Systems medicine and infection

By using a systems based approach, mathematical and computational techniques can be used to develop models that describe the important mechanisms involved in infectious diseases. An iterative approach to model development allows new discoveries to continually improve the model, and ultimately increase the accuracy of predictions. SIR models are used to describe epi demics, predicting the extent and spread of disease. Genome-wide genotyping and sequencing technologies can be used to identify the biological mechanisms behind diseases. These tools help to build strategies for disease prevention and treatment, an example being the recent outbreak of Ebola in West Africa where these techniques were deployed. HIV is a complex disease where much is still to be learnt about the virus and the best effective treatment. With basic mathematical modelling techniques, significant discoveries have been made over the last 20 years. With recent technological advances, the computation al resources now available and interdisciplinary cooperation, further breakthroughs are inevitable. In TB, modelling has traditionally been empirical in nature, with clinical data providing the fuel for this top-down approach. Recently, projects have begun to use data derived from laboratory experiments and clinical trials to create mathematical models that describe the mechanisms responsible for the disease. A systems medicine approach to infection modelling helps identify important biological questions that then direct future experiments , the results of which improve the model in an iterative cycle . This means that data from several model systems can be integrated and synthesised to explore complex biological systems .Postprin

A test on Ellenberg indicator values in the Mediterranean evergreen woods (Quercetea ilicis)

The consistency and reliability of Ellenberg’s indicator values (Eiv) as ecological descriptors of the Mediterranean evergreen vegetation ascribed to the phytosociological class Quercetea ilicis have been checked on a set of 859 phytosociological relevés × 699 species. Diagnostic species were identified through a Twinspan analysis and their Eiv analyzed and related to the following independent variables: (1) annual mean temperatures, (2) annual rainfall. The results provided interesting insights to disentangle the current syntaxonomical framework at the alliance level demonstrating the usefulness of ecological indicator values to test the efficiency and predictivity of the phytosociological classification

Controlling infectious disease outbreaks: Lessons from mathematical modelling.

Accepted versio

Analysis of Rabies in China: Transmission Dynamics and Control

Human rabies is one of the major public-health problems in China. The number of human rabies cases has increased dramatically in the last 15 years, partially due to the poor understanding of the transmission dynamics of rabies and the lack of effective control measures of the disease. In this article, in order to explore effective control and prevention measures we propose a deterministic model to study the transmission dynamics of rabies in China. The model consists of susceptible, exposed, infectious, and recovered subpopulations of both dogs and humans and describes the spread of rabies among dogs and from infectious dogs to humans. The model simulations agree with the human rabies data reported by the Chinese Ministry of Health. We estimate that the basic reproduction number for the rabies transmission in China and predict that the number of the human rabies is decreasing but may reach another peak around 2030. We also perform some sensitivity analysis of in terms of the model parameters and compare the effects of culling and immunization of dogs. Our study demonstrates that (i) reducing dog birth rate and increasing dog immunization coverage rate are the most effective methods for controlling rabies in China; and (ii) large scale culling of susceptible dogs can be replaced by immunization of them

Education for Environmental Citizenship and Responsible Environmental Behaviour

The notion of Environmental Citizenship embodies behaviour – an actively involved citizen who exercises his/her environmental rights and obligations in the private and public spheres. Education for Environmental Citizenship implies behavioural change; its goal is to facilitate an individual’s intellectual growth (cognitive domain) and emotional capacity (affective domain) that may lead to a critical and actively engaged individual. Human behaviour is overwhelmingly sophisticated, and what shapes pro-environmental behaviour is complex and context specific. Furthermore, empirical research indicates a discrepancy between possessing environmental knowledge and environmentally supportive attitudes and behaving pro-environmentally. The point of departure of this chapter is that the social and psychological study of behaviour has much to inform the study of environmental behaviour and, deriving from this, to inform regarding the type of education towards behaviour/action in the goal of sustainable socioecological transformation. The chapter focuses on internal (psychosocial) factors. It presents selected models regarding factors influencing behavioural decisions that are acknowledged as influential theoretical frameworks for investigating pro-environmental behaviour, as well as various theories that inform these models. These are categorised into knowledge-based models; attitude-, value- and norm-oriented models; skills, self-efficacy and situational factors; and new approaches to environmental behaviour models. The chapter concludes with suggestions for Education for Environmental Citizenship deriving from the various models

Man Bites Mosquito: Understanding the Contribution of Human Movement to Vector-Borne Disease Dynamics

In metropolitan areas people travel frequently and extensively but often in highly structured commuting patterns. We investigate the role of this type of human movement in the epidemiology of vector-borne pathogens such as dengue. Analysis is based on a metapopulation model where mobile humans connect static mosquito subpopulations. We find that, due to frequency dependent biting, infection incidence in the human and mosquito populations is almost independent of the duration of contact. If the mosquito population is not uniformly distributed between patches the transmission potential of the pathogen at the metapopulation level, as summarized by the basic reproductive number, is determined by the size of the largest subpopulation and reduced by stronger connectivity. Global extinction of the pathogen is less likely when increased human movement enhances the rescue effect but, in contrast to classical theory, it is not minimized at an intermediate level of connectivity. We conclude that hubs and reservoirs of infection can be places people visit frequently but briefly and the relative importance of human and mosquito populations in maintaining the pathogen depends on the distribution of the mosquito population and the variability in human travel patterns. These results offer an insight in to the paradoxical observation of resurgent urban vector-borne disease despite increased investment in vector control and suggest that successful public health intervention may require a dual approach. Prospective studies can be used to identify areas with large mosquito populations that are also visited by a large fraction of the human population. Retrospective studies can be used to map recent movements of infected people, pinpointing the mosquito subpopulation from which they acquired the infection and others to which they may have transmitted it

ALCAM Regulates Motility, Invasiveness, and Adherens Junction Formation in Uveal Melanoma Cells

ALCAM, a member of the immunoglobulin superfamily, has been implicated in numerous developmental events and has been repeatedly identified as a marker for cancer metastasis. Previous studies addressing ALCAM’s role in cancer have, however, yielded conflicting results. Depending on the tumor cell type, ALCAM expression has been reported to be both positively and negatively correlated with cancer progression and metastasis in the literature. To better understand how ALCAM might regulate cancer cell behavior, we utilized a panel of defined uveal melanoma cell lines with high or low ALCAM levels, and directly tested the effects of manipulating these levels on cell motility, invasiveness, and adhesion using multiple assays. ALCAM expression was stably silenced by shRNA knockdown in a high-ALCAM cell line (MUM-2B); the resulting cells displayed reduced motility in gap-closure assays and a reduction in invasiveness as measured by a transwell migration assay. Immunostaining revealed that the silenced cells were defective in the formation of adherens junctions, at which ALCAM colocalizes with N-cadherin and ß-catenin in native cells. Additionally, we stably overexpressed ALCAM in a low-ALCAM cell line (MUM-2C); intriguingly, these cells did not exhibit any increase in motility or invasiveness, indicating that ALCAM is necessary but not sufficient to promote metastasis-associated cell behaviors. In these ALCAM-overexpressing cells, however, recruitment of ß-catenin and N-cadherin to adherens junctions was enhanced. These data confirm a previously suggested role for ALCAM in the regulation of adherens junctions, and also suggest a mechanism by which ALCAM might differentially enhance or decrease invasiveness, depending on the type of cadherin adhesion complexes present in tissues surrounding the primary tumor, and on the cadherin status of the tumor cells themselves

Pathologic and Phenotypic Alterations in a Mouse Expressing a Connexin47 Missense Mutation That Causes Pelizaeus-Merzbacher–Like Disease in Humans

Gap junction channels are intercellular conduits that allow diffusional exchange of ions, second messengers, and metabolites. Human oligodendrocytes express the gap junction protein connexin47 (Cx47), which is encoded by the GJC2 gene. The autosomal recessive mutation hCx47M283T causes Pelizaeus-Merzbacher–like disease 1 (PMLD1), a progressive leukodystrophy characterized by hypomyelination, retarded motor development, nystagmus, and spasticity. We introduced the human missense mutation into the orthologous position of the mouse Gjc2 gene and inserted the mCx47M282T coding sequence into the mouse genome via homologous recombination in embryonic stem cells. Three-week-old homozygous Cx47M282T mice displayed impaired rotarod performance but unchanged open-field behavior. 10-15-day-old homozygous Cx47M282T and Cx47 null mice revealed a more than 80% reduction in the number of cells participating in glial networks after biocytin injections into oligodendrocytes in sections of corpus callosum. Homozygous expression of mCx47M282T resulted in reduced MBP expression and astrogliosis in the cerebellum of ten-day-old mice which could also be detected in Cx47 null mice of the same age. Three-month-old homozygous Cx47M282T mice exhibited neither altered open-field behavior nor impaired rotarod performance anymore. Adult mCx47M282T expressing mice did not show substantial myelin alterations, but homozygous Cx47M282T mice, additionally deprived of connexin32, which is also expressed in oligodendrocytes, died within six weeks after birth and displayed severe myelin defects accompanied by astrogliosis and activated microglia. These results strongly suggest that PMLD1 is caused by the loss of Cx47 channel function that results in impaired panglial coupling in white matter tissue