Simulating Cortical Development as a Self Constructing Process: A Novel Multi-Scale Approach Combining Molecular and Physical Aspects

Current models of embryological development focus on intracellular processes such as gene expression and protein networks, rather than on the complex relationship between subcellular processes and the collective cellular organization these processes support. We have explored this collective behavior in the context of neocortical development, by modeling the expansion of a small number of progenitor cells into a laminated cortex with layer and cell type specific projections. The developmental process is steered by a formal language analogous to genomic instructions, and takes place in a physically realistic three-dimensional environment. A common genome inserted into individual cells control their individual behaviors, and thereby gives rise to collective developmental sequences in a biologically plausible manner. The simulation begins with a single progenitor cell containing the artificial genome. This progenitor then gives rise through a lineage of offspring to distinct populations of neuronal precursors that migrate to form the cortical laminae. The precursors differentiate by extending dendrites and axons, which reproduce the experimentally determined branching patterns of a number of different neuronal cell types observed in the cat visual cortex. This result is the first comprehensive demonstration of the principles of self-construction whereby the cortical architecture develops. In addition, our model makes several testable predictions concerning cell migration and branching mechanisms.

Pens and Swords: Creative writing and poetry in post-conflict and displacement settings.

An overview of the use of poetry in creative writing and memoir writing in post-conflict contexts and for migrants illustrated with a number of proven activities, in the light of the (alleged) contrast between therapeutic and artistic writing.

The Swiss Public Initiative against Mass Immigration (‘Masseneinwanderungsinitiative’): Caught between Constitutional Sovereignty and Pacta Sunt Servanda

This article seeks to bring some clarity to the publicly held debate on the Swiss federal popular initiative to limit immigration as it was adopted on 9 February 2014 by the Swiss people. It considers the crux of the matter, which is the implementation of the new Swiss constitutional article in the context of public international law. The initiative is stuck in between Swiss constitutional sovereignty and Swiss treaty obligations flowing from the agreement on free movement of persons between the European Union and the Swiss Confederation. Specific attention is paid to the democratic element anchored in the Swiss Constitution which, in contrast to other systems where the judicial element prevails, is of high importance for whole the process of a bilateral contractual relationship between the European Union and the Swiss Confederation.

Memo has a novel role in S1P signaling and crucial for vascular development

Memo is a conserved protein that was identified as an essential mediator of tumor cell motility induced by receptor tyrosine kinase activation. Here we show that Memo null mouse embryonic fibroblasts (MEFs) are impaired in PDGF-induced migration and this is due to a defect in sphingosine-1-phosphate (S1P) signaling. S1P is a bioactive phospholipid produced in response to multiple stimuli, which regulates many cellular processes. S1P is secreted to the extracellular milieu where it exerts its function by binding a family of G-protein coupled receptors (S1PRs), causing their activation in an autocrine or paracrine manner. The process, termed cell-autonomous S1PR signaling, plays a role in survival and migration. Indeed, PDGF uses cell-autonomous S1PR signaling to promote cell migration; we show here that this S1P pathway requires Memo. Using vascular endothelial cells (HUVECs) with Memo knock-down we show that their survival in conditions of serum-starvation is impaired. Furthermore, Memo loss in HUVECs causes a reduction of junctional VE-cadherin and an increase in sprout formation. Each of these phenotypes is rescued by S1P or S1P agonist addition, showing that Memo also plays an important role in cell-autonomous S1PR signaling in endothelial cells. We also produced conventional and endothelial cell-specific conditional Memo knock-out mouse strains and show that Memo is essential for embryonic development. Starting at E13.5 embryos of both strains display bleeding and other vascular problems, some of the phenotypes that have been described in mouse strains lacking S1PRs. The essential role of Memo in embryonic vascular development may be due in part to alterations in S1P signaling. Taken together our results show that Memo has a novel role in the S1P pathway and that Memo is needed to promote cell-autonomous S1PR activation.

An ARHGEF10 deletion is highly associated with a juvenile-onset inherited polyneuropathy in Leonberger and Saint Bernard dogs

An inherited polyneuropathy (PN) observed in Leonberger dogs has clinical similarities to a genetically heterogeneous group of peripheral neuropathies termed Charcot-Marie-Tooth (CMT) disease in humans. The Leonberger disorder is a severe, juvenile-onset, chronic, progressive, and mixed PN, characterized by exercise intolerance, gait abnormalities and muscle atrophy of the pelvic limbs, as well as inspiratory stridor and dyspnea. We mapped a PN locus in Leonbergers to a 250 kb region on canine chromosome 16 (Praw = 1.16×10-10, Pgenome, corrected = 0.006) utilizing a high-density SNP array. Within this interval is the ARHGEF10 gene, a member of the rho family of GTPases known to be involved in neuronal growth and axonal migration, and implicated in human hypomyelination. ARHGEF10 sequencing identified a 10 bp deletion in affected dogs that removes four nucleotides from the 3'-end of exon 17 and six nucleotides from the 5'-end of intron 17 (c.1955_1958+6delCACGGTGAGC). This eliminates the 3'-splice junction of exon 17, creates an alternate splice site immediately downstream in which the processed mRNA contains a frame shift, and generates a premature stop codon predicted to truncate approximately 50% of the protein. Homozygosity for the deletion was highly associated with the severe juvenile-onset PN phenotype in both Leonberger and Saint Bernard dogs. The overall clinical picture of PN in these breeds, and the effects of sex and heterozygosity of the ARHGEF10 deletion, are less clear due to the likely presence of other forms of PN with variable ages of onset and severity of clinical signs. This is the first documented severe polyneuropathy associated with a mutation in ARHGEF10 in any species.

Overexpression of EphB4 in the mammary epithelium shifts the differentiation pathway of progenitor cells and promotes branching activity and vascularization

Postnatally, the mammary gland undergoes continuous morphogenesis and thereby is especially prone to malignant transformation. Thus, the maintenance of the epithelium depends on a tight control of stem cell recruitment. We have previously shown that epithelial overexpression of the EphB4 receptor results in defective mammary epithelial development and conferred a metastasizing tumor phenotype on experimental mouse mammary tumors accompanied by a preponderance of progenitor cells. To analyze the effect of EphB4 overexpression on mammary epithelial cell fate, we have used Fluorescence Activated Cell Sorting (FACS) analyses to quantify epithelial sub-populations and repopulation assays of cleared fat pads to investigate their regenerative potential. These experiments revealed that deregulated EphB4 expression leads to an augmentation of bi-potent progenitor cells and to a shift of the differentiation pathway towards the luminal lineage. The analyses of the ductal outgrowths indicated that EphB4 overexpression leads to enforced branching activity, impedes ductal differentiation and stimulates angiogenesis. To elucidate the mechanisms forwarding EphB4 signals, we have compared the expression profile of defined cell populations between EphB4 transgene and wild type mammary glands concentrating on the wnt signaling pathway and on genes implicated in cell migration. With respect to wnt signaling, the progenitor cell population was the most affected, whereas the stem cell-enriched population showed the most pronounced deregulation of migration-associated genes. Thus, the luminal epithelial EphB4 signaling contributes, most likely via wnt signaling, to the regulation of migration and cell fate of early progenitors and is involved in the determination of branching points along the ductal tree.

Avian area vasculosa and CAM as rapid in vivo pro-angiogenic and antiangiogenic models.

Angiogenesis, the development of new blood vessels from preexisting ones, is driven by coordinated signaling pathways governed by specific molecules, hemodynamic forces, and endothelial and periendothelial cells. The processes involve adhesion, migration, and survival machinery within the target endothelial and periendothelial cells. Factors that interfere with any of these processes may therefore influence angiogenesis either positively (pro-angiogenesis) or negatively (antiangiogenesis). The avian area vasculosa (AV) and the avian chorioallantoic membrane (CAM) are two useful tools for studying both angiogenesis and antiangiogenesis since they are amenable to both intravascular and topical administration of target, agents, are relatively rapid assays, and can be adapted very easily to study angiogenesis-dependent processes, such as tumor growth. Both models provide a physiological setting that permits investigation of pro-angiogenic and antiangiogenic agent interactions in vivo.

Self-initiated expatriates and their career success

Purpose This paper aims to provide conceptual clarity by distinguishing self‐initiated expatriates (SIEs) from company‐assigned expatriates (AEs), and skilled migrants; most importantly, it introduces an overarching conceptual framework based on career capital theory to explain SIEs’ career success. Design/methodology/approach This conceptual framework is based on a review of the relevant literature on SIE, expatriation, career studies, cross‐cultural studies, migration, and other related areas. Findings Protean career attitude, career networks, and cultural intelligence are identified as three major types of career capital influencing SIEs career success positively; the predicting relationships between these are mediated by cultural adjustment in the host country. Cultural distance acts as the moderator, which highlights the influence of macro‐contextual factors on SIEs’ career development. Research limitations/implications The current paper applied career capital theory and did not integrate the impact of family and labour market situation on SIEs’ career development. Further research should test the proposed framework empirically, and integrate the impact of family‐ and career‐related factors into a holistic approach. Practical implications When constructing international talent acquisition and retention strategies, organizations and receiving countries should understand the different career development needs and provide SIEs with opportunities to increase career capital during expatriation. Furthermore, the current framework suggests how to adjust to the host country in order to meet career development goals. Originality/value The multi‐level and sequential framework adds value by identifying specific types of career capital for SIEs and providing a conceptual underpinning for explaining how they interact and foster SIEs’ career success. Moreover, the framework embraces SIEs from both developed and developing economies.

Pollen-based quantitative reconstructions of Holocene regional vegetation cover (plant-functional types and land-cover types) in Europe suitable for climate modelling

We present quantitative reconstructions of regional vegetation cover in north-western Europe, western Europe north of the Alps, and eastern Europe for five time windows in the Holocene around 6k, 3k, 0.5k, 0.2k, and 0.05k calendar years before present (bp)] at a 1 degrees x1 degrees spatial scale with the objective of producing vegetation descriptions suitable for climate modelling. The REVEALS model was applied on 636 pollen records from lakes and bogs to reconstruct the past cover of 25 plant taxa grouped into 10 plant-functional types and three land-cover types evergreen trees, summer-green (deciduous) trees, and open land]. The model corrects for some of the biases in pollen percentages by using pollen productivity estimates and fall speeds of pollen, and by applying simple but robust models of pollen dispersal and deposition. The emerging patterns of tree migration and deforestation between 6k bp and modern time in the REVEALS estimates agree with our general understanding of the vegetation history of Europe based on pollen percentages. However, the degree of anthropogenic deforestation (i.e. cover of cultivated and grazing land) at 3k, 0.5k, and 0.2k bp is significantly higher than deduced from pollen percentages. This is also the case at 6k in some parts of Europe, in particular Britain and Ireland. Furthermore, the relationship between summer-green and evergreen trees, and between individual tree taxa, differs significantly when expressed as pollen percentages or as REVEALS estimates of tree cover. For instance, when Pinus is dominant over Picea as pollen percentages, Picea is dominant over Pinus as REVEALS estimates. These differences play a major role in the reconstruction of European landscapes and for the study of land cover-climate interactions, biodiversity and human resources.

The secretome of endothelial progenitor cells promotes brain endothelial cell activity through PI3-kinase and MAP-kinase

BACKGROUND Angiogenesis and vascular remodelling are crucial events in tissue repair mechanisms promoted by cell transplantation. Current evidence underscores the importance of the soluble factors secreted by stem cells in tissue regeneration. In the present study we investigated the effects of paracrine factors derived from cultured endothelial progenitor cells (EPC) on rat brain endothelial cell properties and addressed the signaling pathways involved. METHODS Endothelial cells derived from rat brain (rBCEC4) were incubated with EPC-derived conditioned medium (EPC-CM). The angiogenic response of rBCEC4 to EPC-CM was assessed as effect on cell number, migration and tubular network formation. In addition, we have compared the outcome of the in vitro experiments with the effects on capillary sprouting from rat aortic rings. The specific PI3K/AKT inhibitor LY294002 and the MEK/ERK inhibitor PD98059 were used to study the involvement of these two signaling pathways in the transduction of the angiogenic effects of EPC-CM. RESULTS Viable cell number, migration and tubule network formation were significantly augmented upon incubation with EPC-CM. Similar findings were observed for aortic ring outgrowth with significantly longer sprouts. The EPC-CM-induced activities were significantly reduced by the blockage of the PI3K/AKT and MEK/ERK signaling pathways. Similarly to the outcome of the rBCEC4 experiments, inhibition of the PI3K/AKT and MEK/ERK pathways significantly interfered with capillary sprouting induced by EPC-CM. CONCLUSION The present study demonstrates that EPC-derived paracrine factors substantially promote the angiogenic response of brain microvascular endothelial cells. In addition, our findings identified the PI3K/AKT and MEK/ERK pathways to play a central role in mediating these effects.

Ian Barbours Methodologie in Wissenschaft und Religion

Die Theology & Science Community, die vor einem halben Jahrhundert begründet worden ist, blüht und gedeiht. Von Anfang an lag dabei die Methodenfrage im Zentrum: wie kann man diese so verschiedenen Gebiete in Beziehung setzen? Dies soll im Folgenden unter Berücksichtigung von Fragen der Erkenntnistheorie, Fragen der Natur wissenschaftlicher und religiöser Sprache und Fragen der Theoriekonstruktion, Theoriewahl und Theorieverteidigung zu beantworten versucht werden.

Does outmigration lead to land degradation? Labour shortage and land management in a western Nepal watershed

In Nepal, changing demographic patterns are leading to changes in land use. The high level of outmigration of men in the hills of Kaski District, Western Development Region of Nepal, is affecting the household structure but also land management. Land is often abandoned, as the burden on those left behind is too high. How do these developments affect the state of the land in terms of land degradation? To find out, we studied land degradation, land abandonment caused by outmigration, and existing sustainable land management practices in a subwatershed in Kaski District. Mapping was done using the methodology of the World Overview of Conservation Approaches and Technologies (WOCAT). While previous studies expected land abandonment to exacerbate slope erosion, we demonstrate in this paper that it is in fact leading to an increase in vegetation cover due to favourable conditions for ecosystem recovery. However, negative impacts are several, including the increase of invasive species harmful to livestock and a decline in soil fertility. Traditional land management practices such as terraces and forest management exist. To date, however, these measures fail to take account of the changing population dynamics in the region, making the question of how migration and land degradation are linked worth revisiting.

Population mixing and the risk of childhood leukaemia in Switzerland: a census-based cohort study.

Childhood leukaemia (CL) may have an infectious cause and population mixing may therefore increase the risk of CL. We aimed to determine whether CL was associated with population mixing in Switzerland. We followed children aged <16 years in the Swiss National Cohort 1990-2008 and linked CL cases from the Swiss Childhood Cancer Registry to the cohort. We calculated adjusted hazard ratios (HRs) for all CL, CL at age <5 years and acute lymphoblastic leukaemia (ALL) for three measures of population mixing (population growth, in-migration and diversity of origin), stratified by degree of urbanisation. Measures of population mixing were calculated for all municipalities for the 5-year period preceding the 1990 and 2000 censuses. Analyses were based on 2,128,012 children of whom 536 developed CL. HRs comparing highest with lowest quintile of population growth were 1.11 [95 % confidence interval (CI) 0.65-1.89] in rural and 0.59 (95 % CI 0.43-0.81) in urban municipalities (interaction: p = 0.271). Results were similar for ALL and for CL at age <5 years. For level of in-migration there was evidence of a negative association with ALL. HRs comparing highest with lowest quintile were 0.60 (95 % CI 0.41-0.87) in urban and 0.61 (95 % CI 0.30-1.21) in rural settings. There was little evidence of an association with diversity of origin. This nationwide cohort study of the association between CL and population growth, in-migration and diversity of origin provides little support for the population mixing hypothesis.

Urban expansion and its impact on urban agriculture – remote sensing based change analysis of Kizinga and Mzinga Valley – Dar Es Salaam, Tanzania

Urban agriculture is a phenomenon that can be observed world-wide, particularly in cities of devel-oping countries. It is contributing significantly to food security and food safety and has sustained livelihood of the urban and peri-urban low income dwellers in developing countries for many years. Population increase due to rural-urban migration and natural, coupled with formal as well as infor-mal urbanization are competing with urban farming for available space and scarce water resources. A multitemporal multisensoral urban change analysis over the period of 25 years (1982-2007) was performed in order to measure and visualize the urban expansion along the Kizinga and Mzinga valley in the South of Dar es Salaam. Airphotos and VHR satellite data were analyzed by using a combination of a composition of anisotropic textural measures and spectral information. The study revealed that unplanned built-up area is expanding continuously and vegetation covers and agricultural lands decline at a fast rate. The validation showed that the overall classification accuracy varied depending on the database. The extracted built-up areas were used for visual in-terpretation mapping purposes and served as information source for another research project. The maps visualize an urban congestion and expansion of nearly 18% of the total analyzed area that had taken place in the Kizinga valley between 1982 and 2007. The same development can be ob-served in the less developed and more remote Mzinga valley between 1981 and 2002. Both areas underwent fast changes where land prices still tend to go up and an influx of people both from rural and urban areas continuously increase density with the consequence of increasing multiple land use interests.

Listeria monocytogenes spreads within the brain by actin-based intra-axonal migration

Listeria monocytogenes rhombencephalitis is a severe progressive disease despite a swift intrathecal immune response. Based on previous observations, we hypothesized that the disease progresses by intra-axonal spread within the central nervous system. To test this hypothesis, neuroanatomical mapping of lesions, immunofluorescence analysis, and electron microscopy were performed on brains of ruminants with naturally occurring rhombencephalitis. In addition, infection assays were performed in bovine brain cell cultures. Mapping of lesions revealed a consistent pattern with a preferential affection of certain nuclear areas and white matter tracts, indicating that Listeria monocytogenes spreads intra-axonally within the brain along interneuronal connections. These results were supported by immunofluorescence and ultrastructural data localizing Listeria monocytogenes inside axons and dendrites associated with networks of fibrillary structures consistent with actin tails. In vitro infection assays confirmed that bacteria were moving within axon-like processes by employing their actin tail machinery. Remarkably, in vivo, neutrophils invaded the axonal space and the axon itself, apparently by moving between split myelin lamellae of intact myelin sheaths. This intra-axonal invasion of neutrophils was associated with various stages of axonal degeneration and bacterial phagocytosis. Paradoxically, the ensuing adaxonal microabscesses appeared to provide new bacterial replication sites, thus supporting further bacterial spread. In conclusion, intra-axonal bacterial migration and possibly also the innate immune response play an important role in the intracerebral spread of the agent and hence the progression of listeric rhombencephalitis.