Mauricio Arias - Academia.edu (original) (raw)

Papers by Mauricio Arias

Biochimica et Biophysica Acta (BBA) - Biomembranes, 2015

Tritrpticin is an antimicrobial peptide with a strong microbicidal activity against Gram-positive... more Tritrpticin is an antimicrobial peptide with a strong microbicidal activity against Gram-positive and Gram-negative bacteria as well as fungi. The 13-residue peptide is essentially symmetrical and possesses a unique cluster of three Trp residues near the center of its amino acid sequence. The mechanism of action of tritrpticin is believed to involve permeabilization of the cytoplasmic membrane of susceptible bacteria. However it has been suggested that intracellular targets may also play a role in its antimicrobial activity. In this work the mechanism of action of several tritrpticin derivatives was studied through substitution of the three Trp residues with 5-hydroxy-tryptophan (5OHW), a naturally occurring non-ribosomal amino acid. Although it is more polar, 5OHW preserves many of the biophysical and biochemical properties of Trp, allowing the use of fluorescence spectroscopy and NMR techniques to study the interaction of the modified peptides with membrane mimetics. Single or triple 5OHW substitution did not have a large effect on the MIC of the parent peptide against Escherichia coli and Bacillus subtilis. However, the mechanism of action was altered by simultaneously replacing all three Trp with 5OHW. Our results suggest that the inner membrane of Gram-negative bacteria did not constitute the main target of this particular tritrpticin derivative. Since the addition of a hydroxyl group to the indole motif of the Trp residue was able to modify the mechanism of action of the peptides, our data confirm the importance of the Trp cluster in tritrpticin. This work also shows that 5OHW constitutes a new probe to modulate the antimicrobial activity and mechanism of action of other Trp-rich antimicrobial peptides.

BioMetals, 2014

Lactoferrin (LF) is an important antimicrobial and immune regulatory protein present in neutrophi... more Lactoferrin (LF) is an important antimicrobial and immune regulatory protein present in neutrophils and most exocrine secretions of mammals. The antimicrobial activity of LF has been related to the presence of an antimicrobial peptide sequence, called lactoferricin (LFcin), located in the N-terminal region of the protein. The antimicrobial activity of bovine LFcin is considerably stronger than the human version. In this work, chimera peptides combining segments of bovine and human LFcin were generated in order to study their antimicrobial activity and mechanism of action. In addition, the relevance of the conserved disulfide bridge and the resulting cyclic structure of both LFcins were analyzed by using ''click chemistry'' and sortase A-catalyzed cyclization of the peptides. The N-terminal region of bovine LFcin (residues 17-25 of bovine LF) proved to be very important for the antimicrobial activity of the chimera peptides against E. coli, when combined with the C-terminal region of human LFcin. Similarly the cyclic bovine LFcin analogs generated by ''click chemistry'' and sortase A preserved the antimicrobial activity of the original peptide, showing the significance of these two techniques in the design of cyclic antimicrobial peptides. The mechanism of action of bovine LFcin and its active derived peptides was strongly correlated with membrane leakage in E. coli and up to some extent with the ability to induce vesicle aggregation. This mechanism was also preserved under conditions of high ionic strength (150 mM NaCl) illustrating the importance of these peptides in a more physiologically relevant system.

Antimicrobial Peptides and Innate Immunity, 2012

The chemokines are a group of small chemotactic cytokines that play an important role in the inna... more The chemokines are a group of small chemotactic cytokines that play an important role in the innate and adaptive immune system. Their main function is related to the recruitment of white blood cells to sites of infection. They bind to specific chemokine receptors, which subsequently triggers signaling pathways in the leukocytes. Recently the discovery of chemokines that possess a direct antimicrobial activity against a broad range of pathogenic bacteria has generated increased interest in the role of these proteins in the innate immune system. Prior studies regarding ligand and receptor binding have already established the structural elements important for chemokine interaction and activation of their receptors. In the same manner, it is important to study the structural features required for the antimicrobial activity of this group of chemokines in order to establish key elements related with this new activity. This review will focus on the structure-function relationships that appear to be related to the direct antimicrobial activity of the chemokines. A close similarity of the C-terminal domain of many chemokines to cationic a-helical antimicrobial peptides suggests that this C-terminal helical region is responsible for the chemokine antimicrobial activity. However, for several chemokines, the antimicrobial activity resides in other parts of the protein, indicating that each chemokine needs to be examined individually. We also discuss the role of dimerization and of linearization of chemokines in their antimicrobial activity.

Antibiotics, 2014

Antimicrobial peptides (AMPs) constitute promising candidates for the development of new antibiot... more Antimicrobial peptides (AMPs) constitute promising candidates for the development of new antibiotics. Among the ever-expanding family of AMPs, tritrpticin has strong antimicrobial activity against a broad range of pathogens. This 13-residue peptide has an unusual amino acid sequence that is almost symmetrical and features three central Trp residues with two Arg residues near each end of the peptide. In this work, the role of the three sequential Trp residues in tritrpticin was studied in a systematic fashion by making a series of synthetic peptides with single-, double-and triple-Trp substitutions to Tyr or Ala. 1 H NMR and fluorescence spectroscopy demonstrated the ability of all of the tritrpticin-analog peptides to interact with negatively-charged membranes. Consequently, most tritrpticin analogs exhibited the ability to permeabilize synthetic ePC:ePG (egg-yolk phosphatidylcholine (ePC), egg-yolk phosphatidylglycerol (ePG)) vesicles and live Escherichia coli bacteria. The membrane perturbation characteristics were highly dependent on the location of the Trp residue substitution, with Trp6 being the most important residue and Trp8 the least. The membrane permeabilization activity of the peptides in synthetic and biological membranes was directly correlated with the antimicrobial potency of the peptides

Biochimica et Biophysica Acta (BBA) - Biomembranes, 2010

Plasma membrane permeabilization by saponin and anticancer avicins was studied using light disper... more Plasma membrane permeabilization by saponin and anticancer avicins was studied using light dispersion measurements, since high correlation between light dispersion changes and hemolysis has been demonstrated. Nevertheless, we observed that rat red blood cell swelling in moderately hypotonic media was accompanied by up to 20% decrease of light dispersion, when hemolysis was not yet detectable. Avicin G and avicin D were significantly more efficient than saponin in inducing cytotoxicity in PC3 human prostate cancer cells. We found that the preincubation of avicins with the plasma membrane, but not with the cytosolic fraction of previously lysed red blood cells, completely protected fresh cells against permeabilization. The data suggest that the plasma membrane can tightly bind the avicins, but not the saponin. Using the "osmotic protection" method with 100 mOsm PEGs of increasing molecular weight in isotonic media, the size of the pores generated by avicin G and avicin D in the plasma membrane was estimated to be higher than the hydrodynamic radius of PEG-8000. The obtained results indicate that the anticancer activity of avicin G and avicin D could be related, at least partially, to their high ability to permeabilize biological membranes. These data might represent interest for possible applications of these anticancer drugs in vivo.

Tuberculosis, 2007

Macrophages play an important role during Mycobacterium tuberculosis (MTB) infection. In humans m... more Macrophages play an important role during Mycobacterium tuberculosis (MTB) infection. In humans most of the studies on MTB-macrophage interactions have been performed using circulating monocytes and monocyte-derived macrophages. However, little research has been performed on this interaction using tissue macrophages. Herein, we used human splenic macrophages to characterize particular responses to MTB infection. Based on morphological, biochemical, and immunological markers, splenic adherent cells exhibit characteristics of tissue macrophages. They were able to efficiently phagocytose both live and heat-killed (h-k) MTB H37Rv. Upon infection with live, but not h-k MTB, an increase in secreted TNF-a was elicited. Splenic macrophages produced high basal levels of IL-10; however, infection with live or h-k MTB resulted in decrease IL-10 secretion. Both IL-12p40 and IL-12p70 basal levels were also decreased upon infection with live or h-k MTB; however, while the reduction for IL-12p40 levels was observed at earlier time points (4 h) for both live and h-k MTB, infection with live MTB, but not h-k MTB, resulted in a timedependent secretion of IL-12p40 at 24 and 48 h after infection. IL-12p70 levels were completely reduced upon infection by either live or h-k MTB. These results support that human splenic macrophages may represent a potential useful model to study MTBmacrophage interactions in vitro.

PLoS ONE, 2013

The Tonle Sap Lake in Cambodia is a dynamic flood-pulsed ecosystem that annually increases its su... more The Tonle Sap Lake in Cambodia is a dynamic flood-pulsed ecosystem that annually increases its surface area from roughly 2,500 km 2 to over 12,500 km 2 driven by seasonal flooding from the Mekong River. This flooding is thought to structure many of the critical ecological processes, including aquatic primary and secondary productivity. The lake also has a large fishery that supports the livelihoods of nearly 2 million people. We used a state-space oxygen mass balance model and continuous dissolved oxygen measurements from four locations to provide the first estimates of gross primary productivity (GPP) and ecosystem respiration (ER) for the Tonle Sap. GPP averaged 4.162.3 g O 2 m 23 d 21 with minimal differences among sites. There was a negative correlation between monthly GPP and lake level (r = 0.45) and positive correlation with turbidity (r = 0.65). ER averaged 24.9620.0 g O 2 m 23 d 21 but had greater than six-fold variation among sites and minimal seasonal change. Repeated hypoxia was observed at most sampling sites along with persistent net heterotrophy (GPP,ER), indicating significant bacterial metabolism of organic matter that is likely incorporated into the larger food web. Using our measurements of GPP, we calibrated a hydrodynamic-productivity model and predicted aquatic net primary production (aNPP) of 2.060.2 g C m 22 d 21 (2.460.2 million tonnes C y 21 ). Considering a range of plausible values for the total fisheries catch, we estimate that fisheries harvest is an equivalent of 7-69% of total aNPP, which is substantially larger than global average for marine and freshwater systems. This is likely due to relatively efficient carbon transfer through the food web and support of fish production from terrestrial NPP. These analyses are an important first-step in quantifying the resource pathways that support this important ecosystem.

The Journal of Infectious Diseases, 1999

In a population-based case-control study, 182 human immunodeficiency virus (HIV)-positive persons... more In a population-based case-control study, 182 human immunodeficiency virus (HIV)-positive persons and 135 healthy control subjects were enrolled from the metropolitan area of Medellin, Colombia. Four genotypes of the natural resistance-associated macrophage protein l (NRAMP1) gene (5 GT repeat, 274C/T, 469+14G/T, and 823C/T) were associated with altered risk of HIV infection ( , .015, .020, and .035, respectively). Three of these P = .013 markers (5 [GT] n , 274C/T, 469+14G/T) are in strong linkage disequilibrium, and genotypes of these markers are associated with reduced risk of HIV infection with relative risks (RRs) of 0.35 (95% confidence interval [CI], 0.14-0.91), 0.31 (CI, 0.10-0.93), and 0.24 (CI, 0.08-0.72), respectively. Conversely, heterozygosity at the fourth independent marker (823C/T) was associated with increased risk of HIV infection (RR, 2.29; CI, 1.06-4.92). These findings suggest that NRAMP1 modifies risk of HIV infection.

Journal of Environmental Management, 2012

The economic value of the Tonle Sap Lake Floodplain to Cambodia is arguably among the highest pro... more The economic value of the Tonle Sap Lake Floodplain to Cambodia is arguably among the highest provided to a nation by a single ecosystem around the world. Nonetheless, the Mekong River Basin is changing rapidly due to accelerating water infrastructure development (hydropower, irrigation, flood control, and water supply) and climate change, bringing considerable modifications to the flood pulse of the Tonle Sap Lake in the foreseeable future. This paper presents research conducted to determine how the historical flooding regime, together with human action, influenced landscape patterns of habitats in the Tonle Sap Lake, and how these habitats might shift as a result of hydrological changes. Maps of water depth, annual flood duration, and flood frequency were created for recent historical hydrological conditions and for simulated future scenarios of water infrastructure development and climate change. Relationships were then established between the historical flood maps and land cover, and these were subsequently applied to assess potential changes to habitat cover in future decades. Five habitat groups were clearly distinguishable based on flood regime, physiognomic patterns, and human activity: (1) Open water, flooded for 12 months in an average hydrological year; (2) Gallery forest, with flood duration of 9 months annually; (3) Seasonally flooded habitats, flooded 5e8 months and dominated by shrublands and grasslands; (4) transitional habitats, flooded 1e5 months and dominated by abandoned agricultural fields, receding rice/floating rice, and lowland grasslands; and (5) Rainfed habitats, flooded up to 1 month and consisting mainly of wet season rice fields and village crops. It was found that water infrastructure development could increase the area of open water (þ18 to þ21%) and the area of rainfed habitats (þ10 to þ14%), while reducing the area covered with seasonally flooded habitats (À13 to À22%) and gallery forest (À75 to À83%). Habitat cover shifts as a result of climate change include a net increase of open water (2e21%), as well as a reduction of rainfed habitats by 2e5% and seasonally flooded habitats by 5e11%. Findings from this study will help guide on-going and future conservation and restoration efforts throughout this unique and critical ecosystem.

Environmental Conservation, 2014

The Tonle Sap is the largest wetland in Southeast Asia and the heart of the largest inland fisher... more The Tonle Sap is the largest wetland in Southeast Asia and the heart of the largest inland fishery in the world. Its unique flood pulse system and annual flow reversal is a hotspot for biodiversity and productivity, as well as an essential habitat for many endangered fishes and birds. Despite predicted changes to the wetland's hydrology due to climate change and hydropower development in the Mekong, the consequent impacts on the fauna of the lake are poorly understood. A spatial modelling framework was developed to simulate the impact of potential scenarios of change using relationships between fauna and biophysical characteristics. Potential impacts on 61 animal species with documented nutritional, conservation or ecological value were examined. A large number of species rely on gallery forest to provide important habitats for their life history, yet this area is likely to be highly impacted by permanent inundation. There is a strong synchronicity between life histories and the flood pulse; consequently continued hydrological disruptions will have a significant impact on ecosystem dynamics, imposing further challenges to conservation. Protecting areas that may become suitable for gallery forests and shrublands under a modified flood regime will be crucial to management planning and the maintenance of a diverse and healthy ecosystem.

Environmental Conservation, 2011

The operation and longevity of hydropower dams are often negatively impacted by sedimentation. Fo... more The operation and longevity of hydropower dams are often negatively impacted by sedimentation. Forest conservation can reduce soil erosion, and therefore efforts to maintain upstream forest cover within a watershed contribute to the economic life span of a hydropower facility. The cost of forest conservation can be viewed as an investment in hydropower and be financed via a payment for ecosystem services (PES) scheme. A novel modelling framework is used to estimate payments for forest conservation consisting of: (1) land-use change projection; (2) watershed erosion modelling; (3) reservoir sedimentation estimation; (4) power generation loss calculation; and (5) PES scheme design. The framework was applied to a proposed dam in Cambodia (Pursat 1). The estimated net present value of forest conservation was US$ 4.7 million when using average annual climate values over 100 years, or US$ 6.4 million when considering droughts every eight years. This can be remunerated with annual payments of US$ 4.26 ha −1 or US$ 5.78 ha −1 , respectively, covering forest protection costs estimated at US$ 0.9 ha −1 yr −1 . The application of this type of PES represents a rational option that allows for conservation and development of hydropower watersheds susceptible to erosion and sedimentation.

RNA, 2014

Pre-mRNA molecules in humans contain mostly short internal exons flanked by longer introns. To ex... more Pre-mRNA molecules in humans contain mostly short internal exons flanked by longer introns. To explain the removal of such introns, exon recognition instead of intron recognition has been proposed. We studied this exon definition using designer exons (DEs) made up of three prototype modules of our own design: an exonic splicing enhancer (ESE), an exonic splicing silencer (ESS), and a Reference Sequence (R) predicted to be neither. Each DE was examined as the central exon in a three-exon minigene. DEs made of R modules showed a sharp size dependence, with exons shorter than 14 nt and longer than 174 nt splicing poorly. Changing the strengths of the splice sites improved longer exon splicing but worsened shorter exon splicing, effectively displacing the curve to the right. For the ESE we found, unexpectedly, that its enhancement efficiency was independent of its position within the exon. For the ESS we found a step-wise positional increase in its effects; it was most effective at the 3 ′ end of the exon. To apply these results quantitatively, we developed a biophysical model for exon definition of internal exons undergoing cotranscriptional splicing. This model features commitment to inclusion before the downstream exon is synthesized and competition between skipping and inclusion fates afterward. Collision of both exon ends to form an exon definition complex was incorporated to account for the effect of size; ESE/ESS effects were modeled on the basis of stabilization/destabilization. This model accurately predicted the outcome of independent experiments on more complex DEs that combined ESEs and ESSs.

Revista de geografía Norte Grande, 2010

Las políticas de Estado junto con la importante oferta/demanda de productos inmobiliarios para po... more Las políticas de Estado junto con la importante oferta/demanda de productos inmobiliarios para población de mayor ingreso han orientado el desarrollo reciente de varias ciudades chilenas, originando nuevas formas urbanas. Si bien estos procesos han sido descritos y analizados para varias ciudades y áreas metropolitanas de Chile central, no existen suficientes antecedentes empíricos que den cuenta de la realidad del desarrollo urbano de las ciudades más australes del país, como el caso de Coyhaique en la Patagonia chilena. Este trabajo pretende identificar y analizar los patrones de urbanización de esta ciudad, en un contexto territorial caracterizado, entre otros aspectos, por la fragmentación geográfica, el aislamiento, dispersión de los centros poblados y concentración de la población en la capital regional. Se analiza la evolución y factores explicativos que dan cuenta de su rápido proceso de urbanización y, sobre la base de documentos técnicos, históricos y geográficos, se presentan estimaciones futuras del crecimiento de la ciudad.

Nature Biotechnology, 2010

Mauricio A. Arias, Shengdong Ke, Lawrence A. Chasin. Nature Biotechnology, Vol. 28, No. 7. (01 Ju... more Mauricio A. Arias, Shengdong Ke, Lawrence A. Chasin. Nature Biotechnology, Vol. 28, No. 7. (01 July 2010), pp. 686-687. A comprehensive study identifies sequence features that predict tissue-specific alternative splicing. The rules governing exon splicing in different cell types to ...

Expert Review of Respiratory Medicine, 2009

Drug treatment is the key strategy in TB control. However, the treatment course lasts 6-9 months ... more Drug treatment is the key strategy in TB control. However, the treatment course lasts 6-9 months because the current anti-TB drugs are poorly effective against nondividing (i.e., persistent) bacilli. As a result, completion rates are unsatisfactory, leading to emergence and spread of multidrug-resistant infection. It would, therefore, be very desirable to design a form of complementary treatment that could speed up the recovery process for people afflicted with TB and reduce the relapse rates. With the advancement of our understanding of the immunopathogenesis of TB, it has become increasingly possible to develop novel adjunctive immunotherapies for both drug-susceptible and drug-resistant TB. Notably, cytokines probably offer the most promising prospect of such a therapy being introduced in routine clinical practice. However, in many ways, the cytokine therapy of TB has reached a crossroad, since, although the initial promise failed to live up to expectations, sufficient encouraging evidence exists to warrant further exploration. There are clear arguments in favor as well as against such treatments. This review aims to provide a rationale for cytokine treatment of TB, to describe the current status of several cytokines that have been considered for that purpose and, ultimately, to make a case for the need for further clinical trials.

Vaccine, 2011

Induction of humoral responses to HIV at mucosal compartments without inflammation is important f... more Induction of humoral responses to HIV at mucosal compartments without inflammation is important for vaccine design. We developed charged wax nanoparticles that efficiently adsorb protein antigens and are internalized by DC in the absence of inflammation. HIV-gp140-adsorbed nanoparticles induced stronger in vitro T-cell proliferation responses than antigen alone. Such responses were greatly enhanced when antigen was co-adsorbed with TLR ligands. Immunogenicity studies in mice showed that intradermal vaccination with HIV-gp140 antigen-adsorbed nanoparticles induced high levels of specific IgG. Importantly, intranasal immunization with HIV-gp140-adsorbed nanoparticles greatly enhanced serum and vaginal IgG and IgA responses. Our results show that HIV-gp140-carrying wax nanoparticles can induce strong cellular/humoral immune responses without inflammation and may be of potential use as effective mucosal adjuvants for HIV vaccine candidates.

Journal of Infectious Diseases - J INFEC DIS, 1997

Financial support: COLCIENCIAS (1115-05-024-92), Santafé de Bogotá, Colombia. row-derived macroph... more Financial support: COLCIENCIAS (1115-05-024-92), Santafé de Bogotá, Colombia. row-derived macrophage lines [21] obtained from mice resistant

PLoS ONE, 2012

Successful vaccine development against HIV will likely require the induction of strong, long-last... more Successful vaccine development against HIV will likely require the induction of strong, long-lasting humoral and cellular immune responses in both the systemic and mucosal compartments. Based on the known immunological linkage between the upper-respiratory and urogenital tracts, we explored the potential of nasal adjuvants to boost immunization for the induction of vaginal and systemic immune responses to gp140. Mice were immunized intranasally with HIV gp140 together with micellar and emulsion formulations of a synthetic TLR4 agonist, Glucopyranosyl Lipid Adjuvant (GLA) and responses were compared to R848, a TLR7/8 agonist, or chitosan, a non TLR adjuvant. GLA and chitosan but not R848 greatly enhanced serum immunoglobulin levels when compared to antigen alone. Both GLA and chitosan induced high IgG and IgA titers in nasal and vaginal lavage and feces. The high IgA and IgG titers in vaginal lavage were associated with high numbers of gp140-specific antibody secreting cells in the genital tract. Whilst both GLA and chitosan induced T cell responses to immunization, GLA induced a stronger Th17 response and chitosan induced a more Th2 skewed response. Our results show that GLA is a highly potent intranasal adjuvant greatly enhancing humoral and cellular immune responses, both systemically and mucosally.

Microbes and Infection, 2006

Alterations of monocyte/macrophages have been reported in patients with tuberculosis (TB), but th... more Alterations of monocyte/macrophages have been reported in patients with tuberculosis (TB), but their significance is poorly understood. Blood mononuclear cells from patients with different clinical forms of TB, at various times of anti-TB treatment, and healthy tuberculin positive individuals, were double-stained for CD14 plus CD206, TLR-2, IFN-gR1, CD40, HLA-DR, CD36 and CD163, and analyzed by flow cytometry. Monocytes were infected with Mycobacterium tuberculosis H37Rv and 24 h later the phenotype, induction of necrosis and apoptosis and production of tumor necrosis factor TNFa, interleukin (IL)-10 and IL-12p40 were determined. TB patients presented higher percentage of CD14 þ cells but lower percentage of CD14 þ DR þ and CD14 þ CD36 þ cells. Expression of CD14, HLA-DR and CD36 was decreased in TB patients. Normal percentages and expression were restored during anti-TB treatment. Monocytes from TB patients underwent necrosis and apoptosis after M. tuberculosis infection, whereas monocytes from healthy controls exhibited only apoptosis. Anti-TB treatment reverted necrosis. There were no differences between the various clinical forms of TB. In vitro M. tuberculosis infection decreased expression of the membrane molecules studied. HLA-DR and CD36 inhibition correlated with induction of apoptosis. Restoration of monocyte alterations during anti-TB treatment suggests that such alterations may be caused by the high M. tuberculosis load present during active disease.

Inflammation & Allergy-Drug Targets, 2009

TNF-� is an essential component of the innate defence mechanism of the host against pathogenic ch... more TNF-� is an essential component of the innate defence mechanism of the host against pathogenic challenge. Unfortunately, it can also play a major role in the pathology of certain diseases, such as tuberculosis. This disease is a striking example of the role of TNF-￻ as a 'double-edged sword', because apart from its role in controlling the Mycobac- terium tuberculosis infection, it can also cause severe tissue damage. TNF-￻ exhibits a very complex network of interac- tions and many of its activities are still not fully understood. This report aims to review the pivotal role of TNF-� in con- trolling the mycobacterial infection, with a particular emphasis on its influence on chemokine expression and cell move- ment during granuloma formation, and the issues surrounding the use of TNF-� inhibitors for therapeutic use in inflamma- tory diseases.