Testing Modeling Assumptions in the West Africa Ebola Outbreak

The Ebola virus in West Africa has infected almost 30,000 and killed over 11,000 people. Recent models of Ebola Virus Disease (EVD) have often made assumptions about how the disease spreads, such as uniform transmissibility and homogeneous mixing within a population. In this paper, we test whether these assumptions are necessarily correct, and offer simple solutions that may improve disease model accuracy. First, we use data and models of West African migration to show that EVD does not homogeneously mix, but spreads in a predictable manner. Next, we estimate the initial growth rate of EVD within country administrative divisions and find that it significantly decreases with population density. Finally, we test whether EVD strains have uniform transmissibility through a novel statistical test, and find that certain strains appear more often than expected by chance.Comment: 16 pages, 14 figure

Metabolomics guides rational development of a simplified cell culture medium for drug screening against <i>Trypanosoma brucei</i>

n vitro culture methods underpin many experimental approaches to biology and drug discovery. The modification of established cell culture methods to make them more biologically relevant or to optimize growth is traditionally a laborious task. Emerging metabolomic technology enables the rapid evaluation of intra- and extracellular metabolites and can be applied to the rational development of cell culture media. In this study, untargeted semiquantitative and targeted quantitative metabolomic analyses of fresh and spent media revealed the major nutritional requirements for the growth of bloodstream form &lt;i&gt;Trypanosoma brucei&lt;/i&gt;. The standard culture medium (HMI11) contained unnecessarily high concentrations of 32 nutrients that were subsequently removed to make the concentrations more closely resemble those normally found in blood. Our new medium, Creek's minimal medium (CMM), supports in vitro growth equivalent to that in HMI11 and causes no significant perturbation of metabolite levels for 94% of the detected metabolome (&#60;3-fold change; α = 0.05). Importantly, improved sensitivity was observed for drug activity studies in whole-cell phenotypic screenings and in the metabolomic mode of action assays. Four-hundred-fold 50% inhibitory concentration decreases were observed for pentamidine and methotrexate, suggesting inhibition of activity by nutrients present in HMI11. CMM is suitable for routine cell culture and offers important advantages for metabolomic studies and drug activity screening

Amino acid transporters in Trypanosoma brucei brucei

Two approaches have been used to investigate the nature of amino acid transport in T. brucei. The first approach involved studying the uptake of radiolabelled amino acids by the parasite, the second approach involved the identification, cloning and expression in a heterologous system of a gene encoding for a putative amino acid transporter.The biochemical approach revealed that methionine uptake was of relatively high affinity in procyclic and bloodstream forms and dependent on a proton motive force. The recognition motif of this transporter encompasses the amino acid core as well as the two carbon atoms of the side chain.The anionic amino acids, aspartate and glutamate, were shown to be taken up poorly or not at all by specific transport mechanisms in the two forms of the parasite. The aromatic amino acids, phenylalanine, tyrosine and tryptophan, are taken up via several different routes indicating the importance of these amino acids for the parasite.The cloning and expression of TbAATP1 in Xenopus oocytes revealed that this gene encodes for an amino acid transporter that is able to transport tyrosine, glutamine and glutamate.TbAATP1 is the first member of what was subsequently shown to be a family of genes, encompassing at least twelve members present on three different chromosomes (IV, VI, VIII). On chromosome IV six of these genes appeared to form a cluster

Polyamine homoeostasis as a drug target in pathogenic protozoa: peculiarities and possibilities

New drugs are urgently needed for the treatment of tropical and subtropical parasitic diseases, such as African sleeping sickness, Chagas' disease, leishmaniasis and malaria. Enzymes in polyamine biosynthesis and thiol metabolism, as well as polyamine transporters, are potential drug targets within these organisms. In the present review, the current knowledge of unique properties of polyamine metabolism in these parasites is outlined. These properties include prozyme regulation of AdoMetDC (S-adenosylmethionine decarboxylase) activity in trypanosomatids, co-expression of ODC (ornithine decarboxylase) and AdoMetDC activities in a single protein in plasmodia, and formation of trypanothione, a unique compound linking polyamine and thiol metabolism in trypanosomatids. Particularly interesting features within polyamine metabolism in these parasites are highlighted for their potential in selective therapeutic strategies

A molecular mechanism for eflornithine resistance in African trypanosomes

Human African trypanosomiasis, endemic to sub-Saharan Africa, is invariably fatal if untreated. Its causative agent is the protozoan parasite Trypanosoma brucei. Eflornithine is used as a first line treatment for human African trypanosomiasis, but there is a risk that resistance could thwart its use, even when used in combination therapy with nifurtimox. Eflornithine resistant trypanosomes were selected in vitro and subjected to biochemical and genetic analysis. The resistance phenotype was verified in vivo. Here we report the molecular basis of resistance. While the drug's target, ornithine decarboxylase, was unaltered in resistant cells and changes to levels of metabolites in the targeted polyamine pathway were not apparent, the accumulation of eflornithine was shown to be diminished in resistant lines. An amino acid transporter gene, TbAAT6 (Tb927.8.5450), was found to be deleted in two lines independently selected for resistance. Ablating expression of this gene in wildtype cells using RNA interference led to acquisition of resistance while expression of an ectopic copy of the gene introduced into the resistant deletion lines restored sensitivity, confirming the role of TbAAT6 in eflornithine action. Eflornithine resistance is easy to select through loss of a putative amino acid transporter, TbAAT6. The loss of this transporter will be easily identified in the field using a simple PCR test, enabling more appropriate chemotherapy to be administered

Identification of Contractile Vacuole Proteins in Trypanosoma cruzi

Contractile vacuole complexes are critical components of cell volume regulation and have been shown to have other functional roles in several free-living protists. However, very little is known about the functions of the contractile vacuole complex of the parasite Trypanosoma cruzi, the etiologic agent of Chagas disease, other than a role in osmoregulation. Identification of the protein composition of these organelles is important for understanding their physiological roles. We applied a combined proteomic and bioinfomatic approach to identify proteins localized to the contractile vacuole. Proteomic analysis of a T. cruzi fraction enriched for contractile vacuoles and analyzed by one-dimensional gel electrophoresis and LC-MS/MS resulted in the addition of 109 newly detected proteins to the group of expressed proteins of epimastigotes. We also identified different peptides that map to at least 39 members of the dispersed gene family 1 (DGF-1) providing evidence that many members of this family are simultaneously expressed in epimastigotes. Of the proteins present in the fraction we selected several homologues with known localizations in contractile vacuoles of other organisms and others that we expected to be present in these vacuoles on the basis of their potential roles. We determined the localization of each by expression as GFP-fusion proteins or with specific antibodies. Six of these putative proteins (Rab11, Rab32, AP180, ATPase subunit B, VAMP1, and phosphate transporter) predominantly localized to the vacuole bladder. TcSNARE2.1, TcSNARE2.2, and calmodulin localized to the spongiome. Calmodulin was also cytosolic. Our results demonstrate the utility of combining subcellular fractionation, proteomic analysis, and bioinformatic approaches for localization of organellar proteins that are difficult to detect with whole cell methodologies. The CV localization of the proteins investigated revealed potential novel roles of these organelles in phosphate metabolism and provided information on the potential participation of adaptor protein complexes in their biogenesis

Transversalidad de género en el programa jóvenes con más y mejor trabajo : problemáticas y desafíos Borrar seleccionados

El período de tiempo que va de 2003 a 2015, abundó en ejemplos de implementación de políticas públicas, que impactaron directa o indirectamente en el mercado de trabajo. El Programa Jóvenes con Más y Mejor Trabajo, se inscribió en el conjunto de políticas desarrolladas para el fomento de la inclusión laboral, y tuvo particularidades que lo hacen relevante para el análisis en el marco de la Ciencia Política. Esas particularidades están dadas porque se trata de una política pública de empleo, que intenta fomentar desde el Estado, la inclusión laboral de una población específica, y que, para su implementación, involucra a una amplia variedad de actores – estatales y no estatales - con diversos grados de poder en la toma de decisiones y en el desarrollo de los procesos. Esta investigación se propone el análisis de la política pública en un marco particular, desde la perspectiva de género que desarrolla, y en un territorio específico que permite extraer valiosas conclusiones, la ciudad de Granadero Baigorria.Fil: Hasne, Yesica Cynthia. Universidad Nacional de Rosario. Facultad de Ciencia Política y Relaciones Internacionales; Argentina

The Effects of the Twist : A qualitative study of the perception of the film twist

This study investigates what aspects are experienced as most memorable in a twist film and if the twist enhances the viewers engagement and appreciation of the movie. By analyzing data collected from various interviews with respondents who have watched The Sixth Sense (1999), this study describes how the narrative structure affects the viewer’s experience and interpretation. By encouraging a transition towards more analytically engaging and complex narratives, this study envisions a future where films even further transcend pure entertainment to invite critical reflection and interpretation. The study has its foundation in the reception theory and grounded theory, and explores how individual experiences affect the reception of the twist. This by conducting semi-structured interviews to delve into the psychological and emotional responses of the viewers to plot twists. Seven respondents, aged 21-27, and with a significant interest in film, and who, before the interviews, watched The Sixth Sense (1999), participated in the study. The study indicates that the majority of the respondents find the twist to be the most memorable element of the twist film and that it also helps enhance the overall experience of the movie. The study’s findings also highlight that plot twists shape viewer’s engagement and appreciation significantly – generating both emotional and cognitive reactions. This knowledge opens up to discussion about the plot structure’s role in cinematic storytelling, and might potentially be a tool of influence for future filmmakers in approach to film production and audience engagement strategies. Finally, the study also emphasizes a value of encouraging more critical reflections from film audiences in an era of increasingly complex narratives

Kunskapsalliansen i Amiralsstaden - En studie av kunskapsalliansen som metod i Amiralsstaden för att främja deltagandet

Att uppnå ett ökat deltagande i planeringsprocesser har länge varit en utmaning i den representativa demokratin. Denna studien syftar på att undersöka Amiralsstadens kunskapsallians. Vi vill även undersöka om kunskapsalliansen, som metod, främjar deltagande och involvering i planeringsprocessen. Meningen med kunskapsalliansen är att det ska ske ett utbyte av kunskap mellan de olika parterna som medverkar för att arbeta och utveckla lösningar inom varje område. Denna kvalitativa studien består av en fallstudie på kunskapsalliansen i Amiralsstaden.Vidare har intervjuer genomförts med tre personer med olika roller som varit engagerade i kunskapsalliansen i Amiralsstaden. Intervjuerna kompletterades med analyser av relevanta dokument för att införskaffa oss en bredare förståelse för fallet.Med utgångspunkt i vår studie och i koppling till vårt teoretiska ramverk framkommer det att det funnits svårigheter i att uppnå ett ökat deltagande i planeringsprocessen vilket har sin grund i resursbrister som utgör hinder för ett ökat deltagande.Achieving an increased level of participation in planning processes have for a very long time been a challenge in the representative democracy. This study aims to investigate the kunskapsallians; meaning it consists of a group of participants (i.e. citizen or officials), applied in Amiralsstaden. We will also examine whether the alliance of knowledge, as a method, encourages participation and involvement in the planning process. The purpose with the method kunskapsalliansen is that there should be an exchange of knowledge between the different parties that contribute to working and developing solutions in each area. This qualitative study consists of a case study focusing on the alliance of knowledge in Amiralsstaden.Furthermore, interviews have been conducted with three individuals; with various roles and tasks ,who have been involved in the alliance of knowledge in Amiralsstaden. The interviews is complemented with an extensive analysis of relevant documents in order for us to obtain a more comprehensive understanding of this case study.With the basis of our study and in connection to our theoretical framework it appears to have been difficulties in reaching an increased level of participation in the planning process. In turn, the difficulties seem to lie in insufficient resources