Towards predictive cardiovascular safety : a systems pharmacology approach

Cardiovascular safety issues related to changes in blood pressure, arise frequently in drug development. In the thesis __Towards predictive cardiovascular safety __ a systems pharmacology approach__, a system-specific model is described to quantify drug effects on the interrelationship between mean arterial pressure, cardiac output, heart rate, stroke volume and total peripheral resistance in rats. The developed model can be used to quantify and predict the dynamic changes in the cardiovascular system (CVS) and elucidate the mechanism of action of novel compounds. An ultimate application of this system-specific CVS model would be to facilitate the anticipation of the clinical response based on preclinical data for newly developed compounds. Furthermore, the developed system-specific CVS model was combined with receptor models to quantify and predict the cardiovascular effects of the sphingosine 1-phosphate (S1P) receptor agonists, fingolimod-phosphate (fingolimod-P)and siponimod, in rats. This systems pharmacology model provided a quantitative understanding of the cardiovascular effects of fingolimod-P and siponimod and can be applied to predict the cardiovascular effects of other S1P receptor agonists with different selectivity profiles in rats. Ultimately, it may constitute a basis for prediction of cardiovascular effects of S1P receptor agonists in humansNovartis, LAP&P Consultants BVUBL - phd migration 201

In-situ spectroscopy of intrinsic Bi2Te3 topological insulator thin films and impact of extrinsic defects

Combined in-situ x-ray photoemission spectroscopy, scanning tunnelling spectroscopy and angle resolved photoemission spectroscopy of molecular beam epitaxy grown Bi2Te3 on lattice mismatched substrates reveal high quality stoichiometric thin films with topological surface states without a contribution from the bulk bands at the Fermi energy. The absence of bulk states at the Fermi energy is achieved without counter doping. We observe that the surface morphology and electronic band structure of Bi2Te3 are not affected by in-vacuo storage and exposure to oxygen, whereas major changes are observed when exposed to ambient conditions. These films help define a pathway towards intrinsic topological devices.Comment: 8 pages, 5 figure

Field of inserted charges during Scanning Electron Microscopy of non-conducting samples

Three different approaches to calculating the electric potential in an inhomogeneous dielectric next to vacuum due to a charge distribution built up by the electron beam are investigated. An analytical solution for the electric potential cannot be found by means of the image charge method or Fourier analysis, both of which do work for a homogenous dielectric with a planar interface to vacuum. A Born approximation gives a good approach to the real electric potential in a homogenous dielectric up to a relative dielectric constant of 5. With this knowledge the electric potential of an inhomogenous dielectric is calculated. Also the electric field is calculated by means of a particle-mesh method. Some inhomogeneous dielectric configurations are calculated and their bound charges are studied. Such a method can yield accurate calculations of the electric potential and can give quantitative insight in the charging process. A capacitor model is described to estimate the potential due to the charge build up. It describes the potential build up in the first microseconds of the charging. Thereafter, it seems that more processes have to be taken into account to describe the potential well. This potential can further be used in a macroscopic approach to the collective motion of the electrons described by the Boltzmann transport equations or a derived density model, which can be a feasible alternative approximation to the more commonly used Monte-Carlo simulation of individual trajectories

Climate adaptation of interconnected infrastructures: a framework for supporting governance

Infrastructures are critical for human society, but vulnerable to climate change. The current body of research on infrastructure adaptation does not adequately account for the interconnectedness of infrastructures, both internally and with one another. We take a step toward addressing this gap through the introduction of a framework for infrastructure adaptation that conceptualizes infrastructures as complex socio-technical “systems of systems” embedded in a changing natural environment. We demonstrate the use of this framework by structuring potential climate change impacts and identifying adaptation options for a preliminary set of cases—road, electricity and drinking water infrastructures. By helping to clarify the relationships between impacts at different levels, we find that the framework facilitates the identification of key nodes in the web of possible impacts and helps in the identification of particularly nocuous weather conditions. We also explore how the framework may be applied more comprehensively to facilitate adaptation governance. We suggest that it may help to ensure that the mental models of stakeholders and the quantitative models of researchers incorporate the essential aspects of interacting climate and infrastructure systems. Further research is necessary to test the framework in these contexts and to determine when and where its application may be most beneficial.Infrastructure Networks Climate Adaptation and Hotspots. Knowledge for Climate Progra

A novel cardiovascular systems model to quantify drugs effects on the inter‐relationship between contractility and other hemodynamic variables

The use of systems-based pharmacological modeling approaches to characterize mode-of-action and concentration-effect relationships for drugs on specific hemodynamic variables has been demonstrated. Here, we (i) expand a previously developed hemodynamic system model through integration of cardiac output (CO) with contractility (CTR) using pressure-volume loop theory, and (ii) evaluate the contribution of CO data for identification of system-specific parameters, using atenolol as proof-of-concept drug. Previously collected experimental data was used to develop the systems model, and included measurements for heart rate (HR), CO, mean arterial pressure (MAP), and CTR after administration of atenolol (0.3-30 mg/kg) from three in vivo telemetry studies in conscious Beagle dogs. The developed cardiovascular (CVS)-contractility systems model adequately described the effect of atenolol on HR, CO, dP/dtmax, and MAP dynamics and allowed identification of both system- and drug-specific parameters with good precision. Model parameters were structurally identifiable, and the true mode of action can be identified properly. Omission of CO data did not lead to a significant change in parameter estimates compared to a model that included CO data. The newly developed CVS-contractility systems model characterizes short-term drug effects on CTR, CO, and other hemodynamic variables in an integrated and quantitative manner. When the baseline value of total peripheral resistance is predefined, CO data was not required to identify drug- and system-specific parameters. Confirmation of the consistency of system-specific parameters via inclusion of data for additional drugs and species is warranted. Ultimately, the developed model has the potential to be of relevance to support translational CVS safety studies.Pharmacolog

Mediterranean-climate streams and rivers: geographically separated but ecologically comparable freshwater systems

Streams and rivers in mediterranean-climate regions (med-rivers in med-regions) are ecologically unique, with flow regimes reflecting precipitation patterns. Although timing of drying and flooding is predictable, seasonal and annual intensity of these events is not. Sequential flooding and drying, coupled with anthropogenic influences make these med-rivers among the most stressed riverine habitat worldwide. Med-rivers are hotspots for biodiversity in all med-regions. Species in med-rivers require different, often opposing adaptive mechanisms to survive drought and flood conditions or recover from them. Thus, metacommunities undergo seasonal differences, reflecting cycles of river fragmentation and connectivity, which also affect ecosystem functioning. River conservation and management is challenging, and trade-offs between environmental and human uses are complex, especially under future climate change scenarios. This overview of a Special Issue on med-rivers synthesizes information presented in 21 articles covering the five med-regions worldwide: Mediterranean Basin, coastal California, central Chile, Cape region of South Africa, and southwest and southern Australia. Research programs to increase basic knowledge in less-developed med-regions should be prioritized to achieve increased abilities to better manage med-rivers

Marine Biodiversity of Aotearoa New Zealand

The marine-biodiversity assessment of New Zealand (Aotearoa as known to Māori) is confined to the 200 nautical-mile boundary of the Exclusive Economic Zone, which, at 4.2 million km2, is one of the largest in the world. It spans 30° of latitude and includes a high diversity of seafloor relief, including a trench 10 km deep. Much of this region remains unexplored biologically, especially the 50% of the EEZ deeper than 2,000 m. Knowledge of the marine biota is based on more than 200 years of marine exploration in the region. The major oceanographic data repository is the National Institute of Water and Atmospheric Research (NIWA), which is involved in several Census of Marine Life field projects and is the location of the Southwestern Pacific Regional OBIS Node; NIWA is also data manager and custodian for fisheries research data owned by the Ministry of Fisheries. Related data sources cover alien species, environmental measures, and historical information. Museum collections in New Zealand hold more than 800,000 registered lots representing several million specimens. During the past decade, 220 taxonomic specialists (85 marine) from 18 countries have been engaged in a project to review New Zealand's entire biodiversity. The above-mentioned marine information sources, published literature, and reports were scrutinized to give the results summarized here for the first time (current to 2010), including data on endemism and invasive species. There are 17,135 living species in the EEZ. This diversity includes 4,315 known undescribed species in collections. Species diversity for the most intensively studied phylum-level taxa (Porifera, Cnidaria, Mollusca, Brachiopoda, Bryozoa, Kinorhyncha, Echinodermata, Chordata) is more or less equivalent to that in the ERMS (European Register of Marine Species) region, which is 5.5 times larger in area than the New Zealand EEZ. The implication is that, when all other New Zealand phyla are equally well studied, total marine diversity in the EEZ may be expected to equal that in the ERMS region. This equivalence invites testable hypotheses to explain it. There are 177 naturalized alien species in New Zealand coastal waters, mostly in ports and harbours. Marine-taxonomic expertise in New Zealand covers a broad number of taxa but is, proportionately, at or near its lowest level since the Second World War. Nevertheless, collections are well supported by funding and are continually added to. Threats and protection measures concerning New Zealand's marine biodiversity are commented on, along with potential and priorities for future research