Social networks, mobility, and exchange systems during the Neolithic and Bronze Age of the Swiss Plateau

Excavations of Neolithic (4000 – 3500 BC) and Late Bronze Age (1200 – 800 BC) wetland sites on the northern Alpine periphery have produced astonishing and detailed information about the life and human environment of prehistoric societies. It is even possible to reconstruct settlement histories and settlement dynamics, which suggest a high degree of mobility during the Neolithic. Archaeological finds—such as pottery—show local typological developments in addition to foreign influences. Furthermore, exogenous lithic forms indicate far reaching interaction. Many hundreds of bronze artefacts are recorded from the Late Bronze Age settlements, demonstrating that some wetland sites were centres of bronzework production. Exogenous forms of bronzework are relatively rare in the wetland settlements during the Late Bronze Age. However, the products produced in the lake-settlements can be found widely across central Europe, indicating their continued involvement in interregional exchange partnerships. Potential motivations and dynamics of the relationships between sites and other regions of Europe will be detailed using case studies focussing on the settlements Seedorf Lobsigensee (BE), Concise (VD), and Sutz-Lattrigen Hauptstation innen (BE), and an initial assessment of intra-site connectivity through Network Analysis of sites within the region of Lake Neuchâtel, Lake Biel, and Lake Murten.

On the traces of XPD: cell cycle matters - untangling the genotype-phenotype relationship of XPD mutations

Abstract Mutations in the human gene coding for XPD lead to segmental progeria - the premature appearance of some of the phenotypes normally associated with aging - which may or may not be accompanied by increased cancer incidence. XPD is required for at least three different critical cellular functions: in addition to participating in the process of nucleotide excision repair (NER), which removes bulky DNA lesions, XPD also regulates transcription as part of the general transcription factor IIH (TFIIH) and controls cell cycle progression through its interaction with CAK, a pivotal activator of cyclin dependent kinases (CDKs). The study of inherited XPD disorders offers the opportunity to gain insights into the coordination of important cellular events and may shed light on the mechanisms that regulate the delicate equilibrium between cell proliferation and functional senescence, which is notably altered during physiological aging and in cancer. The phenotypic manifestations in the different XPD disorders are the sum of disturbances in the vital processes carried out by TFIIH and CAK. In addition, further TFIIH- and CAK-independent cellular activities of XPD may also play a role. This, added to the complex feedback networks that are in place to guarantee the coordination between cell cycle, DNA repair and transcription, complicates the interpretation of clinical observations. While results obtained from patient cell isolates as well as from murine models have been elementary in revealing such complexity, the Drosophila embryo has proven useful to analyze the role of XPD as a cell cycle regulator independently from its other cellular functions. Together with data from the biochemical and structural analysis of XPD and of the TFIIH complex these results combine into a new picture of the XPD activities that provides ground for a better understanding of the patophysiology of XPD diseases and for future development of diagnostic and therapeutic tools.

Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology

Genome-wide association studies (GWAS) have defined over 150 genomic regions unequivocally containing variation predisposing to immune-mediated disease. Inferring disease biology from these observations, however, hinges on our ability to discover the molecular processes being perturbed by these risk variants. It has previously been observed that different genes harboring causal mutations for the same Mendelian disease often physically interact. We sought to evaluate the degree to which this is true of genes within strongly associated loci in complex disease. Using sets of loci defined in rheumatoid arthritis (RA) and Crohn's disease (CD) GWAS, we build protein-protein interaction (PPI) networks for genes within associated loci and find abundant physical interactions between protein products of associated genes. We apply multiple permutation approaches to show that these networks are more densely connected than chance expectation. To confirm biological relevance, we show that the components of the networks tend to be expressed in similar tissues relevant to the phenotypes in question, suggesting the network indicates common underlying processes perturbed by risk loci. Furthermore, we show that the RA and CD networks have predictive power by demonstrating that proteins in these networks, not encoded in the confirmed list of disease associated loci, are significantly enriched for association to the phenotypes in question in extended GWAS analysis. Finally, we test our method in 3 non-immune traits to assess its applicability to complex traits in general. We find that genes in loci associated to height and lipid levels assemble into significantly connected networks but did not detect excess connectivity among Type 2 Diabetes (T2D) loci beyond chance. Taken together, our results constitute evidence that, for many of the complex diseases studied here, common genetic associations implicate regions encoding proteins that physically interact in a preferential manner, in line with observations in Mendelian disease.

Tracking the subprocesses of decision-based action in the human frontal lobes

Situationally adaptive behavior relies on the identification of relevant target stimuli, the evaluation of these with respect to the current context and the selection of an appropriate action. We used functional magnetic resonance imaging (fMRI) to disentangle the neural networks underlying these processes within a single task. Our results show that activation of mid-ventrolateral prefrontal cortex (PFC) reflects the perceived presence of a target stimulus regardless of context, whereas context-appropriate evaluation is subserved by mid-dorsolateral PFC. Enhancing demands on response selection by means of response conflict activated a network of regions, all of which are directly connected to motor areas. On the midline, rostral anterior paracingulate cortex was found to link target detection and response selection by monitoring for the presence of behaviorally significant conditions. In summary, we provide new evidence for process-specific functional dissociations in the frontal lobes. In target-centered processing, target detection in the VLPFC is separable from contextual evaluation in the DLPFC. Response-centered processing in motor-associated regions occurs partly in parallel to these processes, which may enhance behavioral efficiency, but it may also lead to reaction time increases when an irrelevant response tendency is elicited.

Integrative analysis of RUNX1 downstream pathways and target genes

BACKGROUND: The RUNX1 transcription factor gene is frequently mutated in sporadic myeloid and lymphoid leukemia through translocation, point mutation or amplification. It is also responsible for a familial platelet disorder with predisposition to acute myeloid leukemia (FPD-AML). The disruption of the largely unknown biological pathways controlled by RUNX1 is likely to be responsible for the development of leukemia. We have used multiple microarray platforms and bioinformatic techniques to help identify these biological pathways to aid in the understanding of why RUNX1 mutations lead to leukemia. RESULTS: Here we report genes regulated either directly or indirectly by RUNX1 based on the study of gene expression profiles generated from 3 different human and mouse platforms. The platforms used were global gene expression profiling of: 1) cell lines with RUNX1 mutations from FPD-AML patients, 2) over-expression of RUNX1 and CBFbeta, and 3) Runx1 knockout mouse embryos using either cDNA or Affymetrix microarrays. We observe that our datasets (lists of differentially expressed genes) significantly correlate with published microarray data from sporadic AML patients with mutations in either RUNX1 or its cofactor, CBFbeta. A number of biological processes were identified among the differentially expressed genes and functional assays suggest that heterozygous RUNX1 point mutations in patients with FPD-AML impair cell proliferation, microtubule dynamics and possibly genetic stability. In addition, analysis of the regulatory regions of the differentially expressed genes has for the first time systematically identified numerous potential novel RUNX1 target genes. CONCLUSION: This work is the first large-scale study attempting to identify the genetic networks regulated by RUNX1, a master regulator in the development of the hematopoietic system and leukemia. The biological pathways and target genes controlled by RUNX1 will have considerable importance in disease progression in both familial and sporadic leukemia as well as therapeutic implications.

Monitoring thrombin generation by electrochemistry: development of an amperometric biosensor screening test for plasma and whole blood

BACKGROUND: Complete investigation of thrombophilic or hemorrhagic clinical presentations is a time-, apparatus-, and cost-intensive process. Sensitive screening tests for characterizing the overall function of the hemostatic system, or defined parts of it, would be very useful. For this purpose, we are developing an electrochemical biosensor system that allows measurement of thrombin generation in whole blood as well as in plasma. METHODS: The measuring system consists of a single-use electrochemical sensor in the shape of a strip and a measuring unit connected to a personal computer, recording the electrical signal. Blood is added to a specific reagent mixture immobilized in dry form on the strip, including a coagulation activator (e.g., tissue factor or silica) and an electrogenic substrate specific to thrombin. RESULTS: Increasing thrombin concentrations gave standard curves with progressively increasing maximal current and decreasing time to reach the peak. Because the measurement was unaffected by color or turbidity, any type of blood sample could be analyzed: platelet-poor plasma, platelet-rich plasma, and whole blood. The test strips with the predried reagents were stable when stored for several months before testing. Analysis of the combined results obtained with different activators allowed discrimination between defects of the extrinsic, intrinsic, and common coagulation pathways. Activated protein C (APC) predried on the strips allowed identification of APC-resistance in plasma and whole blood samples. CONCLUSIONS: The biosensor system provides a new method for assessing thrombin generation in plasma or whole blood samples as small as 10 microL. The assay is easy to use, thus allowing it to be performed in a point-of-care setting.

The Role of Small and Medium-sized Centers for Territorial Development in Switzerland

This paper describes the role of small and medium-sized urban centers in Switzerland. Switzerland is a highly urbanized country where small and medium-sized urban centers play an important role in ensuring a balanced national urban system. Besides the four largest metropolitan regions （Zurich, Geneva, Basel and Bern）, small and medium-sized towns function as central places for a wider, often extensive hinterland. They provide opportunities for living and working and they connect rural and mountain regions to national and international networks. Using secondary statistics and a case study, the paper shows that small and medium-sized urban centers are home to significant concentrations of export-oriented industries. Firms in these value-adding secondary sectors are rooted in these places and benefit from strong local embeddedness while also being oriented towards global markets. Small and medium-sized urban centers also profit from their strong local identities. While these places face various challenges, they function as important pillars in creating a balanced regional development pattern. Swiss regional development policy follows the goal of polycentric spatial development and it employs various instruments that aim to ensure a balanced urban system.

A satellite-based snow cover climatology (1985–2011) for the European Alps derived from AVHRR data

Seasonal snow cover is of great environmental and socio-economic importance for the European Alps. Therefore a high priority has been assigned to quantifying its temporal and spatial variability. Complementary to land-based monitoring networks, optical satellite observations can be used to derive spatially comprehensive information on snow cover extent. For understanding long-term changes in alpine snow cover extent, the data acquired by the Advanced Very High Resolution Radiometer (AVHRR) sensors mounted onboard the National Oceanic and Atmospheric Association (NOAA) and Meteorological Operational satellite (MetOp) platforms offer a unique source of information. In this paper, we present the first space-borne 1 km snow extent climatology for the Alpine region derived from AVHRR data over the period 1985–2011. The objective of this study is twofold: first, to generate a new set of cloud-free satellite snow products using a specific cloud gap-filling technique and second, to examine the spatiotemporal distribution of snow cover in the European Alps over the last 27 yr from the satellite perspective. For this purpose, snow parameters such as snow onset day, snow cover duration (SCD), melt-out date and the snow cover area percentage (SCA) were employed to analyze spatiotemporal variability of snow cover over the course of three decades. On the regional scale, significant trends were found toward a shorter SCD at lower elevations in the south-east and south-west. However, our results do not show any significant trends in the monthly mean SCA over the last 27 yr. This is in agreement with other research findings and may indicate a deceleration of the decreasing snow trend in the Alpine region. Furthermore, such data may provide spatially and temporally homogeneous snow information for comprehensive use in related research fields (i.e., hydrologic and economic applications) or can serve as a reference for climate models.

Architektura a ideologie. Výchovné instituce Adolfa Hitlera v protektorátu Čechy a Morava a v Říšské župě Sudety

This article examines the architecture of the Nazi regime in two occupied cities of Czechoslovakia, Praha/Prag and Jihlava/Iglau (the latter being one of the traditionally German-speaking island in the bohemia country), and focuses specifically on the process by which Hitler youth organisations (Hitlerjugend) in case of ‘education’ and indoctrination of youth were or were not successfully established in these cities. As comparison, he takes the political-administrative centres of the Sudeten Reichsgau, Ústí/Aussig, Opava/Troppau, Karlovy Vary/Karlsbad and Liberec/Reichenberg. Drawing on Czech and German archive materials, the extensive body of modern analytical literature, and propagandist literature from the period studied, the author examines the extent to which architecture served as a projection screen for Fascist propaganda in the Occupied Eastern territories. He describes the role played by the Reichsstelle für Raumordnung and shows how the Reich’s propagandist objectives came to be reflected in a high specific typology and stylistic lexicon/configuration for the architecture of Hitler youth hostels and homes He examines the process by which these organisations were powerful implanted into the space of occupied Czechoslovakia (and Sudeten) too, a topic that has not yet been addressed in (art) history too. The building projects developed for the Protectorate (published here for the first time) and managed by the Reich’s Hitler Youth Leadership in Berlin (Kulturamt, Reichsjugendführung, RJF, Abteilung HJ) reveal the ties that existed between the construction authorities in the Reich and the Protectorate, including the Planning Committee for the City of Prague. The author asks how many German and Czech architects participated for their own profit in the Nazi system, and for future research raises the hitherto taboo question of guilt and collaboration with the Nazis and the perception of this phenomenon in art history, i.e. the measure of active cooperation of not just German but also Czech architects who contributed to the planning and implementation of projects and thereby unequivocally had a hand in consolidating the totalitarian regime and de facto in the forced „Germanification” of their own people under occupation.

Neonatal dexamethasone induces premature microvascular maturation of the alveolar capillary network.

Postnatal glucocorticoid treatment of preterm infants was mimicked by treating newborn rats with dexamethasone (0.1-0.01 microg/g, days 1-4). This regimen has been shown to cause delayed alveolarization. Knowing that microvascular maturation (transformation of double- to single-layered capillary networks in alveolar septa) and septal thinning prevent further alveolarization, we measured septal maturation on electron photomicrographs in treated and control animals. In treated rats and before day 10, we observed a premature nonreversing microvascular maturation and a transient septal thinning, which both appeared focally. In vascular casts of both groups, we observed contacts between the two capillary layers of immature alveolar septa, which were predictive for capillary fusions. Studying serial electron microscopic sections of human lungs, we were able to confirm the postulated fusion process for the first time. We conclude that alveolar microvascular maturation indeed occurs by capillary fusion and that the dexamethasone-induced impairment of alveolarization is associated with focal premature capillary fusion.

SNARE-fusion mediated insertion of membrane proteins into native and artificial membranes

Membrane proteins carry out functions such as nutrient uptake, ATP synthesis or transmembrane signal transduction. An increasing number of reports indicate that cellular processes are underpinned by regulated interactions between these proteins. Consequently, functional studies of these networks at a molecular level require co-reconstitution of the interacting components. Here, we report a SNARE protein-based method for incorporation of multiple membrane proteins into artificial membrane vesicles of well-defined composition, and for delivery of large water-soluble substrates into these vesicles. The approach is used for in vitro reconstruction of a fully functional bacterial respiratory chain from purified components. Furthermore, the method is used for functional incorporation of the entire F1F0 ATP synthase complex into native bacterial membranes from which this component had been genetically removed. The novel methodology offers a tool to investigate complex interaction networks between membrane-bound proteins at a molecular level, which is expected to generate functional insights into key cellular functions.

SNARE-fusion mediated inserton of membrane proteins into native and artificial membranes

Membrane proteins carry out functions such as nutrient uptake, ATP synthesis or transmembrane signal transduction. An increasing number of reports indicate that cellular processes are underpinned by regulated interactions between these proteins. Consequently, functional studies of these networks at a molecular level require co-reconstitution of the interacting components. Here, we report a SNARE-protein based method for incorporation of multiple membrane proteins into membranes, and for delivery of large water-soluble substrates into closed membrane vesicles. The approach is used for in vitro reconstruction of a fully functional bacterial respiratory chain from purified components. Furthermore, the method is used for functional incorporation of the entire F1F0-ATP synthase complex into native bacterial membranes from which this component had been genetically removed. The novel methodology offers a tool to investigate complex interaction networks between membrane-bound proteins at a molecular level, which is expected to generate functional insights into key cellular functions.

Fast Update of Conditional Simulation Ensembles

Gaussian random field (GRF) conditional simulation is a key ingredient in many spatial statistics problems for computing Monte-Carlo estimators and quantifying uncertainties on non-linear functionals of GRFs conditional on data. Conditional simulations are known to often be computer intensive, especially when appealing to matrix decomposition approaches with a large number of simulation points. This work studies settings where conditioning observations are assimilated batch sequentially, with one point or a batch of points at each stage. Assuming that conditional simulations have been performed at a previous stage, the goal is to take advantage of already available sample paths and by-products to produce updated conditional simulations at mini- mal cost. Explicit formulae are provided, which allow updating an ensemble of sample paths conditioned on n ≥ 0 observations to an ensemble conditioned on n + q observations, for arbitrary q ≥ 1. Compared to direct approaches, the proposed formulae proveto substantially reduce computational complexity. Moreover, these formulae explicitly exhibit how the q new observations are updating the old sample paths. Detailed complexity calculations highlighting the benefits of this approach with respect to state-of-the-art algorithms are provided and are complemented by numerical experiments.