Investigating the role of Bmi-1 in liver growth and function

PhDBmi-1 is a member of the Polycomb group (PcG) family of transcriptional repressors, which are implicated in the maintenance of embryonic and adult stem cells. Previous reports indicate that Bmi-1 plays a key role in repressing the Ink4a/Arf tumour suppressor locus. Overexpression of Bmi-1 in putative liver stem/progenitor cells leads to increased self-renewal in vitro and tumourigenesis following transplantation into immunocompromised mice. However, the in vivo functional requirement for Bmi-1 in liver development, homeostasis and regeneration has not been investigated. For this thesis, the consequences of Bmi-1 deletion for the post-natal murine liver were assessed using a knockout mouse model. Immunohistochemical techniques were first used to examine Bmi-1 expression in normal murine and human liver, and in human liver pathologies. Bmi-1 was highly expressed in biliary cells of both mouse and human liver, and at lower levels in some murine hepatocytes. Strong expression of Bmi-1 was observed in cytokeratin 19-positive oval cells in regenerating murine liver. Bmi-1 knockout mice exhibited structural abnormalities in the liver parenchyma, most strikingly the abnormal development of polyploidy in hepatocytes. Bmi-1 deletion did not result in impaired proliferation in mice, despite increased expression levels of cell cycle inhibitors p16Ink4a, p19Arf and p21. In contrast, an increase in hepatocyte proliferation was observed in 8 week old Bmi-1 deficient mice, which was correlated with upregulation of cyclin D1. Mel-18, a structural homologue of Bmi-1, was also expressed in murine cholangiocytes and was upregulated in the livers of Bmi-1 deficient mice during ageing, suggesting it may have been exerting a compensatory effect. Adult Bmi-1 knockout mice also exhibited excessive iron loading and abnormalities in the expression of key regulators of hepatic iron homeostasis

A virtually 2-step nilpotent group with polynomial geodesic growth

A direct consequence of Gromov's theorem is that if a group has polynomial geodesic growth with respect to some finite generating set then it is virtually nilpotent. However, until now the only examples known were virtually abelian. In this note we furnish an example of a virtually 2-step nilpotent group having polynomial geodesic growth with respect to a certain finite generating set.Comment: 7 pages, 1 figur

Unit interval parking functions and the rr-Fubini numbers

We recall that unit interval parking functions of length $n$ are a subset of parking functions in which every car parks in its preference or in the spot after its preference, and Fubini rankings of length $n$ are rankings of $n$ competitors allowing for ties. We present an independent proof of a result of Hadaway, which establishes that unit interval parking functions and Fubini rankings are in bijection. We also prove that the cardinality of these sets are given by Fubini numbers. In addition, we give a complete characterization of unit interval parking functions by determining when a rearrangement of a unit interval parking function is again a unit interval parking function. This yields an identity for the Fubini numbers as a sum of multinomials over compositions. Moreover, we introduce a generalization of Fubini rankings, which we call the $r$-Fubini rankings of length $n+r$. We show that this set is in bijection with unit interval parking functions of length $n+r$ where the first $r$ cars have distinct preferences. We conclude by establishing that these sets are enumerated by the $r$-Fubini numbers.Comment: 11 pages, 1 tabl

Escala diagramática para quantificação da severidade de manchas em folhas de Eucalyptus globulus Labill. causadas por Teratosphaeria nubilosa (Cooke) Crous & U. Braun

http://dx.doi.org/10.5902/198050989296The leaf spot (Mycosphaerella leaf disease = MLD) caused by Teratosphaeria nubilosa has caused damage in eucalypt plantations in southern and southeastern Brazil. The need to assess the disease in the field to evaluate of this damage, efficiency control, evaluation of germplasm induces to the necessity of having a visual scale for evaluation of disease. The objective was to develop a diagrammatic scale for young leaves and one for adult leaves of Eucalyptus globules for MLD. To do so, the leaves collected in the field were scanned for image analysis. The damaged area, the healthy leaf area and the external area of the same scale RGB (Red, Green, Blue) were determined. Subsequently, it was determinate the levels of severity depending on the sample distribution with seven levels for young leaves and six for adult leaves. For the visual acuity test and validate the scale, the leaves were evaluated for severity, with and without scale. With this proposed scales, the assessors showed good accuracy both for young and adult leaves with R2=0,98 and R2=0,80, respectively. The importance of the development of diagrammatic scales for assessing MLD in eucalyptus must to the fact that allows quantification of the symptoms accurately and precisely.http://dx.doi.org/10.5902/198050989296A mancha foliar (mancha de micosferela) causada por Teratosphaeria nubilosa tem acarretado prejuízos em plantios de eucalipto na região Sul e Sudeste do Brasil. A necessidade de avaliar a doença no campo e os danos causados pela mesma, bem como a busca de formas eficientes de controle e a utilização de germoplasma, leva à necessidade em ter uma escala visual para quantificação da severidade da doença. O objetivo deste trabalho foi elaborar uma escala diagramática com folhas jovens e com folhas adultas de Eucalyptus globulus, para avaliação de mancha de micosferela. Para tal, as folhas coletadas em campo foram escaneadas para digitalização da imagem. Determinou-se a área lesionada, área foliar sadia e área total em escala RGB (Red, Green, Blue). Posteriormente, determinaram-se os níveis de severidade em função da distribuição da amostra, sendo sete níveis para folhas jovens e seis para folhas adultas. Para o teste de acuidade visual e validação da escala, as folhas foram submetidas à avaliação da severidade, com e sem escala. Com a adoção das escalas propostas, a totalidade dos avaliadores apresentou boa acurácia, tanto para folhas jovens como para adultas com R2=0,98 e R2=0,80, respectivamente. A importância da elaboração de escalas diagramáticas para quantificar a severidade de mancha em eucalipto deve-se ao fato de permitir a quantificação dos sintomas de forma acurada e precisa

Stakeholder engagement in eight comparative effectiveness trials in African Americans and Latinos with asthma

BACKGROUND: The effects of stakeholder engagement, particularly in comparative effectiveness trials, have not been widely reported. In 2014, eight comparative effectiveness studies targeting African Americans and Hispanics/Latinos with uncontrolled asthma were funded by the Patient-Centered Outcomes Research Institute (PCORI) as part of its Addressing Disparities Program. Awardees were required to meaningfully involve patients and other stakeholders. Using specific examples, we describe how these stakeholders substantially changed the research protocols and in other ways participated meaningfully as full partners in the development and conduct of the eight studies. METHODS: Using the method content analysis of cases, we identified themes regarding the types of stakeholders, methods of engagement, input from the stakeholders, changes made to the research protocols and processes, and perceived benefits and challenges of the engagement process. We used summaries from meetings of the eight teams, results from an engagement survey, and the final research reports as our data source to obtain detailed information. The descriptive data were assessed by multiple reviewers using inductive and deductive qualitative methods and discussed in the context of engagement literature. RESULTS: Stakeholders participated in the planning, conduct, and dissemination phases of all eight asthma studies. All the studies included clinicians and community representatives as stakeholders. Other stakeholders included patients with asthma, their caregivers, advocacy organizations, and health-system representatives. Engagement was primarily by participation in advisory boards, although six of the eight studies (75%) also utilized focus groups and one-on-one interviews. Difficulty finding a time and location to meet was the most reported challenge to engagement, noted by four of the eight teams (50%). Other reported challenges and barriers to engagement included recruitment of stakeholders, varying levels of enthusiasm among stakeholders, controlling power dynamics, and ensuring that stakeholder involvement was reflected and had true influence on the project. CONCLUSION: Engagement-driven modifications led to specific changes in study design and conduct that were felt to have increased enrollment and the general level of trust and support of the targeted communities. The level of interaction described, between investigators and stakeholders in each study and between investigator-stakeholder groups, is-we believe-unprecedented and may provide useful guidance for other studies seeking to improve the effectiveness of community-driven research

Calling in sick: Impacts of fever on intra-urban human mobility

© 2016 The Author(s) Published by the Royal Society. All rights reserved. Pathogens inflict a wide variety of disease manifestations on their hosts, yet the impacts of disease on the behaviour of infected hosts are rarely studied empirically and are seldom accounted for in mathematical models of transmission dynamics. We explored the potential impacts of one of the most common disease manifestations, fever, on a key determinant of pathogen transmission, host mobility, in residents of the Amazonian city of Iquitos, Peru. We did so by comparing two groups of febrile individuals (dengue-positive and dengue-negative) with an afebrile control group. A retrospective, semi-structured interview allowed us to quantify multiple aspects of mobility during the two-week period preceding each interview. We fitted nested models of each aspect of mobility to data from interviews and compared models using likelihood ratio tests to determine whether there were statistically distinguishable differences in mobility attributable to fever or its aetiology. Compared with afebrile individuals, febrile study participants spent more time at home, visited fewer locations, and, in some cases, visited locations closer to home and spent less time at certain types of locations. These multifaceted impacts are consistent with the possibility that disease-mediated changes in host mobility generate dynamic and complex changes in host contact network structure

Disease-driven Reduction in Human Mobility Influences Human-Mosquito Contacts and Dengue Transmission Dynamics

Heterogeneous exposure to mosquitoes determines an individual’s contribution to vector-borne pathogen transmission. Particularly for dengue virus (DENV), there is a major difficulty in quantifying human-vector contacts due to the unknown coupled effect of key heterogeneities. To test the hypothesis that the reduction of human out-of-home mobility due to dengue illness will significantly influence population-level dynamics and the structure of DENV transmission chains, we extended an existing modeling framework to include social structure, disease-driven mobility reductions, and heterogeneous transmissibility from different infectious groups. Compared to a baseline model, naïve to human pre-symptomatic infectiousness and disease-driven mobility changes, a model including both parameters predicted an increase of 37% in the probability of a DENV outbreak occurring; a model including mobility change alone predicted a 15.5% increase compared to the baseline model. At the individual level, models including mobility change led to a reduction of the importance of out-of-home onward transmission (R, the fraction of secondary cases predicted to be generated by an individual) by symptomatic individuals (up to -62%) at the expense of an increase in the relevance of their home (up to +40%). An individual’s positive contribution to R could be predicted by a GAM including a non-linear interaction between an individual’s biting suitability and the number of mosquitoes in their home (\u3e10 mosquitoes and 0.6 individual attractiveness significantly increased R). We conclude that the complex fabric of social relationships and differential behavioral response to dengue illness cause the fraction of symptomatic DENV infections to concentrate transmission in specific locations, whereas asymptomatic carriers (including individuals in their pre-symptomatic period) move the virus throughout the landscape. Our findings point to the difficulty of focusing vector control interventions reactively on the home of symptomatic individuals, as this approach will fail to contain virus propagation by visitors to their house and asymptomatic carriers

Dengue illness impacts daily human mobility patterns in Iquitos, Peru

Background Human mobility plays a central role in shaping pathogen transmission by generating spatial and/or individual variability in potential pathogen-transmitting contacts. Recent research has shown that symptomatic infection can influence human mobility and pathogen transmission dynamics. Better understanding the complex relationship between symptom severity, infectiousness, and human mobility requires quantification of movement patterns throughout infectiousness. For dengue virus (DENV), human infectiousness peaks 0–2 days after symptom onset, making it paramount to understand human movement patterns from the beginning of illness. Methodology and principal findings Through community-based febrile surveillance and RT-PCR assays, we identified a cohort of DENV+ residents of the city of Iquitos, Peru (n = 63). Using retrospective interviews, we measured the movements of these individuals when healthy and during each day of symptomatic illness. The most dramatic changes in mobility occurred during the first three days after symptom onset; individuals visited significantly fewer locations (Wilcoxon test, p = 0.017) and spent significantly more time at home (Wilcoxon test, p = 0.005), compared to when healthy. By 7–9 days after symptom onset, mobility measures had returned to healthy levels. Throughout an individual’s symptomatic period, the day of illness and their subjective sense of well-being were the most significant predictors for the number of locations and houses they visited. Conclusions/Significance Our study is one of the first to collect and analyze human mobility data at a daily scale during symptomatic infection. Accounting for the observed changes in human mobility throughout illness will improve understanding of the impact of disease on DENV transmission dynamics and the interpretation of public health-based surveillance data