Screening, Identification and Preliminary Investigation of Target Transporters in Pregnancy Pathologies

Screening, Identification and Preliminary Investigation of Target Transporters in Pregnancy Pathologies. INTRODUCTION: Pre-eclampsia (PE), intrauterine growth restriction (IUGR) and gestational diabetes mellitus (GDM) are major sources of clinical morbidity and mortality in pregnant women worldwide. The mechanisms underlying these gestational diseases are complex and not yet fully understood, but one factor contributing to their development is impaired maternal-fetal nutrient transport. Therefore, we aimed to identify candidate membrane transporters involved in transplacental nutrient transfer associated with PE/IUGR or GDM. METHODS: Using in silico strategies, we analysed various gene expression data sets generated on different platforms focusing on solute carriers, ABC transporters and TRP channels in order to identify transporters that are differently expressed between patients and gestational age-matched controls. These bioinformatic analyses were combined with literature data to define a catalogue of target transporters that could be involved in the development of PE/IUGR or GDM. Transporters of interest were then analysed for gene expression using qRT-PCR in placental tissues of patients and controls. For validating the results on protein and functional level, we started to establish an in vitro assay using freshly isolated primary cytotrophoblast cells polarized on the Transwell® system. RESULTS: Using bioinformatics approaches, we initially identified 37 target membrane proteins which were mainly associated with the transport of amino acids, vitamins, and trace elements. At the current state of analysis, the amino acid transporters SLC7A7, SLC38A2, SLC38A5, and the thiamine transporter SLC19A3 showed significant differences in placental mRNA expression between controls and patients affected by PE and/or IUGR. Subsequent gene expression analysis in our in-house GDM placental tissue bank is still ongoing. CONCLUSIONS: Based on our in silico analyses, literature data and first follow-up in vitro validations, we were able to define potentially interesting candidate transporters implicated in PE/IUGR or GDM. To date, additional newly defined candidate targets are being analysed on mRNA level in PE/IUGR and GDM. Subsequent analyses on protein and functional level will reveal whether these targets could be of diagnostic or therapeutical interest in these pregnancy pathologies.

Local Perceptions and Vertical Perspectives of a Large Scale Land Acquisition Project in Northern Sierra Leone

Despite increased scientific interest in the phenomenon of large-scale land acquisitions (LSLA), accurate data on implementation processes remain sparse. This paper aims at filling this gap by providing empirical in-depth knowledge on the case of the Swiss-based Addax Bioenergy Ltd. in Sierra Leone. Extensive fieldwork allowed the interdisciplinary research team 1) the identification of different actors that are necessary for the implementation on a vertical level and 2) the documentation of the heterogeneous group of project affected people’s perceptions and strategies on a horizontal level. Findings reveal that even a project labeled as best-practice example by UN agencies triggers a number of problematic processes for affected communities. The loss of natural resources that comes along with the land lease and the lack of employment possibilities mostly affects already vulnerable groups. On the other hand, strategies and resistance of local people also affect the project implementation. This shows that the horizontal and vertical levels are not separate entities. They are linked by social networks, social interactions, and means of communication and both levels take part in shaping the project’s impacts.

Autophagy in malignant transformation and cancer progression.

Autophagy plays a key role in the maintenance of cellular homeostasis. In healthy cells, such a homeostatic activity constitutes a robust barrier against malignant transformation. Accordingly, many oncoproteins inhibit, and several oncosuppressor proteins promote, autophagy. Moreover, autophagy is required for optimal anticancer immunosurveillance. In neoplastic cells, however, autophagic responses constitute a means to cope with intracellular and environmental stress, thus favoring tumor progression. This implies that at least in some cases, oncogenesis proceeds along with a temporary inhibition of autophagy or a gain of molecular functions that antagonize its oncosuppressive activity. Here, we discuss the differential impact of autophagy on distinct phases of tumorigenesis and the implications of this concept for the use of autophagy modulators in cancer therapy.

Predictive modelling of mineral scaling, corrosion and the performance of solute geothermometers in a granitoid-hosted, enhanced geothermal system

Experience is lacking with mineral scaling and corrosion in enhanced geothermal systems (EGS) in which surface water is circulated through hydraulically stimulated crystalline rocks. As an aid in designing EGS projects we have conducted multicomponent reactive-transport simulations to predict the likely characteristics of scales and corrosion that may form when exploiting heat from granitoid reservoir rocks at ∼200 °C and 5 km depth. The specifications of an EGS project at Basel, Switzerland, are used to constrain the model. The main water–rock reactions in the reservoir during hydraulic stimulation and the subsequent doublet operation were identified in a separate paper (Alt-Epping et al., 2013b). Here we use the computed composition of the reservoir fluid to (1) predict mineral scaling in the injection and production wells, (2) evaluate methods of chemical geothermometry and (3) identify geochemical indicators of incipient corrosion. The envisaged heat extraction scheme ensures that even if the reservoir fluid is in equilibrium with quartz, cooling of the fluid will not induce saturation with respect to amorphous silica, thus eliminating the risk of silica scaling. However, the ascending fluid attains saturation with respect to crystalline aluminosilicates such as albite, microcline and chlorite, and possibly with respect to amorphous aluminosilicates. If no silica-bearing minerals precipitate upon ascent, reservoir temperatures can be predicted by classical formulations of silica geothermometry. In contrast, Na/K concentration ratios in the production fluid reflect steady-state conditions in the reservoir rather than albite–microcline equilibrium. Thus, even though igneous orthoclase is abundant in the reservoir and albite precipitates as a secondary phase, Na/K geothermometers fail to yield accurate temperatures. Anhydrite, which is present in fractures in the Basel reservoir, is predicted to dissolve during operation. This may lead to precipitation of pyrite and, at high exposure of anhydrite to the circulating fluid, of hematite scaling in the geothermal installation. In general, incipient corrosion of the casing can be detected at the production wellhead through an increase in H2(aq) and the enhanced precipitation of Fe-bearing aluminosilicates. The appearance of magnetite in scales indicates high corrosion rates.

The Emergence of Formal Control Specificity in Information Systems Outsourcing: A Process-View

Information systems (IS) outsourcing projects often fail to achieve initial goals. To avoid project failure, managers need to design formal controls that meet the specific contextual demands of the project. However, the dynamic and uncertain nature of IS outsourcing projects makes it difficult to design such specific formal controls at the outset of a project. It is hence crucial to translate high-level project goals into specific formal controls during the course of a project. This study seeks to understand the underlying patterns of such translation processes. Based on a comparative case study of four outsourced software development projects, we inductively develop a process model that consists of three unique patterns. The process model shows that the performance implications of emergent controls with higher specificity depend on differences in the translation process. Specific formal controls have positive implications for goal achievement if only the stakeholder context is adapted, while they are negative for goal achievement if in the translation process tasks are unintendedly adapted. In the latter case projects incrementally drift away from their initial direction. Our findings help to better understand control dynamics in IS outsourcing projects. We contribute to a process theoretic understanding of IS outsourcing governance and we derive implications for control theory and the IS project escalation literature.

Similarity Mapplet: Interactive Visualization of the Directory of Useful Decoys and ChEMBL in High Dimensional Chemical Spaces

An Internet portal accessible at www.gdb.unibe.ch has been set up to automatically generate color-coded similarity maps of the ChEMBL database in relation to up to two sets of active compounds taken from the enhanced Directory of Useful Decoys (eDUD), a random set of molecules, or up to two sets of user-defined reference molecules. These maps visualize the relationships between the selected compounds and ChEMBL in six different high dimensional chemical spaces, namely MQN (42-D molecular quantum numbers), SMIfp (34-D SMILES fingerprint), APfp (20-D shape fingerprint), Xfp (55-D pharmacophore fingerprint), Sfp (1024-bit substructure fingerprint), and ECfp4 (1024-bit extended connectivity fingerprint). The maps are supplied in form of Java based desktop applications called “similarity mapplets” allowing interactive content browsing and linked to a “Multifingerprint Browser for ChEMBL” (also accessible directly at www.gdb.unibe.ch) to perform nearest neighbor searches. One can obtain six similarity mapplets of ChEMBL relative to random reference compounds, 606 similarity mapplets relative to single eDUD active sets, 30 300 similarity mapplets relative to pairs of eDUD active sets, and any number of similarity mapplets relative to user-defined reference sets to help visualize the structural diversity of compound series in drug optimization projects and their relationship to other known bioactive compounds.

Noninvasive 4D pressure difference mapping derived from 4D flow MRI in patients with repaired aortic coarctation: comparison with young healthy volunteers

To assess spatial and temporal pressure characteristics in patients with repaired aortic coarctation compared to young healthy volunteers using time-resolved velocity-encoded three-dimensional phase-contrast magnetic resonance imaging (4D flow MRI) and derived 4D pressure difference maps. After in vitro validation against invasive catheterization as gold standard, 4D flow MRI of the thoracic aorta was performed at 1.5T in 13 consecutive patients after aortic coarctation repair without recoarctation and 13 healthy volunteers. Using in-house developed processing software, 4D pressure difference maps were computed based on the Navier-Stokes equation. Pressure difference amplitudes, maximum slope of pressure amplitudes and spatial pressure range at mid systole were retrospectively measured by three readers, and twice by one reader to assess inter- and intraobserver agreement. In vitro, pressure differences derived from 4D flow MRI showed excellent agreement to invasive catheter measurements. In vivo, pressure difference amplitudes, maximum slope of pressure difference amplitudes and spatial pressure range at mid systole were significantly increased in patients compared to volunteers in the aortic arch, the proximal descending and the distal descending thoracic aorta (p < 0.05). Greatest differences occurred in the proximal descending aorta with values of the three parameters for patients versus volunteers being 19.7 ± 7.5 versus 10.0 ± 2.0 (p < 0.001), 10.9 ± 10.4 versus 1.9 ± 0.4 (p = 0.002), and 8.7 ± 6.3 versus 1.6 ± 0.9 (p < 0.001). Inter- and intraobserver agreements were excellent (p < 0.001). Noninvasive 4D pressure difference mapping derived from 4D flow MRI enables detection of altered intraluminal aortic pressures and showed significant spatial and temporal changes in patients with repaired aortic coarctation.