Latent protein trees

Unbiased, label-free proteomics is becoming a powerful technique for measuring protein expression in almost any biological sample. The output of these measurements after preprocessing is a collection of features and their associated intensities for each sample. Subsets of features within the data are from the same peptide, subsets of peptides are from the same protein, and subsets of proteins are in the same biological pathways, therefore, there is the potential for very complex and informative correlational structure inherent in these data. Recent attempts to utilize this data often focus on the identification of single features that are associated with a particular phenotype that is relevant to the experiment. However, to date, there have been no published approaches that directly model what we know to be multiple different levels of correlation structure. Here we present a hierarchical Bayesian model which is specifically designed to model such correlation structure in unbiased, label-free proteomics. This model utilizes partial identification information from peptide sequencing and database lookup as well as the observed correlation in the data to appropriately compress features into latent proteins and to estimate their correlation structure. We demonstrate the effectiveness of the model using artificial/benchmark data and in the context of a series of proteomics measurements of blood plasma from a collection of volunteers who were infected with two different strains of viral influenza.Comment: Published in at http://dx.doi.org/10.1214/13-AOAS639 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

"La deserción: un fenómeno social". Vivencias de los estudiantes del Programa de Enfermería de la Universidad del Tolima

It has been recognized as an academic dropout problem that is present in all levels of schooling, and in all academic programs in both classroom and distance of the world. The statistics thrown in studies conducted by university students in Latin America show that levels drop from 49% to 73%, and those specifically in the nursing program in Colombia demonstrate higher academic levels drop to 45 %. Objective: To identify the meaning of the experience of having deserted and the factors that led to the desertion of students in nursing program at the University of Tolima. Methodology: Research was conducted with a phenomenological approach, during 2009, with the participation of eight men and six women aged between 19 and 22 years of age, who said that his desertion from the nursing program came from two main causes: the motivation for academic medicine and for reasons of economic order. The technique of data collection was the in-depth interview. Results: The description of each experience helped found between students who dropped into the medicine category such as “life project”, “take your time,” medicine “if science” and nursing “living with the disease”. Conclusion: In contrast to the results of other research in the area, for students of nursing from the University of Tolima who moved to the medical program, desertion meant to make your life plan supported by the environment family.La deserción académica se ha reconocido en el ámbito mundial como un problema presente en todos los niveles de formación escolar y en todos los programas académicos, tanto de modalidad presencial como en modalidad a distancia. Las estadísticas arrojadas por los estudios realizados en estudiantes universitarios en Latinoamérica arrojan niveles de deserción que van desde 49 % hasta el 73 %. Específicamente los estudios efectuados en los programas de enfermería en Colombia demuestran niveles de deserción académica superiores al 45 %. Objetivo: Identificar el significado de la experiencia y los factores que llevaron a la deserción en estudiantes del Programa de Enfermería de la Universidad del Tolima. Metodología: Se realizó una investigación con enfoque fenomenológico durante el 2009, que contó con la participación de ocho hombres y seis mujeres con edades entre 19 y 22 años de edad, quienes expresaron que su decisión de desertar del Programa de Enfermería se dio por dos causas principales: motivación por el programa académico de Medicina, y por problemas de orden económico. La técnica de recolección de la información fue la entrevista en profundidad. Resultados: La descripción de cada experiencia permitió encontrar entre los estudiantes que desertaron hacia el Programa de Medicina categorías como "proyecto de vida"; "tómese su tiempo"; medicina "si es ciencia" y enfermería es "viviendo con la enfermedad". Conclusión: En contraste con los resultados de otros trabajo de investigación realizados en el área, para los estudiantes del Programa de Enfermería de la Universidad del Tolima que se trasladaron al Programa de Medicina la deserción significó poder realizar sus proyectos de vida apoyados por el grupo familiar

"La deserción: un fenómeno social". Vivencias de los estudiantes del Programa de Enfermería de la Universidad del Tolima

It has been recognized as an academic dropout problem that is present in all levels of schooling, and in all academic programs in both classroom and distance of the world. The statistics thrown in studies conducted by university students in Latin America show that levels drop from 49% to 73%, and those specifically in the nursing program in Colombia demonstrate higher academic levels drop to 45 %. Objective: To identify the meaning of the experience of having deserted and the factors that led to the desertion of students in nursing program at the University of Tolima. Methodology: Research was conducted with a phenomenological approach, during 2009, with the participation of eight men and six women aged between 19 and 22 years of age, who said that his desertion from the nursing program came from two main causes: the motivation for academic medicine and for reasons of economic order. The technique of data collection was the in-depth interview. Results: The description of each experience helped found between students who dropped into the medicine category such as “life project”, “take your time,” medicine “if science” and nursing “living with the disease”. Conclusion: In contrast to the results of other research in the area, for students of nursing from the University of Tolima who moved to the medical program, desertion meant to make your life plan supported by the environment family.La deserción académica se ha reconocido en el ámbito mundial como un problema presente en todos los niveles de formación escolar y en todos los programas académicos, tanto de modalidad presencial como en modalidad a distancia. Las estadísticas arrojadas por los estudios realizados en estudiantes universitarios en Latinoamérica arrojan niveles de deserción que van desde 49 % hasta el 73 %. Específicamente los estudios efectuados en los programas de enfermería en Colombia demuestran niveles de deserción académica superiores al 45 %. Objetivo: Identificar el significado de la experiencia y los factores que llevaron a la deserción en estudiantes del Programa de Enfermería de la Universidad del Tolima. Metodología: Se realizó una investigación con enfoque fenomenológico durante el 2009, que contó con la participación de ocho hombres y seis mujeres con edades entre 19 y 22 años de edad, quienes expresaron que su decisión de desertar del Programa de Enfermería se dio por dos causas principales: motivación por el programa académico de Medicina, y por problemas de orden económico. La técnica de recolección de la información fue la entrevista en profundidad. Resultados: La descripción de cada experiencia permitió encontrar entre los estudiantes que desertaron hacia el Programa de Medicina categorías como "proyecto de vida"; "tómese su tiempo"; medicina "si es ciencia" y enfermería es "viviendo con la enfermedad". Conclusión: En contraste con los resultados de otros trabajo de investigación realizados en el área, para los estudiantes del Programa de Enfermería de la Universidad del Tolima que se trasladaron al Programa de Medicina la deserción significó poder realizar sus proyectos de vida apoyados por el grupo familiar

From serological surveys to disease burden: a modelling pipeline for Chagas disease.

In 2012, the World Health Organization (WHO) set the elimination of Chagas disease intradomiciliary vectorial transmission as a goal by 2020. After a decade, some progress has been made, but the new 2021–2030 WHO roadmap has set even more ambitious targets. Innovative and robust modelling methods are required to monitor progress towards these goals. We present a modelling pipeline using local seroprevalence data to obtain national disease burden estimates by disease stage. Firstly, local seroprevalence information is used to estimate spatio-temporal trends in the Force-of-Infection (FoI). FoI estimates are then used to predict such trends across larger and fine-scale geographical areas. Finally, predicted FoI values are used to estimate disease burden based on a disease progression model. Using Colombia as a case study, we estimated that the number of infected people would reach 506 000 (95% credible interval (CrI) = 395 000–648 000) in 2020 with a 1.0% (95%CrI = 0.8–1.3%) prevalence in the general population and 2400 (95%CrI = 1900–3400) deaths (approx. 0.5% of those infected). The interplay between a decrease in infection exposure (FoI and relative proportion of acute cases) was overcompensated by a large increase in population size and gradual population ageing, leading to an increase in the absolute number of Chagas disease cases over time. This article is part of the theme issue ‘Challenges and opportunities in the fight against neglected tropical diseases: a decade from the London Declaration on NTDs’

Silent Phase of Johne’s Disease in Experimentally Infected Goats – A Study on New and Established Diagnostic Approaches Using Specific and Non-Specific Parameters

The current gold standard diagnostic test for Johne’s disease (JD) is detecting Mycobacterium avium subsp. paratuberculosis (MAP) from fecal samples via culture and/or PCR. Other commercially available JD diagnostic tests focus on the detection of specific antibodies within the serum or milk of infected ruminants. These tests have a high specificity but low their sensitivity and usually fail to diagnose the disease until later stages of the disease. The ideal diagnostic test should detect infected animals already during the silent phase. Here, we evaluate the use of new and established approaches to define the silent phase of JD in experimentally infected goats. None of the established diagnostic tests or new approaches for the detection of humoral and cellular immune responses were positive during the first year of infection. Only the characterization of various subsets of peripheral blood leukocytes and the weight development gave some indication for the presence of a chronic, but silent, infection. Weight differences were present throughout the first year. In addition, some of the subsets of leukocytes (WC1+ T cells, MHC class II+ leukocytes, CD1+ leukocytes, CD14+ granulocytes, and CD14+/MHC class II+ granulocytes) demonstrated significant differences, but only at certain time points

Functional drug screening reveals anticonvulsants as enhancers of mTOR-independent autophagic killing of Mycobacterium tuberculosis through inositol depletion.

Mycobacterium tuberculosis (MTB) remains a major challenge to global health made worse by the spread of multidrug resistance. We therefore examined whether stimulating intracellular killing of mycobacteria through pharmacological enhancement of macroautophagy might provide a novel therapeutic strategy. Despite the resistance of MTB to killing by basal autophagy, cell-based screening of FDA-approved drugs revealed two anticonvulsants, carbamazepine and valproic acid, that were able to stimulate autophagic killing of intracellular M. tuberculosis within primary human macrophages at concentrations achievable in humans. Using a zebrafish model, we show that carbamazepine can stimulate autophagy in vivo and enhance clearance of M. marinum, while in mice infected with a highly virulent multidrug-resistant MTB strain, carbamazepine treatment reduced bacterial burden, improved lung pathology and stimulated adaptive immunity. We show that carbamazepine induces antimicrobial autophagy through a novel, evolutionarily conserved, mTOR-independent pathway controlled by cellular depletion of myo-inositol. While strain-specific differences in susceptibility to in vivo carbamazepine treatment may exist, autophagy enhancement by repurposed drugs provides an easily implementable potential therapy for the treatment of multidrug-resistant mycobacterial infection

Small Extracellular Vesicles from Peripheral Blood of Aged Mice Pass the Blood-Brain Barrier and Induce Glial Cell Activation

Extracellular vesicles (EVs), including small EVs (sEVs), are involved in neuroinflammation and neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Yet, increased neuroinflammation can also be detected in the aging brain, and it is associated with increased glial activation. Changes in EV concentration are reported in aging tissues and senescence cells, suggesting a role of EVs in the process of aging. Here, we investigated the effect of peripheral sEVs from aged animals on neuroinflammation, specifically on glial activation. sEVs were isolated from the peripheral blood of young (3 months) and aged (24 months) C57BL/6J wildtype mice and injected into the peripheral blood from young animals via vein tail injections. The localization of EVs and the expression of selected genes involved in glial cell activation, including Gfap , Tgf- β , Cd68 , and Iba1 , were assessed in brain tissue 30 min, 4 h, and 24 h after injection. We found that sEVs from peripheral blood of aged mice but not from young mice altered gene expression in the brains of young animals. In particular, the expression of the specific astrocyte marker, Gfap , was significantly increased, indicating a strong response of this glial cell type. Our study shows that sEVs from aged mice can pass the blood-brain barrier (BBB) and induce glial cell activation

A new antibiotic with potent activity targets MscL

The growing problem of antibiotic-resistant bacteria is a major threat to human health. Paradoxically, new antibiotic discovery is declining, with most of the recently approved antibiotics corresponding to new uses for old antibiotics or structurally similar derivatives of known antibiotics. We used an in silico approach to design a new class of nontoxic antimicrobials for the bacteria-specific mechanosensitive ion channel of large conductance, MscL. One antimicrobial of this class, compound 10, is effective against methicillin-resistant Staphylococcus aureus with no cytotoxicity in human cell lines at the therapeutic concentrations. As predicted from in silico modeling, we show that the mechanism of action of compound 10 is at least partly dependent on interactions with MscL. Moreover we show that compound 10 cured a methicillin-resistant S. aureus infection in the model nematode Caenorhabditis elegans. Our work shows that compound 10, and other drugs that target MscL, are potentially important therapeutics against antibiotic-resistant bacterial infections.Irene Iscla, Robin Wray, Paul Blount, Jonah Larkins-Ford, Annie L Conery, Frederick M Ausubel, Soumya Ramu, Angela Kavanagh, Johnny X Huang, Mark A Blaskovich, Matthew A Cooper, Andres Obregon-Henao, Ian Orme, Edwin S Tjandra, Uwe H Stroeher, Melissa H Brown, Cindy Macardle, Nick van Holst, Chee Ling Tong, Ashley D Slattery, Christopher T Gibson, Colin L Raston and Ramiz A Boulo

Lectin-like bacteriocins from pseudomonas spp. utilise D-rhamnose containing lipopolysaccharide as a cellular receptor

Lectin-like bacteriocins consist of tandem monocot mannose-binding domains and display a genus-specific killing activity. Here we show that pyocin L1, a novel member of this family from Pseudomonas aeruginosa, targets susceptible strains of this species through recognition of the common polysaccharide antigen (CPA) of P. aeruginosa lipopolysaccharide that is predominantly a homopolymer of d-rhamnose. Structural and biophysical analyses show that recognition of CPA occurs through the C-terminal carbohydrate-binding domain of pyocin L1 and that this interaction is a prerequisite for bactericidal activity. Further to this, we show that the previously described lectin-like bacteriocin putidacin L1 shows a similar carbohydrate-binding specificity, indicating that oligosaccharides containing d-rhamnose and not d-mannose, as was previously thought, are the physiologically relevant ligands for this group of bacteriocins. The widespread inclusion of d-rhamnose in the lipopolysaccharide of members of the genus Pseudomonas explains the unusual genus-specific activity of the lectin-like bacteriocins