A network-based approach for predicting key enzymes explaining metabolite abundance alterations in a disease phenotype

<p>Background The study of metabolism has attracted much attention during the last years due to its relevance in various diseases. The advance in metabolomics platforms allows us to detect an increasing number of metabolites in abnormal high/low concentration in a disease phenotype. Finding a mechanistic interpretation for these alterations is important to understand pathophysiological processes, however it is not an easy task. The availability of genome scale metabolic networks and Systems Biology techniques open new avenues to address this question.</p> <p>Results In this article we present a novel mathematical framework to find enzymes whose malfunction explains the accumulation/depletion of a given metabolite in a disease phenotype. Our approach is based on a recently introduced pathway concept termed Carbon Flux Paths (CFPs), which extends classical topological definition by including network stoichiometry. Using CFPs, we determine the Connectivity Curve of an altered metabolite, which allows us to quantify changes in its pathway structure when a certain enzyme is removed. The influence of enzyme removal is then ranked and used to explain the accumulation/depletion of such metabolite. For illustration, we center our study in the accumulation of two metabolites (L-Cystine and Homocysteine) found in high concentration in the brain of patients with mental disorders. Our results were discussed based on literature and found a good agreement with previously reported mechanisms. In addition, we hypothesize a novel role of several enzymes for the accumulation of these metabolites, which opens new strategies to understand the metabolic processes underlying these diseases.</p> <p>Conclusions With personalized medicine on the horizon, metabolomic platforms are providing us with a vast amount of experimental data for a number of complex diseases. Our approach provides a novel apparatus to rationally investigate and understand metabolite alterations under disease phenotypes. This work contributes to the development of Systems Medicine, whose objective is to answer clinical questions based on theoretical methods and high-throughput “omics” data.</p&gt

A Bayesian generalized random regression model for estimating heritability using overdispersed count data

Background: Faecal egg counts are a common indicator of nematode infection and since it is a heritable trait, it provides a marker for selective breeding. However, since resistance to disease changes as the adaptive immune system develops, quantifying temporal changes in heritability could help improve selective breeding programs. Faecal egg counts can be extremely skewed and difficult to handle statistically. Therefore, previous heritability analyses have log transformed faecal egg counts to estimate heritability on a latent scale. However, such transformations may not always be appropriate. In addition, analyses of faecal egg counts have typically used univariate rather than multivariate analyses such as random regression that are appropriate when traits are correlated. We present a method for estimating the heritability of untransformed faecal egg counts over the grazing season using random regression. Results: Replicating standard univariate analyses, we showed the dependence of heritability estimates on choice of transformation. Then, using a multitrait model, we exposed temporal correlations, highlighting the need for a random regression approach. Since random regression can sometimes involve the estimation of more parameters than observations or result in computationally intractable problems, we chose to investigate reduced rank random regression. Using standard software (WOMBAT), we discuss the estimation of variance components for log transformed data using both full and reduced rank analyses. Then, we modelled the untransformed data assuming it to be negative binomially distributed and used Metropolis Hastings to fit a generalized reduced rank random regression model with an additive genetic, permanent environmental and maternal effect. These three variance components explained more than 80 % of the total phenotypic variation, whereas the variance components for the log transformed data accounted for considerably less. The heritability, on a link scale, increased from around 0.25 at the beginning of the grazing season to around 0.4 at the end. Conclusions: Random regressions are a useful tool for quantifying sources of variation across time. Our MCMC (Markov chain Monte Carlo) algorithm provides a flexible approach to fitting random regression models to non-normal data. Here we applied the algorithm to negative binomially distributed faecal egg count data, but this method is readily applicable to other types of overdispersed data

Implementation of an extended ZINB model in the study of low levels of natural gastrointestinal nematode infections in adult sheep

Background: In this study, two traits related with resistance to gastrointestinal nematodes (GIN) were measured in 529 adult sheep: faecal egg count (FEC) and activity of immunoglobulin A in plasma (IgA). In dry years, FEC can be very low in semi-extensive systems, such as the one studied here, which makes identifying animals that are resistant or susceptible to infection a difficult task. A zero inflated negative binomial model (ZINB) model was used to calculate the extent of zero inflation for FEC; the model was extended to include information from the IgA responses. Results: In this dataset, 64 % of animals had zero FEC while the ZINB model suggested that 38 % of sheep had not been recently infected with GIN. Therefore 26 % of sheep were predicted to be infected animals with egg counts that were zero or below the detection limit and likely to be relatively resistant to nematode infection. IgA activities of all animals were then used to decide which of the sheep with zero egg counts had been exposed and which sheep had not been recently exposed. Animals with zero FEC and high IgA activity were considered resistant while animals with zero FEC and low IgA activity were considered as not recently infected. For the animals considered as exposed to the infection, the correlations among the studied traits were estimated, and the influence of these traits on the discrimination between unexposed and infected animals was assessed. Conclusions: The model presented here improved the detection of infected animals with zero FEC. The correlations calculated here will be useful in the development of a reliable index of GIN resistance that could be of assistance for the study of host resistance in studies based on natural infection, especially in adult sheep, and also the design of breeding programs aimed at increasing resistance to parasites

An explicit immunogenetic model of gastrointestinal nematode infection in sheep

Gastrointestinal nematodes are a global cause of disease and death in humans, wildlife and livestock. Livestock infection has historically been controlled with anthelmintic drugs, but the development of resistance means that alternative controls are needed. The most promising alternatives are vaccination, nutritional supplementation and selective breeding, all of which act by enhancing the immune response. Currently, control planning is hampered by reliance on the faecal egg count (FEC), which suffers from low accuracy and a nonlinear and indirect relationship with infection intensity and host immune responses. We address this gap by using extensive parasitological, immunological and genetic data on the sheep–Teladorsagia circumcincta interaction to create an immunologically explicit model of infection dynamics in a sheep flock that links host genetic variation with variation in the two key immune responses to predict the observed parasitological measures. Using our model, we show that the immune responses are highly heritable and by comparing selective breeding based on low FECs versus high plasma IgA responses, we show that the immune markers are a much improved measure of host resistance. In summary, we have created a model of host–parasite infections that explicitly captures the development of the adaptive immune response and show that by integrating genetic, immunological and parasitological understanding we can identify new immune-based markers for diagnosis and control

Quantification of host-parasite interactions: sheep and their nematodes

The objective of this dissertation is to use modelling and statistical approaches to expand our knowledge of the immune responses against gastrointestinal nematode infections, to assess the impact of nematode infection, and to use our improved knowledge to examine novel means of selective breeding in farm animals (sheep) as a control strategy. To expand the knowledge of the host immune response against infection, Chapter 2 of this dissertation focuses on immunoglobulin A (IgA), an antibody that binds nematode molecules, and its transfer through the body from the abomasal mucus (i.e. site of infection, where it is produced) to the blood plasma, where it is typically measured. These findings have been published in Parasitology (Prada Jimenez de Cisneros et al., 2014a). The implications of low levels of infection in adult milking ewes, which are more resistant than lambs, were also studied. A relationship is generated between infection levels using parasitological data and production data. There were however limitations in the dataset, which are discussed at the end of Chapter 3. Parasite resistance in adults sheep at low levels of infection was also studied, especially since the most common parasitological marker of disease is the faecal egg count (i.e. number of nematode eggs in the animals faeces) which is subject to substantial measurement error, among other limitations. Chapter 4 analyses a dataset of adult animals with low infection levels using a zero inflated binomial model (ZINB) and extends the model by including other evidence of parasite resistance to discriminate between exposed and unexposed animals. To examine selective breeding, an individual-based data-driven immunogenetically explicit mathematical model was developed. One application of this model is to compare the efficacy of two selective breeding schemes, each based on a different marker for disease, namely faecal egg counts and plasma IgA. This work has been published in Journal of the Royal Society Interface (Prada Jimenez de Cisneros et al., 2014b). The model can be extended to create a distribution for the variation in larval intake that best fits the field data. This allows the partitioning of the variation in adult worm burden into different components. The purpose is to quantify the contribution of the immune response and larval intake to determine which of the two accounts for more of the variation in the level of infection. The model can be also extended to explore selection schemes in the two components of the immune response (i.e. namely the IgA mediated and IgE mediated immune response) and estimate animal size at the end of the grazing season

Treatment of a Complex Distal Triceps Tendon Rupture With a New Technique: A Case Report

Introduction: The distal triceps tendon rupture is an uncommon injury. The acute treatment is well-defined, but when a delayed diagnosis is made or when a tendon retraction is present the alternatives or reconstruction are limited and sometimes complex. Case Presentation: In this case, we report on a 28-year-old man who presented with a chronic disruption of the distal triceps tendon with a gap of approximately 15 cm. The patient was diagnosed in another center with an inveterate breakage of the distal triceps tendon and was initially treated with an Achilles allograft that was complicated by a wound infection and required more than ten surgeries. Nearly 22 months after the initial trauma, and 12 months after the first surgery, we performed a reconstruction with an Achilles tendon allograft using the new technique of distal attachment. At the 12-month follow-up the patient presented a joint balance from -5º to 110º and presented with no pain. Conclusions: The use of an Achilles tendon allograft provides excellent results in complex distal triceps tendon ruptures. We report the use of a new technique to anchor a distal Achilles allograft

La lúdica del circo en las tradiciones coreográficas demosóficas de la cultura Embera en la vereda Kemberde

Las propuestas de investigación se resumen en 5 familias que fueron retornadas nuevamente al municipio de Pueblo Rico en el departamento de Risaralda, ya que fueron en su momento víctimas por conflicto armado (plan retorno con garantías de no repetición), de esta situación se plantea la estrategia de intervención psicosocial El circo, es una expresión artística que nace de la propia necesidad humana de buscar, de conocer y expresar, más allá de lo que la realidad cercana nos ofrece, en el cual está impregnado todo lo relacionado a los talentos, colores y tradiciones de las culturas que se intervienen de manera lúdica y pedagógica en la cual se enfoca en: Imaginario: las familias comparten su historia de vida, el apoyo emocional, el apoyo del grupo de pares e instancias del SNBF, derechos y deberes, la gratificación por pertenecer a esa comunidad, que en este caso sería el circo social de Kemberde. Influencia, la capacidad de inducir a otros a que actúen de cierta manera, así a través de la escucha, ya que su opinión es importante y debe pesar en las decisiones de la comunidad. Se espera que dentro de la propuesta de la comunidad en las siguientes fases de proyección y sensibilización se adquieran: La integración y satisfacción de sus tradiciones, refiriéndose a los beneficios que las familias recibirán al ser parte de la comunidad en términos de rango, talentos (coreográficos-demosóficos), habilidades, y la importancia de pertenecer a la comunidad.The investigation proposals are summarized in 5 families that were returned again to the municipality of Pueblo Rico in the department of Risaralda, since they were at the time victims of the armed conflict (return plan with guarantees of non-repetition), of this situation the psychosocial intervention strategy The circus is an artistic expression that arises from the human need to seek, to know and express, beyond what the near reality offers us, in which everything related to talents, colors is impregnated and traditions of the cultures that are intervened in a playful and pedagogical way in which it focuses on: Imaginary: families share their life history, emotional support, support from the peer group and SNBF bodies, rights and duties, the gratification for belonging to that community, which in this case would be the Kemberde social circus. Influence, the ability to induce others to act in a certain way, thus through listening, since their opinion is important and must weigh in the decisions of the community. It is expected that within the community proposal the following projection and awareness phases will be acquired: The integration and satisfaction of their traditions, referring to the benefits that families will receive from being part of the community in terms of rank, talents (choreographic-demosophics), abilities, and the importance of belonging to the community

Importance of nursing care in patients with breast cancer: a Narrative review

Objective: To demonstrate the importance of nursing care in patients with breast cancer.Materials and Methods: Narrative review of the literature, which analyzed 34 studies that were selected from 5 databases, taking into account the recommendations of the report Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) during the search strategy, keeping the Methodological rigor.Results: In addition to the descriptive aspects found in the 34 studies, two major categories were identified that allow to describe the importance of nursing care in patients with breast cancer. The categories are: Aspects valued by nurses and approach to nursing care.Conclussion: The importance of nursing care is evident through the humanized, dignified and palliative treatment that this type of patients requires. The literature continues to show the need for nursing care to be comprehensive and strengthened in the light of interdisciplinarity.

Differential expression and localization of transient receptor potential vanilloid 1 in rabbit and human eyes

Producción CientíficaSummary. Introduction: The superfamily of transient receptor potential (TRP) cation channels is involved in nociception. Members of this family, such as the vanilloid receptor type 1 (TRPV1) channel, are activated by a wide range of stimuli including heat (>43°C), low pH (<6.5), hypoxia, and hypertonicity. Here we report TRPV1 expression in rabbit and human eyes. Material and methods: We analyzed the expression of TRPV1 mRNA by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and protein by immunohistochemistry in eyes of New Zealand White rabbits and humans. Results: In rabbit and human eyes, TRPV1 protein was present in all layers of the corneal epithelium, but only in the basal layer of the conjunctiva. It was also in the ciliary and lens epithelia of both species as well as in the secretory cells of the rabbit lacrimal gland. The retinal pigment epithelium was positive for this protein in both species. TRPV1 was also present in rabbit Müller cells, where it had a similar pattern of expression to vimentin intermediate filaments. Analysis by qRT-PCR showed that TRPV1 mRNA was found in all of the structures where the protein was present. The highest level was in the lens and the lowest in the retina. Conclusion: TRPV1 is expressed in cells that are particularly active in Ca2+ exchange as well as in cells with significant water transport activity. Because TRPV1 is a Ca2+ channel, it probably functions in the regulation of both water and Ca2+ movements in ocular tissues

Plan comercial para una marca de ropa juvenil de los distritos de la zona 7 de Lima Metropolitana

En la presente investigación, se plantea un estudio de caso que busca conocer la situación actual de una empresa del sector retail de prendas de vestir, para luego proponer un plan comercial de relanzamiento de la marca que contribuya al crecimiento de sus ventas y a su sostenibilidad. Dicha marca tiene como grupo objetivo mujeres jóvenes de 14 a 19 años de los distritos de la zona 7 de Lima Metropolitana y del nivel socioeconómico A y B. En ese sentido, se desarrolla un análisis del entorno en el que se desenvuelve el caso de estudio para poder conocer la situación actual en la que se encuentra. Con el fin de obtener mayor información, se realizó un estudio de base exploratorio a través de un método cualitativo y cuantitativo. Luego de ello, se desarrolla el plan comercial a partir de la generación de una nueva propuesta de valor, la cual se guía de modelos de estrategias de marketing. La nueva propuesta de valor fue sometida a una investigación de mercado a través de los métodos cualitativo y cuantitativo. El primer método permitió recoger opiniones sobre la aceptación de la nueva propuesta de valor con los grupos de interés. Se consultó, además, a la gerencia de la empresa si es que esta nueva propuesta se alineaba a sus objetivos y disponibilidad presupuestal. El segundo permitió conocer el nivel de aceptación de la nueva propuesta de valor, la intención de compra y la disposición económica de las jóvenes frente a los precios del mercado. Ambos métodos posibilitaron la recopilación de información para la elaboración de la propuesta comercial. Finalmente, se presentan las conclusiones y recomendaciones del estudio para la marca en mención, el cual permitirá ser un precedente y una guía general para futuras investigaciones en el sector de moda y retail de prendas de vestir juveniles.Tesi