controlled by transcription factors which are competing and cooperating for common binding sites. We have made mathematical representations of the different expression rates which depend on multiple factors and variables. The expressions obtained with the model have been refined to produce simpler equivalent formulae which allow for their mathematical analysis. Thanks to this, we can evaluate the correlation between the different interactions involved in transcription and the biological features observed at tissular level. These mathematical models can be applied to other morphogenes to help understand the complex transcriptional logic of opposing activator and repressor gradients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209349PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322776PMC
September 2019

A cross-cultural study of sex-typicality and averageness: Correlation between frontal and lateral measures of human faces.

Am J Hum Biol 2018 09;30(5):e23147

Department of Philosophy and History of Sciences, Faculty of Sciences, Charles University, Praha, Czech Republic.

Objectives: Facial averageness and sexual dimorphism are extensively studied attractiveness markers, which are viewed as possible indicators of biological quality. Both are complex morphological traits, and both can be easily assessed from frontal and lateral projection of a human face. Interestingly, examination of mutual relations between the frontal and lateral dimensions of these markers has so far received little attention in published research.

Methods: In our cross-cultural study, we used geometric morphometric data from male and female faces from Brazil, Cameroon, Colombia, and the Czech Republic, and analyzed correlations between frontal and lateral measurements of averageness and degree of maleness/femaleness, that is, the individual variation in features that characterize sexual dimorphism. We also analyzed whether the association between frontal and lateral measurements differed in men and women.

Results: In general, our results showed a moderate correlation in sexually dimorphic features between lateral and frontal facial configuration in both sexes, while frontal and lateral facial averageness was moderately correlated only in women. This pattern was less consistent when individual populations were analyzed separately.

Conclusions: We suggest that, in general, the weak association between lateral and frontal facial configurations may be the result of selection pressures in favor of individual identity signals. Moreover, especially in women, the frontal and lateral dimension of a given facial attractiveness marker may provide similar information about the qualities of the individual. The absence of a significant correlation in male facial averageness suggests that frontal and lateral averageness convey different information about an individual.
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http://dx.doi.org/10.1002/ajhb.23147DOI Listing
September 2018

Anaerobic sulfatase maturase AslB from Escherichia coli activates human recombinant iduronate-2-sulfate sulfatase (IDS) and N-acetylgalactosamine-6-sulfate sulfatase (GALNS).

Gene 2017 Nov 4;634:53-61. Epub 2017 Sep 4.

Grupo de Bioquímica Molecular Computacional y Bioinformática, Departamento de Nutrición y Bioquímica, Faculty of Sciences, Pontificia Universidad Javeriana, Bogotá, Colombia. Electronic address:

Maturation of type I sulfatases requires the conversion of the cysteine (Cys) or serine (Ser) present in the active site to formylglycine (FGly). This activation represents a limiting step during the production of recombinant sulfatases in bacteria and eukaryotic hosts. AslB, YdeM and YidF have been proposed to participate in the activation of sulfatases in Escherichia coli. In this study, we combined in-silico and experimental approaches to study the interaction between Escherichia coli BL21(DE3) AslB and human sulfatases, more specifically iduronate-2-sulfate sulfatase (IDS) and N-acetylgalactosamine-6-sulfate sulfatase (GALNS). In-silico results show that AslB has a higher affinity for the residual motif of GALNS (-9.4kcalmol), Cys- and Ser-type, than for the one of IDS (-8.0kcalmol). However, the distance between the AslB active residue and the target motif favors the interaction with IDS (4.4Å) more than with GALNS (5.5Å). Experimental observations supported in-silico results where the co-expression of AslB with GALNS Cys- and Ser-type presented an activity increment of 2.0- and 1.5-fold compared to the control cultures, lacking overexpressed AslB. Similarly, IDS activity was increased in 4.6-fold when co-expressed with AslB. The higher sulfatase activity of AslB-IDS suggests that the distance between the AslB active residue and the motif target is a key parameter for the in-silico search of potential sulfatase activators. In conclusion, our results suggest that AslB is involve in the maturation of heterologous human sulfatases in E. coli BL21(DE3), and that it can have important implications in the production of recombinant sulfatases for therapeutic purposes and research.
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http://dx.doi.org/10.1016/j.gene.2017.08.043DOI Listing
November 2017

Atrazine exposure decreases the activity of DNMTs, global DNA methylation levels, and dnmt expression.

Food Chem Toxicol 2017 Nov 30;109(Pt 1):727-734. Epub 2017 Aug 30.

School of Health Sciences, Purdue University, West Lafayette, IN, 47907, USA. Electronic address:

Atrazine, a herbicide used on agricultural crops is widely applied in the Midwestern United States as well as other areas of the globe. Atrazine frequently contaminates potable water supplies and is a suspected endocrine disrupting chemical. Previous studies have reported morphological, hormonal, and molecular alterations due to developmental and adulthood atrazine exposure; however, studies examining epigenetic alterations are limited. In this study, the effects of atrazine exposure on DNA methyltransferase (DNMT) activity and kinetics were evaluated. Global DNA methylation levels and dnmt expression in zebrafish larvae exposed to 0, 3, or 30 parts per billion (ppb) atrazine throughout embryogenesis was then assessed. Results indicate that atrazine significantly decreased the activity of maintenance DNMTs and that the inhibition mechanism can be described using non-competitive Michaelis-Menten kinetics. Furthermore, results show that an embryonic atrazine exposure decreases global methylation levels and the expression of dnmt4 and dnmt5. These findings indicate that atrazine exposure can decrease the expression and activity of DNMTs, leading to decreased DNA methylation levels.
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http://dx.doi.org/10.1016/j.fct.2017.08.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656531PMC
November 2017

Compost supplementation with nutrients and microorganisms in composting process.

Waste Manag 2017 Nov 18;69:136-153. Epub 2017 Aug 18.

Bioprocess and Agro-industry Plant, Department of Engineering, Universidad de Caldas, Manizales, Colombia.

The composting is an aerobic, microorganism-mediated, solid-state fermentation process by which different organic materials are transformed into more stable compounds. The product obtained is the compost, which contributes to the improvement of physical, chemical and microbiological properties of the soil. However, the compost usage in agriculture is constrained because of its long-time action and reduced supply of nutrients to the crops. To enhance the content of nutrients assimilable by the plants in the compost, its supplementation with nutrients and inoculation with microorganisms have been proposed. The objective of this work was to review the state of the art on compost supplementation with nutrients and the role played by the microorganisms involved (or added) in their transformation during the composting process. The phases of composting are briefly compiled and different strategies for supplementation are analyzed. The utilization of nitrogenous materials and addition of microorganisms fixing nitrogen from the atmosphere or oxidizing ammonia into more assimilable for plants nitrogenous forms are analyzed. Several strategies for nitrogen conservation during composting are presented as well. The supplementation with phosphorus and utilization of microorganisms solubilizing phosphorus and potassium are also discussed. Main groups of microorganisms relevant during the composting process are described as well as most important strategies to identify them. In general, the development of this type of nutrient-enriched bio-inputs requires research and development not only in the supplementation of compost itself, but also in the isolation and identification of microorganisms and genes allowing the degradation and conversion of nitrogenous substances and materials containing potassium and phosphorus present in the feedstocks undergoing the composting process. In this sense, most important research trends and strategies to increase nutrient content in the compost are provided in this work.
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http://dx.doi.org/10.1016/j.wasman.2017.08.012DOI Listing
November 2017

Production of human recombinant phenylalanine hydroxylase in Lactobacillus plantarum for gastrointestinal delivery.

Eur J Pharm Sci 2017 Nov 30;109:48-55. Epub 2017 Jul 30.

Institute for the Study of Inborn Errors of Metabolism, School of Sciences, Pontificia Universidad Javeriana, Bogotá, Colombia. Electronic address:

Phenylketonuria (PKU) is an autosomal recessive disorder caused by a defective phenylalanine hydroxylase (PAH), which catalyzes the hydroxylation of l-phenylalanine (l-Phe) to l-tyrosine (l-Tyr) in presence of the cofactor tetrahydrobiopterin (BH4). Defective PAH causes accumulation of phenylalanine, which has neurotoxic effects and leads to dermatological, behavioral, and neurocognitive problems. Treatments for this disease consist in life-long diets that are hard for patients to keep, or supplementation with BH4. In this study, we propose a system where a probiotic lactic acid bacteria (LAB) can be used as vehicle to express in situ an engineered human PAH. Engineered PAHs contain a secretion peptide, a gastrointestinal signal (GI), the human PAH, and a flexible glycine linker followed by the fluorescence protein mEGFP. Engineered constructs were successfully transformed, expressed, and secreted in Lactobacillus plantarum CM_PUJ411. PAH construct containing either the signal peptide GI1 or GI2 were transported through a Caco-2 cell monolayer. Nevertheless, the one containing GI1 allowed the highest transport through the cell monolayer. Co-culture of L. plantarum and Caco-2 cells showed that engineered PAH is produced in-situ and transported through the cell monolayer. Finally, the activity test showed that the engineered PAH secreted by L. plantarum CM_PUJ411 is active, leading to a reduction in l-Phe and an increase in l-Tyr levels, respectively. These results show the potential of this system as a new therapeutic alternative for the treatment of PKU patients.
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http://dx.doi.org/10.1016/j.ejps.2017.07.033DOI Listing
November 2017

Engineering Recombinant Protein Sensors for Quantifying Histone Acetylation.

ACS Sens 2017 Mar 17;2(3):426-435. Epub 2017 Feb 17.

School of Chemical Engineering, Purdue University , 480 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.

H3K14ac (acetylation of lysine 14 of histone H3) is one of the most important epigentic modifications. Aberrant changes in H3K14ac have been associated with various diseases, including cancers and neurological disorders. Tools that enable detection and quantification of H3K14ac levels in cell extracts and in situ are thus of critical importance to reveal its role in various biological processes. Current detection techniques of specific histone modifications, however, are constrained by tedious sample pretreatments, lack of quantitative accuracy, and reliance on high quality antibodies. To address this issue, we engineered recombinant sensors that are suitable for probing histone acetylation levels using various biological samples. The protein sensor contains recongition domain(s) with sequences derived from the bromodomain of human polybromo-1 (PB1), a natural H3K14ac reader domain. Various sensor designs were tested using nuclear extracts and live cells. The sensor containing dimeric repeats of bromodomain was found most effective in quantifying H3K14ac level in both in vitro and in situ assays. The sensor has a linear detection range of 0.5-50 nM when mixed with nuclear extracts. The sensor colocalizes with H3K14ac antibodies in situ when transfected into human embryonic kidney 293T (HEK293T) cells and is thus capable of providing spatial details of histone modification within the nucleus. Corrected nuclear fluorescence intensity was used to quantify the modification level in situ and found to correlate well with our in vitro assays. Our sensor offers a novel tool to characterize the histone modification level using nuclear extracts and probe histone modification change in live cells.
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http://dx.doi.org/10.1021/acssensors.7b00026DOI Listing
March 2017

CpG dinucleotide positioning patterns determine the binding affinity of methyl-binding domain to nucleosomes.

Biochim Biophys Acta Gene Regul Mech 2017 Jun 1;1860(6):713-720. Epub 2017 Apr 1.

Davidson School of Chemical Engineering, Purdue University, West Lafayette, IN 47906, USA; Purdue University Center for Cancer Research, West Lafayette, IN 47906, USA. Electronic address:

The methyl-binding domain of MBD1 is a common methyl CpG binding motif and has been linked to transcriptional repression. Understanding the dynamics of MBD1 binding to nucleosomal DNA is crucial, but the molecular interactions between MBD1 and chromatin remain elusive. In this study, we found the binding of MBD1 to nucleosomes demonstrates sequence preferences depending on the position of the methyl groups on the nucleosome. Specifically, binding was favored at CpG sites in the dyad proximal region and facing towards the histone octamers. At locations where the CpG sites face away from the histone octamer, the binding affinity was significantly lower. Interestingly, the binding of ΔMBD1 at methylated CpG sites facing away from histone octamers induces conformational changes of nucleosomes, resulting in a more "open" conformation. The biological implication of DNA methylation is thus likely to be synergistically regulated via DNA sequences contents and their nucleosome-positioning patterns based on our in vitro findings.
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http://dx.doi.org/10.1016/j.bbagrm.2017.03.006DOI Listing
June 2017

Lead (Pb) exposure reduces global DNA methylation level by non-competitive inhibition and alteration of dnmt expression.

Metallomics 2017 02;9(2):149-160

School of Chemical Engineering, Purdue University, West Lafayette, IN 47907, USA.

Low-dose exposure to lead (Pb) is connected to developmental neurological alterations by inducing molecular changes, such as aberrant gene expression patterns. The attributing molecular mechanism, however, is not well-elucidated. In this study, we revealed epigenetic features and mechanisms that can alter gene expression patterns by identifying changes in DNA methyltransferase (DNMT) activity, expression pattern and DNA methylation level using moelcular studies and a zebrafish animal model. We characterized the effects of Pb on the activities of various DNMTs in vitro and determined the molecular role of Pb in modulating DNMT activity via kinetic experiments. An exposure of 100 or 500 ppb of Pb was found to significantly lower the activity of maintenance DNMTs. The inhibition mechanism can be described using non-competitive Michaelis-Menten kinetics. A zebrafish animal model was then used to assess the biological significance of our findings. An embryonic exposure to 100 or 500 ppb Pb resulted in a significant change in global methylation levels consistent with previous studies using human and rodent model. Our study also suggests that Pb exposure in zebrafish alters the expression patterns of dnmt3 and dnmt4 which are human DNMT3b orthologs. The knowledge from this study suggests that Pb exposure can affect the activity of maintenance DNMTs via non-competitive inhibition, which has not been reported previously. Meanwhile, the expression pattern of de novo methyltransferases can also be altered. Collectively, they result in a reduction in global DNA methylation level in Pb-exposed zebrafish model, which can be compared to findings in human and rodent studies.
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http://dx.doi.org/10.1039/c6mt00198jDOI Listing
February 2017

In Silico Analysis of the Structure of Fungal Fructooligosaccharides-Synthesizing Enzymes.

Interdiscip Sci 2018 Mar 15;10(1):53-67. Epub 2016 Feb 15.

School of Chemical Engineering, Purdue University, Forney Hall of Chemical Engineering, 480 Stadium Mall Drive, West Lafayette, IN, 47907-2100, USA.

Fructooligosaccharides (FOS) are prebiotics commonly manufactured using fungal fructosyltransferases (FTases) or β-fructofuranosidases. Several reports have attempted to optimize FOS production by changing operational conditions. Nevertheless, there is a lack of information related to the molecular enzyme-substrate interaction. In this study, we present an in silico evaluation of the interactions between substrates (i.e., glucose, sucrose, GF, GF, and GF) and native FOS-synthesizing enzymes from fungi, with reported FOS production yield. In addition, a molecular dynamic simulation was conducted to assess the stability of these interactions. Six fungal enzymes with reported data of FOS production were selected: sucrose-sucrose 1-fructosyltransferase from A. foetidus (GenBank No. CAA04131); intracellular invertase from A. niger (GenBank No. ABB59679); extracellular invertase from A. niger (GenBank No. ABB59678); β-fructofuranidase from A. japonicus ATCC 20611 (GenBank No. BAB67771); fructosyltransferase from A. oryzae N74 (GenBank No. ACZ48670); and fructosyltransferase from A. japonicus (PDB ID 3LF7). These enzymes shared an identity between 15 and 96 %, but have a highly conserved folding, and the characteristic FTases domains. Docking results showed that these enzymes also share a similar protein-ligand interaction profile. It was observed that the production yield of total FOS correlated with the sum of affinity energies for GF, GF, and GF. Finally, we present the first molecular dynamic simulation for FOS and fungal FOS-synthesizing enzymes, showing that the protein-ligand interaction does not induce significant changes on the enzyme stability. Overall, these results represent valuable information to continue understanding the FOS synthesis process by fungal FOS-synthesizing enzymes, and they can have a significant impact toward the improvement in their catalytic properties and the synthesis of specific FOS.
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http://dx.doi.org/10.1007/s12539-016-0154-yDOI Listing
March 2018

Cerebral Protection During MitraClip Implantation: Initial Experience at 2 Centers.

JACC Cardiovasc Interv 2016 Jan 23;9(2):171-9. Epub 2015 Dec 23.

Department of Cardiology, Asklepios Klinik St. Georg, Hamburg, Germany.

Objectives: This study sought to assess the feasibility and safety of using a filter-based cerebral protection system (CPS) during MitraClip implantation and to report on the histopathologic analysis of the captured debris.

Background: Stroke is one of the serious adverse events associated with MitraClip therapy.

Methods: Between July 2014 and March 2015, 14 surgical high-risk patients (age 75 ± 7 years; 7 men; median logistic EuroSCORE 21%) underwent MitraClip implantation employing cerebral protection with a dual embolic filter system. All patients had severe mitral regurgitation of predominantly functional origin.

Results: All procedures were successfully completed for both CPS deployment/retrieval and MitraClip implantation. A total of 28 filters (2 from each patient) were analyzed. Microscopically, debris was identified in all 14 patients. The most common tissue types were acute thrombus and small fragments of foreign material, which were found in 12 patients (85.7%) each. Organizing thrombus was present in 4 patients (28.6%), valve tissue and/or superficial atrial wall tissue in 9 patients (64.3%), and fragments of myocardium in 2 patients (14.3%). No transient ischemic attacks, strokes, or deaths occurred peri-procedurally or during a median follow-up interval of 8.4 months.

Conclusions: In this small study of patients undergoing MitraClip treatment with cerebral protection, embolic debris potentially conducive to cerebrovascular events was found in all patients. Debris was composed most often of acute thrombus, foreign material likely originating from the hydrophilic device coating, and valve/atrial wall tissue. Further studies are warranted to assess the impact of cerebral protection on the incidence of cerebrovascular events after MitraClip therapy.
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http://dx.doi.org/10.1016/j.jcin.2015.09.039DOI Listing
January 2016

Modeling Hedgehog Signaling Through Flux-Saturated Mechanisms.

Methods Mol Biol 2015 ;1322:19-33

Departamento de Matemática Aplicada, Universidad de Granada, Campus de Fuentenueva, Granada, 18071, Spain.

Hedgehog (Hh) molecules act as morphogens directing cell fate during development by activating various target genes in a concentration dependent manner. Hitherto, modeling morphogen gradient formation in multicellular systems has employed linear diffusion, which is very far from physical reality and needs to be replaced by a deeper understanding of nonlinearities. We have developed a novel mathematical approach by applying flux-limited spreading (FLS) to Hh morphogenetic actions. In the new model, the characteristic velocity of propagation of each morphogen is a new key biological parameter. Unlike in linear diffusion models, FLS modeling predicts concentration fronts and correct patterns and cellular responses over time. In addition, FLS considers not only extracellular binding partners influence, but also channels or bridges of information transfer, such as specialized filopodia or cytonemes as a mechanism of Hh transport. We detect and measure morphogen particle velocity in cytonemes in the Drosophila wing imaginal disc. Indeed, this novel approach to morphogen gradient formation can contribute to future research in the field.
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http://dx.doi.org/10.1007/978-1-4939-2772-2_3DOI Listing
April 2016

Human recombinant lysosomal enzymes produced in microorganisms.

Mol Genet Metab 2015 Sep-Oct;116(1-2):13-23. Epub 2015 Jun 6.

Institute for the Study of Inborn Errors of Metabolism, School of Sciences, Pontificia Universidad Javeriana, Bogotá, Colombia.

Lysosomal storage diseases (LSDs) are caused by accumulation of partially degraded substrates within the lysosome, as a result of a function loss of a lysosomal protein. Recombinant lysosomal proteins are usually produced in mammalian cells, based on their capacity to carry out post-translational modifications similar to those observed in human native proteins. However, during the last years, a growing number of studies have shown the possibility to produce active forms of lysosomal proteins in other expression systems, such as plants and microorganisms. In this paper, we review the production and characterization of human lysosomal proteins, deficient in several LSDs, which have been produced in microorganisms. For this purpose, Escherichia coli, Saccharomyces cerevisiae, Pichia pastoris, Yarrowia lipolytica, and Ogataea minuta have been used as expression systems. The recombinant lysosomal proteins expressed in these hosts have shown similar substrate specificities, and temperature and pH stability profiles to those produced in mammalian cells. In addition, pre-clinical results have shown that recombinant lysosomal enzymes produced in microorganisms can be taken-up by cells and reduce the substrate accumulated within the lysosome. Recently, metabolic engineering in yeasts has allowed the production of lysosomal enzymes with tailored N-glycosylations, while progresses in E. coli N-glycosylations offer a potential platform to improve the production of these recombinant lysosomal enzymes. In summary, microorganisms represent convenient platform for the production of recombinant lysosomal proteins for biochemical and physicochemical characterization, as well as for the development of ERT for LSD.
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http://dx.doi.org/10.1016/j.ymgme.2015.06.001DOI Listing
July 2016