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.

Endocannabinoid transport revisited.

Endocannabinoids are arachidonic acid-derived endogenous lipids that activate the endocannabinoid system which plays a major role in health and disease. The primary endocannabinoids are anandamide (AEA, N-arachidonoylethanolamine) and 2-arachidonoyl glycerol. While their biosynthesis and metabolism have been studied in detail, it remains unclear how endocannabinoids are transported across the cell membrane. In this review, we critically discuss the different models of endocannabinoid trafficking, focusing on AEA cellular uptake which is best studied. The evolution of the current knowledge obtained with different AEA transport inhibitors is reviewed and the confusions caused by the lack of their specificity discussed. A comparative summary of the most important AEA uptake inhibitors and the studies involving their use is provided. Based on a comprehensive literature analysis, we propose a model of facilitated AEA membrane transport followed by intracellular shuttling and sequestration. We conclude that novel and more specific probes will be essential to identify the missing targets involved in endocannabinoid membrane transport.

Social motility of African trypanosomes is a property of a distinct life-cycle stage that occurs early in tsetse fly transmission

The protozoan pathogen Trypanosoma brucei is transmitted between mammals by tsetse flies. The first compartment colonised by trypanosomes after a blood meal is the fly midgut lumen. Trypanosomes present in the lumen-designated as early procyclic forms-express the stage-specific surface glycoproteins EP and GPEET procyclin. When the trypanosomes establish a mature infection and colonise the ectoperitrophic space, GPEET is down-regulated, and EP becomes the major surface protein of late procyclic forms. A few years ago, it was discovered that procyclic form trypanosomes exhibit social motility (SoMo) when inoculated on a semi-solid surface. We demonstrate that SoMo is a feature of early procyclic forms, and that late procyclic forms are invariably SoMo-negative. In addition, we show that, apart from GPEET, other markers are differentially expressed in these two life-cycle stages, both in culture and in tsetse flies, indicating that they have different biological properties and should be considered distinct stages of the life cycle. Differentially expressed genes include two closely related adenylate cyclases, both hexokinases and calflagins. These findings link the phenomenon of SoMo in vitro to the parasite forms found during the first 4-7 days of a midgut infection. We postulate that ordered group movement on plates reflects the migration of parasites from the midgut lumen into the ectoperitrophic space within the tsetse fly. Moreover, the process can be uncoupled from colonisation of the salivary glands. Although they are the major surface proteins of procyclic forms, EP and GPEET are not essential for SoMo, nor, as shown previously, are they required for near normal colonisation of the fly midgut.

A review of fluorescent ligands for studying 5-HT3 receptors

The use of fluorescence is a valuable and increasingly accessible means of probing the pharmacology and physiology of cells and their receptors. To date, the use of fluorescence-based methods for 5-HT3 receptor research has been quite limited and, although a variety of approaches have been described, these are broadly distributed throughout the literature. In this review we condense these findings into a single, accessible source of reference with the hope of promoting the use of these valuable molecular probes.

Tumor budding in colorectal cancer revisited: results of a multicenter interobserver study.

Tumor budding in colorectal cancer (CRC) is recognized as a valuable prognostic factor but its translation into daily histopathology practice has been delayed by lack of agreement on the optimal method of assessment. Within the context of the Swiss Association of Gastrointestinal Pathology (SAGIP), we performed a multicenter interobserver study on tumor budding, comparing hematoxylin and eosin (H&E) with pan-cytokeratin staining using a 10 high power field (10HPF) and hotspot (1HPF) method. Two serial sections of 50 TNM stage II-IV surgically treated CRC were stained for H&E and pan-cytokeratin. Tumor buds were scored by independent observers at six participating centers in Switzerland and Austria using the 10HPF and 1HPF method on a digital pathology platform. Pearson correlation (r) and intra-class correlation coefficients (ICC) comparing scores between centers were calculated. Three to four times more tumor buds were detected in pan-cytokeratin compared to H&E slides. Correlation coefficients for tumor budding counts between centers ranged from r = 0.46 to r = 0.91 for H&E and from r = 0.73 to r = 0.95 for pan-cytokeratin slides. Interobserver agreement across all centers was excellent for pan-cytokeratin [10HPF: ICC = 0.83 and 1HPF: ICC = 0.8]. In contrast, assessment of tumor budding on H&E slides reached only moderate agreement [10HPF: ICC = 0.58 and 1HPF: ICC = 0.49]. Based on previous literature and our findings, we recommend (1) pan-cytokeratin staining whenever possible, (2) 10HPF method for resection specimens, and (3) 1HPF method for limited material (preoperative biopsy or pT1). Since tumor budding counts can be used to determine probabilities of relevant outcomes and as such more optimally complement clinical decision making, we advocate the avoidance of cutoff scores.

Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids.

BACKGROUND Pulmonary carcinoids (PCs) are rare tumors. As there is a paucity of randomized studies, this expert consensus document represents an initiative by the European Neuroendocrine Tumor Society to provide guidance on their management. PATIENTS AND METHODS Bibliographical searches were carried out in PubMed for the terms 'pulmonary neuroendocrine tumors', 'bronchial neuroendocrine tumors', 'bronchial carcinoid tumors', 'pulmonary carcinoid', 'pulmonary typical/atypical carcinoid', and 'pulmonary carcinoid and diagnosis/treatment/epidemiology/prognosis'. A systematic review of the relevant literature was carried out, followed by expert review. RESULTS PCs are well-differentiated neuroendocrine tumors and include low- and intermediate-grade malignant tumors, i.e. typical (TC) and atypical carcinoid (AC), respectively. Contrast CT scan is the diagnostic gold standard for PCs, but pathology examination is mandatory for their correct classification. Somatostatin receptor imaging may visualize nearly 80% of the primary tumors and is most sensitive for metastatic disease. Plasma chromogranin A can be increased in PCs. Surgery is the treatment of choice for PCs with the aim of removing the tumor and preserving as much lung tissue as possible. Resection of metastases should be considered whenever possible with curative intent. Somatostatin analogs are the first-line treatment of carcinoid syndrome and may be considered as first-line systemic antiproliferative treatment in unresectable PCs, particularly of low-grade TC and AC. Locoregional or radiotargeted therapies should be considered for metastatic disease. Systemic chemotherapy is used for progressive PCs, although cytotoxic regimens have demonstrated limited effects with etoposide and platinum combination the most commonly used, however, temozolomide has shown most clinical benefit. CONCLUSIONS PCs are complex tumors which require a multidisciplinary approach and long-term follow-up.

Effects of intrinsic pleasantness and goal conduciveness appraisals on somatovisceral responding: Somewhat similar, but not identical.

In the emotion literature, appraisals of an event's pleasantness and goal conduciveness are often considered as interchangeable and subsumed under the term valence. Some appraisal theories, however, emphasize that there is a conceptual difference between these two appraisals. With the current study, we investigated whether such a conceptual difference would be reflected in different somatovisceral response profiles for intrinsic pleasantness and goal conduciveness. Participants viewed unpleasant and pleasant pictures (intrinsic pleasantness) and performed either goal conducive (i.e., decreasing the size of unpleasant pictures, increasing the size of pleasant pictures) or goal obstructive (i.e., increasing the size of unpleasant pictures, decreasing the size of pleasant pictures) arm movements. Our data suggest that the two appraisals have somewhat similar, but not identical, response patterns. Thus, our results emphasize the importance of distinguishing between intrinsic pleasantness and goal conduciveness. Moreover, we find evidence that the efferent effects of the two appraisals combine multiplicatively, and that predictability of goal conduciveness may influence the impact of goal conduciveness appraisals on somatovisceral responding.

The changing pace of insular life: 5000 years of microevolution in the Orkney vole (Microtus arvalis orcadensis)

Island evolution may be expected to involve fast initial morphological divergence followed by stasis. We tested this model using the dental phenotype of modern and ancient common voles (Microtus arvalis), introduced onto the Orkney archipelago (Scotland) from continental Europe some 5000 years ago. First, we investigated phenotypic divergence of Orkney and continental European populations and assessed climatic influences. Second, phenotypic differentiation among Orkney populations was tested against geography, time, and neutral genetic patterns. Finally, we examined evolutionary change along a time series for the Orkney Mainland. Molar gigantism and anterior-lobe hypertrophy evolved rapidly in Orkney voles following introduction, without any transitional forms detected. Founder events and adaptation appear to explain this initial rapid evolution. Idiosyncrasy in dental features among different island populations of Orkney voles is also likely the result of local founder events following Neolithic translocation around the archipelago. However, against our initial expectations, a second marked phenotypic shift occurred between the 4th and 12th centuries AD, associated with increased pastoral farming and introduction of competitors (mice and rats) and terrestrial predators (foxes and cats). These results indicate that human agency can generate a more complex pattern of morphological evolution than might be expected in island rodents.

The Social Life of African Trypanosomes

The unicellular parasite Trypanosoma brucei shuttles between its definitive host, the tsetse fly, and various mammals including humans. In the fly digestive tract, T. brucei must first migrate to the ectoperitrophic space, establish a persistent infection of the midgut and then migrate to the salivary glands before being transmitted to a new mammalian host. In 2010, it was shown that insect stages of the parasite (procyclic forms) exhibit social motility (SoMo) when cultured on a semi-solid surface, and it was postulated that this behaviour might reflect a migration step in the tsetse fly. Now, almost 5 years after the initial report, several new publications shed some light on the biological function of SoMo and provide insights into the underlying signalling pathways.

Epigallocatechin gallate (EGCG) affects glucose metabolism and enhances fitness and life span in Drosophila melanogaster

In this study, we tested whether a standardized epigallocatechin-3-gallate (EGCG) rich green tea extract (comprising > 90% EGCG) affects fitness and lifespan as well as parameters of glucose metabolism and energy homeostasis in the fruit fly, Drosophila melanogaster. Following the application of the green tea extract a significant increase in the mean lifespan (+ 3.3 days) and the 50% survival (+ 4.3 days) as well as improved fitness was detected. These effects went along an increased expression of Spargel, the homolog of mammalian PGC1α, which has been reported to affect lifespan in flies. Intriguingly, in flies, treatment with the green tea extract decreased glucose concentrations, which were accompanied by an inhibition of α-amylase and α-glucosidase activity. Computational docking analysis proved the potential of EGCG to dock into the substrate binding pocket of α-amylase and to a greater extent into α-glucosidase. Furthermore, we demonstrate that EGCG downregulates insulin-like peptide 5 and phosphoenolpyruvate carboxykinase, major regulators of glucose metabolism, as well as the Drosophila homolog of leptin, unpaired 2. We propose that a decrease in glucose metabolism in connection with an upregulated expression of Spargel contribute to the better fitness and the extended lifespan in EGCG-treated flies.

Competition and cooperation between antiferrodistortive and ferroelectric instabilities in the model perovskite SrTiO₃

We use density functional theory to explore the interplay between octahedral rotations and ferroelectricity in the model compound SrTiO3. We find that over the experimentally relevant range octahedral rotations suppress ferroelectricity as is generally assumed in the literature. Somewhat surprisingly, we observe that at larger angles the previously weakened ferroelectric instability strengthens significantly. By analyzing geometry changes, energetics, force constants and charges, we explain the mechanisms behind this transition from competition to cooperation with increasing octahedral rotation angle.

The Psychological Outcome of Religious Coping with Stressful Life Events in a Swiss Sample of Church Attendees

Background: Recent research suggested thatreligious coping, based on dispositional religiousness and spirituality (R/S), is an important modulating factor in the process of dealing with adversity. In contrast to the United States, the effect of R/S on psychological adjustment to stress is a widely unexplored area in Europe. Methods: We examined a Swiss sample of 328 church attendees in the aftermath of stressful life events to explore associations of positive or negative religious coping with the psychological outcome. Applying a cross-sectional design, we used Huber’s Centrality Scale to specify religiousness and Pargament’s measure of religious coping (RCOPE) for the assessment of positive and negative religious coping. Depressive symptoms and anxiety as outcome variables were examined by the Brief Symptom Inventory. The Stress-Related Growth Scale and the Marburg questionnaire for the assessment of well-being were used to assess positive outcome aspects. We conducted Mann-Whitney tests for group comparisons and cumulative logit analysis for the assessmentof associations of religious coping with our outcome variables. Results: Both forms of religious coping were positively associated with stress-related growth (p < 0.01). However, negative religious coping additionally reduced well-being (p = 0.05, β = 0.52, 95% CI = 0.27–0.99) and increased anxiety (p = 0.02, β = 1.94, 95% CI = 1.10–3.39) and depressive symptoms (p = 0.01, β = 2.27, 95% CI = 1.27–4.06). Conclusions: The effects of religious coping on the psychological adjustment to stressful life events seem relevant. These findings should be confirmed in prospective studies.

Comparison of several wood smoke markers and source apportionment methods for wood burning particulate mass

Residential wood combustion has only recently been recognized as a major contributor to air pollution in Switzerland and in other European countries. A source apportionment method using the aethalometer light absorption parameters was applied to five winter campaigns at three sites in Switzerland: a village with high wood combustion activity in winter, an urban background site and a highway site. The particulate mass from traffic (PMtraffic) and wood burning (PMwb) emissions obtained with this model compared fairly well with results from the 14C source apportionment method. PMwb from the model was also compared to well known wood smoke markers such as anhydrosugars (levoglucosan and mannosan) and fine mode potassium, as well as to a marker recently suggested from the Aerodyne aerosol mass spectrometer (mass fragment m/z 60). Additionally the anhydrosugars were compared to the 14C results and were shown to be comparable to literature values from wood burning emission studies using different types of wood (hardwood, softwood). The levoglucosan to PMwb ratios varied much more strongly between the different campaigns (4–13%) compared to mannosan to PMwb with a range of 1–1.5%. Possible uncertainty aspects for the various methods and markers are discussed.

129I/127I ratios and 129I concentrations in a recent sea sediment core and in rainwater from Sevilla (Spain) by AMS

In spite of the environmental relevance of 129I, there is still a scarcity of data about its presence in the different natural compartments. In this work, results are presented on the concentration of 129I in rainwater samples taken in Sevilla (southwestern Spain) and in a sediment core taken near the Ringhals coast (Sweden). Typical concentrations of 108 and 109129I at/l are found in rainwater samples, similar to other values in literature. In the case of the sediment core, our results clearly show the impact of anthropogenic sources, with concentrations in the order of 1013129I at./kg and isotopic ratios 129I/127I in the order of 10−8 in the higher layers.

A Word. Palaver and Its Transferal Residues

The word 'palaver' is colloquially associated with useless verbiage and the nuisance of a tediously long, aimless and superfluous debate. At the same time, it insinuates an uncivilized culture of discourse beyond reason. Thus it appears to be of vaguely exotic origin but still firmly set in the European lexicon. Yet behind this contemporary meaning there lies a long history of linguistic and cultural transfers which is encased in a context of different usages of language and their intersections. By tracing the usage and semantics of 'palaver' in various encyclopaedias, glossaries and dictionaries of English, French, German, Portuguese and Spanish, the following article explores the rich history of this word. Moreover, it also regards the travelling semantics of the term 'palaver' as a process of cultural transfer that can be likened to the microcellular workings of a (retro)virus. Viral reproduction and evolution work through processes of transfer that enable the alteration of the host to adjust it to the replication and reproduction of the virus. In some cases, these processes also allow for the mutation or modification of the virus, making it suitable for transfer from one host to another. The virus is thus offered here as a vital model for cultural transfer: It not only encompasses the necessary adoption and adaption of contents or objects of cultural transfer in different contexts. It contributes to a conceptual understanding of the transferal residue that the transferred content is endowed with by its diversifying contexts. This model thereby surpasses an understanding of cultural transfer as literal translation or transmission: it conceptualizes cultural transfer as an agent of evolutionary processes, allowing for mutational effects of transfer as endowment.