Understanding immunopathology of severe dengue: lessons learnt from sepsis

Endothelial dysfunction leading to vascular permeability and plasma leakage are characteristic features of severe dengue and sepsis. However, the mechanisms underlying these immune-pathologies remain unclear. The risk of severe dengue and sepsis development depend on patient-related and pathogen-related factors. Additionally, comorbidities increase the risk of severe disease and their incidence hampers correct diagnosis and treatments. To date, there is no efficient therapy to combat severe dengue and sepsis. Here, we discuss the differences and similarities between the pathogenesis of severe dengue and that of bacterial sepsis. We identify gaps in knowledge that need to be better understood in order to move towards the rational development and/or usage of therapeutic strategies to ameliorate severe dengue disease

Sulphated polysaccharides from Ulva clathrata and Cladosiphon okamuranus seaweeds both inhibit viral attachment/entry and cell-cell fusion, in NDV infection

Sulphated polysaccharides (SP) extracted from seaweeds have antiviral properties and are much less cytotoxic than conventional drugs, but little is known about their mode of action. Combination antiviral chemotherapy may offer advantages over single agent therapy, increasing efficiency, potency and delaying the emergence of resistant virus. The paramyxoviridae family includes pathogens causing morbidity and mortality worldwide in humans and animals, such as the Newcastle Disease Virus (NDV) in poultry. This study aims at determining the antiviral activity and mechanism of action in vitro of an ulvan (SP from the green seaweed Ulva clathrata), and of its mixture with a fucoidan (SP from Cladosiphon okamuranus), against La Sota NDV strain. The ulvan antiviral activity was tested using syncytia formation, exhibiting an IC50 of 0.1 μg/mL; ulvan had a better anti cell-cell spread effect than that previously shown for fucoidan, and inhibited cell-cell fusion via a direct effect on the F0 protein, but did not show any virucidal effect. The mixture of ulvan and fucoidan showed a greater anti-spread effect than SPs alone, but ulvan antagonizes the effect of fucoidan on the viral attachment/entry. Both SPs may be promising antivirals against paramyxovirus infection but their mixture has no clear synergistic advantag

Sensing dengue and chikungunya virus (co-) infections

Dengue and chikungunya are two of the most important diseases transmitted by mosquitos. Over the past decades their global burden has increased dramatically. Furthermore, due to the geographic overlap of both viruses as well as their common mosquito vectors, the incidence of dengue and chikungunya co-infections is also increasing. The clinical manifestations of the acute phase of dengue and chikungunya virus induced disease are very similar making their diagnosis a real challenge. In this thesis, we investigated the role of monocytes, a cell type within the immune system that protects and combats infectious diseases. Our work shows that monocytes can sense dengue and chikungunya viruses resulting in the production of inflammatory mediators that may contribute to disease burden. By analyzing blood samples from dengue virus infected children, we discovered a role for toll-like receptor (TLR2) as a sensor of DENV infection and identified a prognostic value of its expression in a subset of monocytes known as classical monocytes. We found that TLR2 on monocytes is also able to detect fully immature dengue particles. In addition, our studies described the effect of dengue and chikungunya virus co-infections in vitro in primary human primary cells. However, there are still knowledge gaps of these diseases that need to be further investigated in order to understand the role of monocytes in the immunopathology of these diseases. The use of high-dimensional molecular biology techniques will be crucial to address these gaps and help us to develop new therapies to combat dengue and chikungunya virus infections

Identification and in silico structural and functional analysis of a trypsin-like protease from shrimp Macrobrachium carcinus

Macrobrachium carcinus (Linnaeus, 1758) is a species of freshwater shrimp widely distributed from Florida southwards to southern Brazil, including southeast of Mexico. In the present work, we identified a putative trypsin-like protease cDNA fragment of 736 nucleotides from M. carcinus hepatopancreas tissue by the 3′RACE technique and compared the deduced amino acid sequence to other trypsin-related proteases to describe its structure and function relationship. The bioinformatics analyses showed that the deduced amino acid sequence likely corresponds to a trypsin-like protease closely related to brachyurins, which comprise a subset of serine proteases with collagenolytic activity found in crabs and other crustacea. The M. carcinus trypsin-like protease sequence showed a global sequence identity of 94% with an unpublished trypsin from Macrobrachium rosenbergii (GenBank accession no. AMQ98968), and only 57% with Penaeus vannamei trypsin (GenBank accession no. CAA60129). A detailed analysis of the amino acid sequence revealed specific differences with crustacean trypsins, such as the sequence motif at the beginning of the mature protein, activation mechanism of the corresponding zymogen, amino acid residues of the catalytic triad and residues responsible for substrate specificity

TLR2 axis on peripheral blood mononuclear cells regulates inflammatory responses to non-infectious immature dengue virus particles

Severe dengue virus (DENV) infection is characterized by exacerbated inflammatory responses that lead to endothelial dysfunction and plasma leakage. We have recently demonstrated that Toll-like receptor 2 (TLR2) on blood monocytes senses DENV infection leading to endothelial activation. Here, we report that non-infectious immature DENV particles, which are released in large numbers by DENV-infected cells, drive endothelial activation via the TLR2 axis. We show that fully immature DENV particles induce a rapid, within 6 hours post-infection, inflammatory response in PBMCs. Furthermore, pharmacological blocking of TLR2/TLR6/CD14 and/or NF-kB prior to exposure of PBMCs to immature DENV reduces the initial production of inter alia TNF-α and IL-1β by monocytes and prevents endothelial activation. However, prolonged TLR2 block induces TNF-α production and leads to exacerbated endothelial activation, indicating that TLR2-mediated responses play an important role not only in the initiation but also the resolution of inflammation. Altogether, these data indicate that the maturation status of the virus has the potential to influence the kinetics and extent of inflammatory responses during DENV infection

Precios unitarios y elaboración de las propuestas técnica y económica para licitación de obra pública, con aplicación de software, en un estudio de caso.

A través de la historia el ser humano se ha preocupado por satisfacer sus necesidades básicas, además de extender sus dominios consiguiendo poder obtener una forma de lograrlo, sin lugar a dudas es el de contar con bienes materiales y económicos, los cuales están estrechamente relacionados con la moneda como forma de pago, aunque al principio de los tiempos esto se realizaba por medio de trueques de mercancías o productos, luego, con la aparición del dinero, los cambios se facilitaron ya que se pagaba realmente por el valor de un bien. De manera que el tiempo ha ido transcurriendo se han generado nuevas formas de pago desde la moneda hecha de metal, hasta la aparición de dinero electrónico. Además de que todas las áreas de estudio están influenciadas por este factor (dinero). Y cuando hablamos del dinero a cambio de alguna mercancía o producto es inevitable caer en el término “Precio” y la rama de la ingeniería civil no está exenta de esta problemática ya que el creciente desarrollo de los países ha generado mayor demanda de construcciones en cada uno de ellos. La presente investigación de tesis, corresponde a: “Precios unitarios y elaboración de las propuestas técnica y económica para licitación de obra pública”. Es indispensable para un Ingeniero Civil comprender que La licitación Públicaes un procedimiento administrativo de preparación de la voluntad contractual, por el que un ente público en ejercicio de la función administrativa invita a los interesados para que, sujetándose al pliego de condiciones (Bases de la licitación), formulen propuestas (Técnica y Económica) de entre las cuales seleccionará la más conveniente (Adjudicación). Cuando es necesario contratar obra pública, existen leyes que obligan a los entes gubernamentales a seguir un proceso legalmente definido por el derecho administrativo. En México, el Artículo 134 Constitucional determina como el gobierno debe realizar las adquisiciones y contratación de obra pública; de esa Ley se deriva la Ley de Adquisiciones, Arrendamiento y Servicios del Sector Público y Ley de Obras Públicas y Servicios relacionados con las mismas

Clinical characterization of data-driven diabetes subgroups in Mexicans using a reproducible machine learning approach

Introduction Previous reports in European populations demonstrated the existence of five data-driven adult-onset diabetes subgroups. Here, we use self-normalizing neural networks (SNNN) to improve reproducibility of these data-driven diabetes subgroups in Mexican cohorts to extend its application to more diverse settings.Research design and methods We trained SNNN and compared it with k-means clustering to classify diabetes subgroups in a multiethnic and representative population-based National Health and Nutrition Examination Survey (NHANES) datasets with all available measures (training sample: NHANES-III, n=1132; validation sample: NHANES 1999–2006, n=626). SNNN models were then applied to four Mexican cohorts (SIGMA-UIEM, n=1521; Metabolic Syndrome cohort, n=6144; ENSANUT 2016, n=614 and CAIPaDi, n=1608) to characterize diabetes subgroups in Mexicans according to treatment response, risk for chronic complications and risk factors for the incidence of each subgroup.Results SNNN yielded four reproducible clinical profiles (obesity related, insulin deficient, insulin resistant, age related) in NHANES and Mexican cohorts even without C-peptide measurements. We observed in a population-based survey a high prevalence of the insulin-deficient form (41.25%, 95% CI 41.02% to 41.48%), followed by obesity-related (33.60%, 95% CI 33.40% to 33.79%), age-related (14.72%, 95% CI 14.63% to 14.82%) and severe insulin-resistant groups. A significant association was found between the SLC16A11 diabetes risk variant and the obesity-related subgroup (OR 1.42, 95% CI 1.10 to 1.83, p=0.008). Among incident cases, we observed a greater incidence of mild obesity-related diabetes (n=149, 45.0%). In a diabetes outpatient clinic cohort, we observed increased 1-year risk (HR 1.59, 95% CI 1.01 to 2.51) and 2-year risk (HR 1.94, 95% CI 1.13 to 3.31) for incident retinopathy in the insulin-deficient group and decreased 2-year diabetic retinopathy risk for the obesity-related subgroup (HR 0.49, 95% CI 0.27 to 0.89).Conclusions Diabetes subgroup phenotypes are reproducible using SNNN; our algorithm is available as web-based tool. Application of these models allowed for better characterization of diabetes subgroups and risk factors in Mexicans that could have clinical applications

Compilación de Proyectos de Investigacion de 1984-2002

Instituto Politecnico Nacional. UPIICS