Stimulus-Section Coupling in Endocrine Cell Models

Detailed understanding of biological systems governing specific mechanisms and pathways is essential in the development of novel disease therapies. Stimulus-secretion coupling in hormone secreting cells is a complex system of pathways that link activation of cellular processes by i.e. nutrients to the release of hormone. Stimulus-secretion coupling in the insulin secreting beta-cell is intensely researched to improve our understanding of type 2 diabetes (T2D), a perpetually growing global pandemic. Such research requires availability of model systems that are metabolically and functionally faithful to the cell type they represent. In my research I have characterized, evaluated and applied cell models for metabolic research in endocrine cells. In studies I and II cellular function in response to nutrient stimuli in human and murine beta cell models and isolated islets was evaluated. In these studies I investigated functional aspects such as insulin secretion as well as metabolic changes such as changes in intracellular metabolite levels, oxygen consumption rates and energy production. I found that the response was qualitatively similar in human and rat beta cell models. The same was found when comparing a clonal rat beta cell model to isolated rat islets. Hence, I concluded that the similarities outweigh the differences and as such the in vitro models investigated lend themselves useful in metabolic studies, but with the recommend use of primary material for confirmation of key findings. Stimulus-secretion coupling has been widely studied in the beta cell, providing extensive knowledge on the mechanisms governing insulin secretion elicited by various nutrients. In study III and IV, I used established alpha, beta and L-cell models to investigate similarities and differences in stimulus-secretion coupling in different endocrine cell types. In study III, an important difference in mitochondrial shuttles was found between alpha and beta cells, highlighting the malate-aspartate shuttle to be critical for glucagon secretion. These findings were subsequently verified in mouse islets. In study IV, a striking difference in the activity of glutamate dehydrogenase was found between L and beta cells. Accumulation of glycogen in the beta cell has been associated with T2D. In study V, I investigated the potential role of glycogen metabolism in beta cells and its potential role in regulation of insulin secretion. This study revealed glycogen metabolism to be active and accumulation of glycogen to occurs in response to elevated glucose levels both in a clonal cell line and human islets. Moreover, perturbation of glycogen metabolism was shown to decrease insulin secretion in vitro. Stimulus-secretion coupling is highly complex as is the pathogenesis of T2D. These studies highlight how well-characterized metabolic models may be used to further the understanding of stimulus secretion coupling in endocrine cells

Social Influence in Stockmarkets: A Conceptual Analysis of Social Influence Processes in Stock Markets

This paper focuses on the role of social factors for booms-bubbles-busts cycles in stock markets. It is argued that indirect and direct social influences are important contributors by reinforcing stock investors’ cognitive biases exaggerated by affective influences. A review of herding research primarily undertaken by financial economists is followed by a demonstration that psychological theories of direct social influence (imitation) have bearings on the understanding of the herding phenomenon in stock markets. How to continue this research with relevance for regulations of stock markets is discussed.Social influence; stock investments; conceptual analysis

Use of participatory scenario modelling as platforms in stakeholder dialogues

A participatory methodology, based on dialogues between stakeholders and experts has been developed and tested in the drainage area to Kaggebo Bay in the Baltic Sea. This study is focused on the EU Water Framework Directive, with emphasis on reduction of eutrophication. The drainage area is included in the WFD administrative area of the Motala Ström River basin. A similar approach is now applied in a recently initiated project in the Thukela River basin, with focus on impacts of climate change on water resources. The methodology is based on the idea that a catchment model serves as a platform for the establishment of a common view of present conditions and the causes behind these conditions. In the following steps, this is followed by model-assisted agreement on environmental goals (i.e. what do we want the future to look like?) and local agreement on a remedy or mitigation plans in order to reduce environmental impact (e.g. eutrophication); alternatively to adapt to conditions that cannot be determined by local actions (e.g. climate change). By involving stakeholder groups in this model-supported stepwise process, it is ensured that all stakeholder groups involved have a high degree of confidence in the presented model results, and thereby enable various actors involved to share a common view, regarding both present conditions, goals and the way to reach these goals. Although this is a process that is time- (and cost-) consuming, it is hypothesised that the use of this methodology is two-pronged: it increases the willingness to carry out remedies or necessary adaptations to a changing environment, and it increases the level of understanding between the various groups and therefore ameliorates the potential for future conflicts. Compared to traditional use of model results in environmental decision-making, the experts’ role is transformed from a one-way communication of final results to assistance in the various steps of the participatory process.Keywords: participatory, catchment, coastal zone, modelling, nutrient

Supervisory control of integrated continuous downstream processes

Smart downstream processing can be performed with a sequence of integrated purification steps, which minimize the number of storage tanks and reduce hold-up time. The result is an integrated unit operation sequence that performs straight through processing of the target protein, with minimal time from expression to formulation. This downstream processing technique is well suited to be connected to a continuous upstream process based on perfusion. To develop these kinds of processes it is important to do studies in small-scale in a convenient way. This paper presents a methodology for supervisory control of integrated continuous downstream processes in lab-scale. A general platform in lab-scale for sequential processing of integrated downstream processes is developed using ÄKTA/UNICORN-systems. The modification of the physical setup to handle multiple processing steps in sequence on one single machine makes it possible to study advanced and complex process configurations without a lot of resources. To make it easy to program and run the complicated setup a new supervisory controller is developed on top of UNICORN. The new controller, called orbit, is extendable and flexible to handle very different configurations and processes. To facilitate the usage even further the actual controller code is automatically generated from a high level presentation of the separation problem. Tools for design, control and verification makes it possible to virtual test the concept before making the actual experiment. The power of this concept is illustrated by some case studies. Please click Additional Files below to see the full abstract

Blood pressure changes during the first 24 hours of life and the association with the persistence of a patent ductus arteriosus and occurrence of intraventricular haemorrhage

Very low birthweight (VLBW) infants are at risk of intraventricular haemorrhage (IVH) and delayed closure of ductus arteriosus. We investigated mean arterially recorded blood pressure (MAP) changes during the first day of life in VLBW infants as potential risk factors for a patent ductus arteriosus (PDA) and IVH. This retrospective cohort study exploring MAP changes during adaption and risk factors for a PDA and IVH comprised 844 VLBW infants admitted to the Helsinki University Children's Hospital during 2005-2013. For each infant, we investigated 600 time-points of MAP recorded 4-24 hours after birth. Based on blood pressure patterns revealed by a data-driven method, we divided the infants into two groups. Group 1 (n = 327, mean birthweight = 1019 g, mean gestational age = 28 + (1/7) weeks) consisted of infants whose mean MAP was lower at 18-24 hours than at 4-10 hours after birth. Group 2 (n = 517, mean birthweight = 1070 g, mean gestational age = 28 + (5/7) weeks) included infants with a higher mean MAP at 18-24 hours than at 4-10 hours after birth. We used the group assignments, MAP, gestational age at birth, relative size for gestational age, surfactant administration, inotrope usage, invasive ventilation, presence of respiratory distress syndrome or sepsis, fluid intake, and administration of antenatal steroids to predict the occurrence of IVH and use of pharmacological or surgical therapy for a PDA before 42 weeks of gestational age. Infants whose mean MAP is lower at 18-24 hours than at 4-10 hours after birth are more likely to undergo surgical ligation of a PDA (odds ratio = 2.1; CI 1.14-3.89; p = 0.018) and to suffer from IVH (odds ratio = 1.83; CI 1.23-2.72; p = 0.003).Peer reviewe

Length of Nutritional Transition Associates Negatively with Postnatal Growth in Very Low Birthweight Infants

Very low birthweight (VLBW

Length of Nutritional Transition Associates Negatively with Postnatal Growth in Very Low Birthweight Infants

Very low birthweight (VLBW

Impact of climate change and development scenarios on flow patterns in the Okavango River

This paper lays the foundation for the use of scenario modelling as a tool for integrated water resource management in the Okavango River basin. The Pitman hydrological model is used to assess the impact of various development and climate change scenarios on downstream river flow. The simulated impact on modelled river discharge of increased water use for domestic use, livestock, and informal irrigation (proportional to expected population increase) is very limited. Implementation of all likely potential formal irrigation schemes mentioned in available reports is expected to decrease the annual flow by 2% and the minimum monthly flow by 5%. The maximum possible impact of irrigation on annual average flow is estimated as 8%, with a reduction of minimum monthly flow by 17%. Deforestation of all areas within a 1 km buffer around the rivers is estimated to increase the flow by 6%. However, construction of all potential hydropower reservoirs in the basin may change the monthly mean flow distribution dramatically, although under the assumed operational rules, the impact of the dams is only substantial during wet years. The simulated impacts of climate change are considerable larger that those of the development scenarios (with exception of the high development scenario of hydropower schemes) although the results are sensitive to the choice of GCM and the IPCC SRES greenhouse gas (GHG) emission scenarios. The annual mean water flow predictions for the period 2020-2050 averaged over scenarios from all the four GCMs used in this study are close to the present situation for both the A2 and B2 GHG scenarios. For the 2050-2080 and 2070-2099 periods the all-GCM mean shows a flow decrease of 20% (14%) and 26% (17%) respectively for the A2 (B2) GHG scenarios. However, the uncertainty in the magnitude of simulated future changes remains high. The simulated effect of climate change on minimum monthly flow is proportionally higher