Exosomes

Exosomes are small natural membrane vesicles released by a wide variety of cell types into the extracellular compartment by exocytosis. The biological functions of exosomes are only slowly unveiled, but it is clear that they serve to remove unnecessary cellular proteins (e.g., during reticulocyte maturation) and act as intercellular messengers because they fuse easily with the membranes of neighboring cells, delivering membrane and cytoplasmic proteins from one cell to another. Recent findings suggests that cell-derived vesicles (exosomes are also named membranous vesicles or microvesicles) could also induce immune tolerance, suppression of natural killer cell function, T cell apoptosis, or metastasis. For example, by secreting exosomes, tumors may be able to accomplish the loss of those antigens that may be immunogenic and capable of signaling to immune cells as well as inducing dysfunction or death of immune effector cells. On the other hand, dendritic cell-derived exosomes have the potential to be an attractive powerful immunotherapeutic tool combining the antitumor activity of dendritic cells with the advantages of a cell-free vehicle. Although the full understanding of the significance of exosomes requires additional studies, these membrane vesicles could become a new important component in orchestrating responses between cells.

Parameter-free extraction of the functional network topology from intracranial EEG recordings: a time-resolved study of graph properties in focal onset seizures

Rationale: Focal onset epileptic seizures are due to abnormal interactions between distributed brain areas. By estimating the cross-correlation matrix of multi-site intra-cerebral EEG recordings (iEEG), one can quantify these interactions. To assess the topology of the underlying functional network, the binary connectivity matrix has to be derived from the cross-correlation matrix by use of a threshold. Classically, a unique threshold is used that constrains the topology [1]. Our method aims to set the threshold in a data-driven way by separating genuine from random cross-correlation. We compare our approach to the fixed threshold method and study the dynamics of the functional topology. Methods: We investigate the iEEG of patients suffering from focal onset seizures who underwent evaluation for the possibility of surgery. The equal-time cross-correlation matrices are evaluated using a sliding time window. We then compare 3 approaches assessing the corresponding binary networks. For each time window: * Our parameter-free method derives from the cross-correlation strength matrix (CCS)[2]. It aims at disentangling genuine from random correlations (due to finite length and varying frequency content of the signals). In practice, a threshold is evaluated for each pair of channels independently, in a data-driven way. * The fixed mean degree (FMD) uses a unique threshold on the whole connectivity matrix so as to ensure a user defined mean degree. * The varying mean degree (VMD) uses the mean degree of the CCS network to set a unique threshold for the entire connectivity matrix. * Finally, the connectivity (c), connectedness (given by k, the number of disconnected sub-networks), mean global and local efficiencies (Eg, El, resp.) are computed from FMD, CCS, VMD, and their corresponding random and lattice networks. Results: Compared to FMD and VMD, CCS networks present: *topologies that are different in terms of c, k, Eg and El. *from the pre-ictal to the ictal and then post-ictal period, topological features time courses that are more stable within a period, and more contrasted from one period to the next. For CCS, pre-ictal connectivity is low, increases to a high level during the seizure, then decreases at offset. k shows a ‘‘U-curve’’ underlining the synchronization of all electrodes during the seizure. Eg and El time courses fluctuate between the corresponding random and lattice networks values in a reproducible manner. Conclusions: The definition of a data-driven threshold provides new insights into the topology of the epileptic functional networks.

Back to the future in one week - implementing a Smalltalk VM in PyPy

We report on our experiences with the Spy project, including implementation details and benchmark results. Spy is a re-implementation of the Squeak (i.e., Smalltalk-80) VM using the PyPy toolchain. The PyPy project allows code written in RPython, a subset of Python, to be translated to a multitude of different backends and architectures. During the translation, many aspects of the implementation can be independently tuned, such as the garbage collection algorithm or threading implementation. In this way, a whole host of interpreters can be derived from one abstract interpreter definition. Spy aims to bring these benefits to Squeak, allowing for greater portability and, eventually, improved performance. The current Spy codebase is able to run a small set of benchmarks that demonstrate performance superior to many similar Smalltalk VMs, but which still run slower than in Squeak itself. Spy was built from scratch over the course of a week during a joint Squeak-PyPy Sprint in Bern last autumn.

Pedagogical quality in e-learning

The article is concerned with design and use of e-learning technology to develop education qualitatively. The purpose is to develop a framework for a pedagogical evaluation of e-learning technology. The approach is that evaluation and design must be grounded in a learning theoretical approach, and it is argued that it is necessary to make a reflection of technology in relation to activities, learning principles, and a learning theory in order to qualitatively develop education. The article presents three frameworks developed on the basis of cognitivism, radical constructivism and activity theory. Finally, on the basis of the frameworks, the article discusses e-learning technology and, more specifically, design of virtual learning environments and learning objects. It is argued that e-learning technology is not pedagogically neutral, and that it is therefore necessary to focus on design of technology that explicitly supports a certain pedagogical approach. Further, it is argued that design should direct its focus away from organisation of content and towards design of activities.

Mobile Learning – Begriff, Modelle, Forschung

Der vorliegende Übersichtsartikel betrachtet Mobile Learning aus einer pädagogisch-psychologischen und didaktischen Perspektive. Mobile Learning (M-Learning), das seit Mitte der 1990er in unterschiedlichsten Kontexten Einzug in den Bildungssektor hielt, ist ein dynamisches und interdisziplinäres Feld. Dynamisch, weil M-Learning durch die rasche Entwicklung im Bereich der Informations- und Kommunikationstechnologie, wie kaum ein anderes Forschungsfeld, einem derart großen Wandel unterworfen ist. Interdisziplinär, weil durch das Zusammentreffen von mobiler Technik und Lernen auch unterschiedliche Fachdisziplinen betroffen sind. Die verschiedenen Sichtweisen und auch die Komplexität des Feldes haben dazu geführt, dass bis heute keine einheitliche Definition des Begriffs besteht. Ziel dieses Übersichtsartikels ist es, den aktuellen Forschungsstand aus didaktischer und pädagogisch-psychologischer Sicht aufzuzeigen. Dazu werden zunächst wichtige Komponenten des M-Learning-Begriffs herausgearbeitet und daran anschließend didaktisch bedeutsame theoretische Ansätze und Modelle vorgestellt sowie kritisch betrachtet. Basierend auf dieser theoretischen Ausgangslage wird dann ein Rahmen gezeichnet, der verdeutlichen soll, wo empirische Forschung aus didaktischer und pädagogisch-psychologischer Sicht ansetzen kann. Entsprechende empirische Studien werden ebenfalls vorgestellt, um einen Eindruck des aktuellen empirischen Forschungsstandes zu geben. Dies alles soll als Ausgangspunkt für den zukünftigen Forschungsbedarf dienen.

Abstrahierendes Lernen durch aktive Modellbildung: Evaluation eines Prozesses und einer Lernumgebung

Die Fähigkeit zum Lernen durch Abstraktion aus Erfahrungen unterscheidet Experten von Novizen. Wir stellen einen Prozess für individuelles abstrahierendes Lernen und eine diesen Prozess unterstützende Lernumgebung vor. Die Ergebnisse einer Pilotstudie zeigen, dass Lernende unter Nutzung der Lernumgebung aus Fallbeispielen ein abstraktes Modell erstellen und über ihren Prozess reflektieren konnten. Dies fiel ihnen leichter, wenn die Fallbeispiele wenige gemeinsame Oberflächenmerkmale aufwiesen. Im Gegensatz zum intendierten Lernprozess wandten manche Lernende einen anderen Prozess an.

Deleterious effects of roving on learned tasks

In typical perceptual learning experiments, one stimulus type (e.g., a bisection stimulus offset either to the left or right) is presented per trial. In roving, two different stimulus types (e.g., a 30′ and a 20′ wide bisection stimulus) are randomly interleaved from trial to trial. Roving can impair both perceptual learning and task sensitivity. Here, we investigate the relationship between the two. Using a bisection task, we found no effect of roving before training. We next trained subjects and they improved. A roving condition applied after training impaired sensitivity.

Solute transport in crystalline rocks at Äspö — II: Blind predictions, inverse modelling and lessons learnt from test STT1

Based on the results from detailed structural and petrological characterisation and on up-scaled laboratory values for sorption and diffusion, blind predictions were made for the STT1 dipole tracer test performed in the Swedish A¨ spo¨ Hard Rock Laboratory. The tracers used were nonsorbing, such as uranine and tritiated water, weakly sorbing 22Na+, 85Sr2 +, 47Ca2 +and more strongly sorbing 86Rb+, 133Ba2 +, 137Cs+. Our model consists of two parts: (1) a flow part based on a 2D-streamtube formalism accounting for the natural background flow field and with an underlying homogeneous and isotropic transmissivity field and (2) a transport part in terms of the dual porosity medium approach which is linked to the flow part by the flow porosity. The calibration of the model was done using the data from one single uranine breakthrough (PDT3). The study clearly showed that matrix diffusion into a highly porous material, fault gouge, had to be included in our model evidenced by the characteristic shape of the breakthrough curve and in line with geological observations. After the disclosure of the measurements, it turned out that, in spite of the simplicity of our model, the prediction for the nonsorbing and weakly sorbing tracers was fairly good. The blind prediction for the more strongly sorbing tracers was in general less accurate. The reason for the good predictions is deemed to be the result of the choice of a model structure strongly based on geological observation. The breakthrough curves were inversely modelled to determine in situ values for the transport parameters and to draw consequences on the model structure applied. For good fits, only one additional fracture family in contact with cataclasite had to be taken into account, but no new transport mechanisms had to be invoked. The in situ values for the effective diffusion coefficient for fault gouge are a factor of 2–15 larger than the laboratory data. For cataclasite, both data sets have values comparable to laboratory data. The extracted Kd values for the weakly sorbing tracers are larger than Swedish laboratory data by a factor of 25–60, but agree within a factor of 3–5 for the more strongly sorbing nuclides. The reason for the inconsistency concerning Kds is the use of fresh granite in the laboratory studies, whereas tracers in the field experiments interact only with fracture fault gouge and to a lesser extent with cataclasite both being mineralogically very different (e.g. clay-bearing) from the intact wall rock.

Gene therapy of cancer: Mechanisms of ``bystander effect'' killing in cells expressing the herpes simplex virus-thymidine kinase gene and its potential clinical applications

At the fore-front of cancer research, gene therapy offers the potential to either promote cell death or alter the behavior of tumor-cells. One example makes use of a toxic phenotype generated by the prodrug metabolizing gene, thymidine kinase (HSVtk) from the Herpes Simplex Virus. This gene confers selective toxicity to a relatively nontoxic prodrug, ganciclovir (GCV). Tumor cells transduced with the HSVtk gene are sensitive to 1-50 $\mu$M GCV; normal tissue is insensitive up to 150-250 $\mu$M GCV. Utilizing these different sensitivities, it is possible to selectively ablate tumor cells expressing this gene. Interestingly, if a HSVtk$\sp+$ expressing population is mixed with a HSVtk$\sp-$ population at high density, all the cells are killed after GCV administration. This phenomenon for killing all neighboring cells is termed the "bystander effect", which is well documented in HSVtk$\sp-$ GCV systems, though its exact mechanism of action is unclear.^ Using the mouse colon carcinoma cell line CT26, data are presented supporting possible mechanisms of "bystander effect" killing of neighboring CT26-tk$\sp-$cells. A major requirement for bystander killing is the prodrug GCV: as dead or dying CT26tk$\sp+$ cells have no toxic effect on neighboring cells in its absence. In vitro, it appears the bystander effect is due to transfer of toxic GCV-metabolites, through verapamil sensitive intracellular-junctions. Additionally, possible transfer of the HSVtk enzyme to bystander cells after GCV addition, may play a role in bystander killing. A nude mouse model suggests that in a 50/50 (tk$\sp+$/tk$\sp-$) mixture of CT26 cells the bystander eradication of tumors does not involve an immune component. Additionally in a possible clinical application, the "bystander effect" can be directly exploited to eradicate preexisting CT26 colon carcinomas in mice by intratumoral implantation of viable or lethally irradiated CT26tk$\sp+$ cells and subsequent GCV administration. Lastly, an application of this toxic phenotype gene to a clinical marking protocol utilizing a recombinant adenoviral vector carrying the bifunctional protein GAL-TEK to eradicate spontaneously-arisen or vaccine-induced fibrosarcomas in cats is demonstrated. ^

Does the educational success of children growing up in stepfamilies differ from children growing up in single parent households?

Within the framework of research into educational inequality, this paper focuses on the educational success of children who experience parental separation prior to the transition from primary into secondary education. Related to this, the first education passage following primary school is observed. The question arises as to whether children growing up in single parent households after parental separation and whether children in this category who in addition experienced the formation of a stepfamily differ from one another and from children growing up in “nuclear families” in regard to their scholastic performance and transition success. For that reason, not only scholastic performance (grades) but also the type of school attended following primary school are of particular interest. Furthermore, differences regarding parental educational decision-making are examined (vgl. Stocké 2007). The analyses are based on data from the longitudinal study "BIKS 8-14" (educational processes, competence development and selection decisions in preschool- and school age) that has been undertaken at the Otto Friedrich University in Bamberg.

Atmospheric Soluble Dust Records from a Tibetan Ice Core: Possible Climate Proxies and Teleconnection With the Pacific Decadal Oscillation

In autumn 2005, a joint expedition between the University of Maine and the Institute of Tibetan Plateau Research recovered three ice cores from Guoqu Glacier (33 degrees 34'37.80 '' N, 91 degrees 10'35.3 '' E, 5720 m above sea level) on the northern side of Mt. Geladaindong, central Tibetan Plateau. Isotopes ( delta(18)O), major soluble ions (Na(+), K(+), Mg(2+), Ca(2+), Cl(-), NO(3)(-), SO(4)(2-)), and radionuclide (beta-activity) measurements from one of the cores revealed a 70-year record (1935-2005). Statistical analysis of major ion time series suggests that atmospheric soluble dust species dominate the chemical signature and that background dust levels conceal marine ion species deposition. The soluble dust time series have interspecies relations and common structure (empirical orthogonal function (EOF) 1), suggesting a similar soluble dust source or transport route. Annual and seasonal correlations between the EOF 1 time series and National Centers for Environmental Prediction/National Center for Atmospheric Research reanalysis climate variables (1948-2004) suggest that the Mt. Geladaindong ice core record provides a proxy for local and regional surface pressure. An approximately threefold decrease of soluble dust concentrations in the middle to late 1970s, accompanied by regional increases in pressure and temperature and decreases in wind velocity, coincides with the major 1976-1977 shift of the Pacific Decadal Oscillation (PDO) from a negative to a positive state. This is the first ice core evidence of a potential teleconnection between central Asian atmospheric soluble dust loading and the PDO. Analysis of temporally longer ice cores from Mt. Geladaindong may enhance understanding of the relationship between the PDO and central Asian atmospheric circulation and subsequent atmospheric soluble dust loading.

Elemental and Lead Isotopic Data of Copper Finds from the Singen Cemetery, Germany – a Methodological Approach to Investigate Early Bronze Age Trade Networks

We report a trace element - Pb isotope analytical (LIA) database on the "Singen Copper", a peculiar type of copper found in the North Alpine realm, from its type locality, the Early Bronze Age Singen Cemetery (Germany). What distinguishes “Singen Copper” from other coeval copper types? (i) is it a discrete metal lot with a uniform provenance (if so, can its provenance be constrained)? (ii) was it manufactured by a special, unique metallurgical process that can be discriminated from others? Trace element concentrations can give clues on the ore types that were mined, but they can be modified (more or less intentionally) by metallurgical operations. A more robust indicator are the ratios of chemically similar elements (e.g. Co/Ni, Bi/Sb, etc.), since they should remain nearly constant during metallurgical operations, and are expected to behave homogeneously in each mineral of a given mining area, but their partition amongst the different mineral species is known to cause strong inter-element fractionations. We tested the trace element ratio pattern predicted by geochemical arguments on the Brixlegg mining area. Brixlegg itself is not compatible with the Singen Copper objects, and we only report it because it is a rare instance of a mining area for which sufficient trace element analyses are available in the literature. We observe that As/Sb in fahlerz varies by a factor 1.8 above/below median; As/Sb in enargite varies by a factor of 2.5 with a 10 times higher median. Most of the 102 analyzed metal objects from Singen are Sb-Ni-rich, corresponding to “antimony-nickel copper” of the literature. Other trace element concentrations vary by > 100 times, ratios by factors > 50. Pb isotopic compositions are all significantly different from each other. They do not form a single linear array and require > 3 ore batches that certainly do not derive from one single mining area. Our data suggest a heterogeneous provenance of “Singen copper”. Archaeological information limits the scope to Central European sources. LIA requires a diverse supply network from many mining localities, including possibly Brittany. Trace element ratios show more heterogeneity than LIA; this can be explained either by deliberate selection of one particular ore mineral (from very many sources) or by processing of assorted ore minerals from a smaller number of sources, with the unintentional effect that the quality of the copper would not be constant, as the metallurgical properties of alloys would vary with trace element concentrations.

Incomplete Distal Renal Tubular Acidosis from a Heterozygous Mutation of the V-ATPase B1 Subunit

Congenital distal renal tubular acidosis (dRTA) from mutations of the B1 subunit of the V-ATPase is considered an autosomal recessive disease. We analyzed a dRTA kindred with a truncation-mutation of B1 (p.Phe468fsX487) previously shown to have failure of assembly into the V1 domain of the V-ATPase. All heterozygous carriers in this kindred have normal plasma bicarbonate concentrations, thus evaded the diagnosis of RTA. However, inappropriately high urine pH, hypocitraturia, and hypercalciuria are present either individually or in combination in the heterozygotes at baseline. Two of the heterozygotes studied also have inappropriate urinary acidification with acute ammonium chloride loading and impaired urine-blood pCO2 gradient during bicarbonaturia indicating presence of H+ gradient and flux defects. In normal human renal papillae, wild type B1 is located primarily on the plasma membrane but papilla from one of the heterozygote who had kidney stones had renal tissue secured from surgery showed B1 in both plasma membrane as well as a diffuse intracellular staining. Titrating increasing amounts of the mutant B1 subunit did not exhibit negative dominance over the expression, cellular distribution, or H+-pump activity of the wild type B1 in mammalian HEK293 cells and in V-ATPase-deficient S. cerevisiae. This is the first demonstration of renal acidification defects and nephrolithiasis in heterozygous carriers of mutant B1 subunit; which cannot be attributable to negative dominance. We propose that heterozygosity may lead to mild real acidification defects due to haploinsufficiency. B1 heterozygosity should be considered in patients with calcium nephrolithiasis and urinary abnormalities such as alkalinuria or hypocitraturia.

67P/Churyumov-Gerasimenko: Activity between March and June 2014 as observed from Rosetta/OSIRIS

Aims. 67P/Churyumov-Gerasimenko is the target comet of the ESA’s Rosetta mission. After commissioning at the end of March 2014, the Optical, Spectroscopic, and Infrared Remote Imaging System (OSIRIS) onboard Rosetta, started imaging the comet and its dust environment to investigate how they change and evolve while approaching the Sun. Methods. We focused our work on Narrow Angle Camera (NAC) orange images and Wide Angle Camera (WAC) red and visible-610 images acquired between 2014 March 23 and June 24 when the nucleus of 67P was unresolved and moving from approximately 4.3 AU to 3.8 AU inbound. During this period the 67P – Rosetta distance decreased from 5 million to 120 thousand km. Results. Through aperture photometry, we investigated how the comet brightness varies with heliocentric distance. 67P was likely already weakly active at the end of March 2014, with excess flux above that expected for the nucleus. The comet’s brightness was mostly constant during the three months of approach observations, apart from one outburst that occurred around April 30 and a second increase in flux after June 20. Coma was resolved in the profiles from mid-April. Analysis of the coma morphology suggests that most of the activity comes from a source towards the celestial north pole of the comet, but the outburst that occurred on April 30 released material in a different direction.

Third-Generation-Cephalosporin-Resistant Klebsiella pneumoniae Isolates from Humans and Companion Animals in Switzerland: Spread of a DHA-Producing Sequence Type 11 Clone in a Veterinary Setting.

Characterization of third-generation-cephalosporin-resistant Klebsiella pneumoniae isolates originating mainly from one human hospital (n = 22) and one companion animal hospital (n = 25) in Bern (Switzerland) revealed the absence of epidemiological links between human and animal isolates. Human infections were not associated with the spread of any specific clone, while the majority of animal infections were due to K. pneumoniae sequence type 11 isolates producing plasmidic DHA AmpC. This clonal dissemination within the veterinary hospital emphasizes the need for effective infection control practices.