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Highly promising preclinical data obtained in cultured cells and in nude mice bearing xenografts contrast with the rather modest clinical efficacy of Polo-like kinase 1 (Plk1) inhibitors. In the present study, we investigated if Plk1 might be a suitable target in hepatocellular carcinoma (HCC) and if a genetically engineered mouse tumor model that well reflects the tumor cell and micro-environmental features of naturally occurring cancers might be suitable to study anti-Plk1 therapy. Analysis of Plk1 expression in human HCC samples confirmed that HCC express much higher Plk1 levels than the adjacent normal liver tissue. Inhibition of Plk1 by an adenovirus encoding for a short hairpin RNA against Plk1 or by the small-molecule inhibitor BI 2536 reduced the viability of HCC cell lines and inhibited HCC xenograft progression in nude mice. Treatment of transforming growth factor (TGF) α/c-myc bitransgenic mice with BI 2536 during hepatocarcinogenesis reduced the number of dysplastic foci and of Ki-67-positive cells within the foci, indicating diminished tumorigenesis. In contrast, BI 2536 had no significant effect on HCC progression in the transgenic mouse HCC model as revealed by magnetic resonance imaging. Measurement of BI 2536 by mass spectrometry revealed considerably lower BI 2536 levels in HCC compared with the adjacent normal liver tissue. In conclusion, low intratumoral levels are a novel mechanism of resistance to the Plk1 inhibitor BI 2536. Plk1 inhibitors achieving sufficient intratumoral levels are highly promising in HCC treatment.
We report on posttransplant relapsed pediatric patients with B-precursor acute lymphoblastic leukemia with no further standard of care therapy who were treated with the T-cell engaging CD19/CD3-bispecific single-chain antibody construct blinatumomab on a compassionate use basis. Blast load was assessed prior to, during and after blinatumomab cycle using flow cytometry to detect minimal residual disease, quantitative polymerase chain reaction for rearrangements of the immunoglobulin or T-cell receptor genes, and bcr/abl mutation detection in one patient with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blinatumomab was administered as a 4-week continuous intravenous infusion at a dosage of 5 or 15 μg/m2/day. Nine patients received a total of 18 cycles. Four patients achieved complete remission after the first cycle of treatment; 2 patients showed a complete remission from the second cycle after previous reduction of blast load by chemotherapy. Three patients did not respond, of whom one patient proceeded to a second cycle without additional chemotherapy and again did not respond. Four patients were successfully retransplanted in molecular remission from haploidentical donors. After a median follow up of 398 days, the probability of hematologic event-free survival is 30%. Major toxicities were grade 3 seizures in one patient and grade 3 cytokine release syndrome in 2 patients. Blinatumomab can induce molecular remission in pediatric patients with posttransplant relapsed B-precursor acute lymphoblastic leukemia and facilitate subsequent allogeneic hematopoietic stem cell transplantation from haploidentical donor with subsequent long-term leukemia-free survival.
• Endomicroscopy is a new imaging tool for gastrointestinal endoscopy.
• Panchromoendoscopy with targeted biopsies has become the method of choice for surveillance of patients with inflammatory bowel disease.
• Endomicroscopy can be added after chromoendoscopy to clarify whether standard biopsies are still needed.
• This smart biopsy concept can increase the diagnostic yield of intraepithelial neoplasia and substantially reduce the need for biopsies.
• Endomicroscopy is still mainly used for research but clinical acceptance is increasing because of a multitude of positive studies about the diagnostic value of endomicroscopy.
The highly conserved eukaryotic process of macroautophagy (autophagy) is a non-specific bulk-degradation program critical for maintaining proper cellular homeostasis, and for clearing aged and damaged organelles. This decision is inextricably dependent upon prevailing metabolic demands and energy requirements of the cell. Soluble monomeric decorin functions as a natural tumor repressor that antagonizes a variety of receptor tyrosine kinases. Recently, we discovered that decorin induces endothelial cell autophagy, downstream of VEGFR2. This process was wholly dependent upon Peg3, a decorin-inducible genomically imprinted tumor suppressor gene. However, the signaling cascades responsible have remained elusive. In this report we discovered that Vps34, a class III phosphoinositide kinase, is an upstream kinase required for Peg3 induction. Moreover, decorin triggered differential formation of Vps34/Beclin 1 complexes with concomitant dissolution of inhibitive Bcl-2/Beclin 1 complexes. Further, decorin inhibited anti-autophagic signaling via suppression of Akt/mTOR/p70S6K activity with the concurrent activation of pro-autophagic AMPK-mediated signaling cascades. Mechanistically, AMPK is downstream of VEGFR2 and inhibition of AMPK signaling abrogated decorin-evoked autophagy. Collectively, these findings hint at the complexity of the underlying molecular relays necessary for decorin-evoked endothelial cell autophagy and reveal important therapeutic targets for augmenting autophagy and combatting tumor angiogenesis.
The highly conserved eukaryotic process of macroautophagy (autophagy) is a non-specific bulk-degradation program critical for maintaining proper cellular homeostasis, and for clearing aged and damaged organelles. This decision is inextricably dependent upon prevailing metabolic demands and energy requirements of the cell. Soluble monomeric decorin functions as a natural tumor repressor that antagonizes a variety of receptor tyrosine kinases. Recently, we discovered that decorin induces endothelial cell autophagy, downstream of VEGFR2. This process was wholly dependent upon Peg3, a decorin-inducible genomically imprinted tumor suppressor gene. However, the signaling cascades responsible have remained elusive. In this report we discovered that Vps34, a class III phosphoinositide kinase, is an upstream kinase required for Peg3 induction. Moreover, decorin triggered differential formation of Vps34/Beclin 1 complexes with concomitant dissolution of inhibitive Bcl-2/Beclin 1 complexes. Further, decorin inhibited anti-autophagic signaling via suppression of Akt/mTOR/p70S6K activity with the concurrent activation of pro-autophagic AMPK-mediated signaling cascades. Mechanistically, AMPK is downstream of VEGFR2 and inhibition of AMPK signaling abrogated decorin-evoked autophagy. Collectively, these findings hint at the complexity of the underlying molecular relays necessary for decorin-evoked endothelial cell autophagy and reveal important therapeutic targets for augmenting autophagy and combatting tumor angiogenesis.
The web and the social web play an increasingly important role as an information source for Members of Parliament and their assistants, journalists, political analysts and researchers. It provides important and crucial background information, like reactions to political events and comments made by the general public. The case study presented in this paper is driven by two European parliaments (the Greek and the Austrian parliament) and targets an effective exploration of political web archives. In this paper, we describe semantic technologies deployed to ease the exploration of the archived web and social web content and present evaluation results.
The World Wide Web is the largest information repository available today. However, this information is very volatile and Web archiving is essential to preserve it for the future. Existing approaches to Web archiving are based on simple definitions of the scope of Web pages to crawl and are limited to basic interactions with Web servers. The aim of the ARCOMEM project is to overcome these limitations and to provide flexible, adaptive and intelligent content acquisition, relying on social media to create topical Web archives. In this article, we focus on ARCOMEM’s crawling architecture. We introduce the overall architecture and we describe its modules, such as the online analysis module, which computes a priority for the Web pages to be crawled, and the Application-Aware Helper which takes into account the type of Web sites and applications to extract structure from crawled content. We also describe a large-scale distributed crawler that has been developed, as well as the modifications we have implemented to adapt Heritrix, an open source crawler, to the needs of the project. Our experimental results from real crawls show that ARCOMEM’s crawling architecture is effective in acquiring focused information about a topic and leveraging the information from social media.
The constantly growing amount of Web content and the success of the SocialWeb lead to increasing needs for Web archiving. These needs go beyond the pure preservationo of Web pages. Web archives are turning into “community memories” that aim at building a better understanding of the public view on, e.g., celebrities, court decisions and other events. Due to the size of the Web, the traditional “collect-all” strategy is in many cases not the best method to build Web archives. In this paper, we present the ARCOMEM (From Future Internet 2014, 6 689 Collect-All Archives to Community Memories) architecture and implementation that uses semantic information, such as entities, topics and events, complemented with information from the Social Web to guide a novel Web crawler. The resulting archives are automatically enriched with semantic meta-information to ease the access and allow retrieval based on conditions that involve high-level concepts.
Atrial fibrillation (AF) continues to be a leading cause of cerebrovascular morbidity and mortality resulting from cardioembolic stroke. Oral anticoagulation therapy has been shown to decrease the incidence of cardioembolic stroke in patients with AF by more than 50%. Appropriate use of anticoagulation with vitamin K antagonists requires precise adherence and monitoring. A number of factors that potentially induce patients' dissatisfaction reduce quality of patient life. New direct oral anticoagulants, such as the direct factor Xa inhibitors rivaroxaban, apixaban, edoxaban, and the thrombin inhibitor dabigatran, were developed to overcome the limitations of the conventional anticoagulant drugs. However, models to optimize the benefit of therapy and to ensure that therapy can be safely continued are missing for the new oral anticoagulants. This review will briefly describe the new oral anticoagulants dabigatran, rivaroxaban, apixaban, and edoxaban with focus on their use for prevention of embolic events in AF. Moreover, it will discuss the safety, efficacy, cost data, and benefit for patients' quality of life and adherence.
The ( J, T ) = (1, 1) parity doublet in 20Ne at 11.26 MeV is a good candidate to study parity violation in nuclei. However, its energy splitting is known with insufficient accuracy for quantitative estimates of parity violating effects. To improve on this unsatisfactory situation, nuclear resonance fluorescence experiments using linearly and circularly polarized γ -ray beams were used to determine the energy difference of the parity doublet E = E(1−) − E(1+) = −3.2(±0.7)stat( +0.6 −1.2)sys keV and the ratio of their integrated cross sections I (+) s,0 /I (−) s,0 = 29(±3)stat( +14 −7 )sys. Shell-model calculations predict a parityviolating matrix element having a value in the range 0.46–0.83 eV for the parity doublet. The small energy difference of the parity doublet makes 20Ne an excellent candidate to study parity violation in nuclear excitations.
In this paper we discuss to what extent one can infer details of the interior structure of a black hole based on its horizon. Recalling that black hole thermal properties are connected to the non-classical nature of gravity, we circumvent the restrictions of the no-hair theorem by postulating that the black hole interior is singularity free due to violations of the usual energy conditions. Further these conditions allow one to establish a one-to-one, holographic projection between Planckian areal “bits” on the horizon and “voxels”, representing the gravitational degrees of freedom in the black hole interior. We illustrate the repercussions of this idea by discussing an example of the black hole interior consisting of a de Sitter core postulated to arise from the local graviton quantum vacuum energy. It is shown that the black hole entropy can emerge as the statistical entropy of a gas of voxels.
Peripheral T-cell lymphoma (PTCL) represents a relatively rare group of heterogeneous non-Hodgkin lymphomas with a very poor prognosis. Current therapies, based on historical regimens for aggressive B-cell lymphomas, have resulted in insufficient patient outcomes. The majority of patients relapse rapidly, and current 5-year overall survival rates are only 10–30%. It is evident that new approaches to treat patients with PTCL are required. In recent years, prospective studies in PTCL have been initiated, mainly in patients with relapsed/refractory disease. In some of these, selected histologic subtypes have been evaluated in detail. As a consequence, numerous new therapies have been developed and shown activity in PTCL, including: agents targeting the immune system (e.g. brentuximab vedotin, alemtuzumab, lenalidomide); histone deacetylase inhibitors (romidepsin, belinostat); antifolates (pralatrexate); fusion proteins (denileukin diftitox); nucleoside analogs (pentostatin, gemcitabine); and other agents (e.g. alisertib, plitidepsin, bendamustine, bortezomib). A variety of interesting novel combinations is also emerging. It is hoped that these innovative approaches, coupled with a greater understanding of the clinicopathologic features, pathogenesis, molecular biology, and natural history of PTCL will advance the field and improve outcomes in this challenging group of diseases. This review summarizes the currently available clinical evidence on the various approaches to treating relapsed/refractory PTCL, including the role of stem cell transplantation, with an emphasis on potential new drug therapies.
Based on a meta-analysis, Redick and Lindsey (2013) found that complex span and n-back tasks show an average correlation of r = 0.20, and concluded that "complex span and n-back tasks cannot be used interchangeably as working memory measures in research applications" (p. 1102). Here, we comment on this conclusion from a psychometric perspective. In addition to construct variance, performance on a test contains measurement error, task-specific variance, and paradigm-specific variance. Hence, low correlations among dissimilar indicators do not provide strong evidence for the existence, or absence, of a construct common to both indicators. One way to arrive at such evidence is to fit hierarchical latent factors that model task-specific, paradigm-specific, and construct variance. We report analyses for 101 younger and 103 older adults who worked on nine different working memory tasks. The data are consistent with a hierarchical model of working memory, according to which both complex span and n-back tasks are valid indicators of working memory. The working memory factor predicts 71% of the variance in a factor of reasoning among younger adults (83% for among older adults). When the working memory factor was restricted to any possible triplet of working memory tasks, the correlation between working memory and reasoning was inversely related to the average magnitude of the correlations among the indicators, indicating that more highly intercorrelated indicators may provide poorer coverage of the construct space. We stress the need to go beyond specific tasks and paradigms when studying higher-order cognitive constructs, such as working memory.
Smac (second mitochondria-derived activator of caspase) mimetics are considered as promising anticancer therapeutics and used to induce apoptosis by antagonizing inhibitor of apoptosis proteins, which are often abundantly expressed in cancer cells. Here, we identify interferon regulatory factor 1 (IRF1) as a novel critical regulator of Smac mimetic BV6-induced apoptosis and proinflammatory cytokine secretion with impact on the immune response. IRF1 knockdown rescues cells from BV6-induced apoptosis and attenuates BV6-stimulated upregulation of tumor necrosis factor-α (TNFα), indicating that IRF1 mediates BV6-triggered cell death, at least in part, by inducing TNFα. This notion is supported by data showing that exogenous supply of TNFα restores BV6-induced cell death in IRF-knockdown cells. Interestingly, IRF1 selectively controls the induction of nuclear factor-κB (NF-κB) target genes, as IRF1 depletion attenuates BV6-stimulated upregulation of TNFα and interleukin-8 (IL-8) but not p100 and RelB. Concomitant knockdown of IRF1 and p65 cooperate to inhibit BV6-induced cell death, implying a cooperative interaction of IRF1 and NF-κB. In addition, IRF1 silencing hampers TNFα induction by TNFα itself as an another prototypical NF-κB stimulus. Importantly, IRF1 depletion impedes BV6-stimulated secretion of additional proinflammatory cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-8, IL-6 and monocyte chemoattractant protein-1, and migration of primary monocytes to BV6-treated tumor cells. In conclusion, this identification of IRF1 as a dual regulator of BV6-induced apoptosis and inflammatory cytokine secretion provides novel insights into determinants of sensitivity towards Smac mimetic and possible implications of Smac mimetic treatment on tumor microenvironment and immune response.
How to write (international) legal histories that would be true to their protagonists while simultaneously relevant to present audiences? Most of us would also want to write "critically" – that is to say, at least by aiming to avoid Eurocentrism, hagiography and commitment to an altogether old-fashioned view of international law as an instrument of progress. Hence we write today our histories "in context". But this cannot be all. Framing the relevant "context" is only possible by drawing upon more or less conscious jurisprudential and political preferences. Should attention be focused on academic debates, military power, class structures or assumptions about the longue durée? Such choices determine for us what we think of as relevant "contexts", and engage us as participants in large conversations about law and power that are not only about what once "was" but also what there will be in the future.
Political theology’s recent rise to academic prominence has, no doubt, been inspired by the sense of a certain staleness of standard (read: Anglo-American) analytical political and legal theory. Especially postcolonial and postmodern philosophy has resuscitated debates about the reality of secularization in Europe, pointing out that much of our shared political metaphysic is indeed that – a metaphysic – with close historical links to debates in theology. That should be no surprise. For almost half a millennium theology stood as the primus inter pares among the three "higher faculties" at European universities. The best minds at work in Europe explained the social and political changes to European audiences within a fully God-centric intellectual universe. Awareness of that fact, as Wim Decock points out in this massive and brilliant work, not only assists us in understanding the development of our political and legal vocabularies. It also enables us to grasp the contingency of our present debates, the way opposite standpoints on political and legal obligation refer back to assumptions about human nature, the roles of individual and society and the nature of "law" that are hard to detach from religious speculation. ...
The children's book "Duck! Rabbit!" dramatizes the lesson that just because one is right, others don’t have to be wrong. An endless dispute is quickly settled once the quarrellers experience an aspect change or gestalt switch and thereby realize that the same picture can be seen in different ways. This simple scenario offers an intriguing model for arbitrating between conflicting positions by going back and forth between different aspects and thereby realizing that conflicting accounts can be equally valid.
The notion of ambivalence currently seems to be an invigorating figure with heuristic potential in political, social, and art theory. It refers to a plurality of possibilities, a paradoxical multiplicity, and a complex relationality. It foregrounds thinking in terms of indeterminacy and incommensurability, as well as in terms of the possible. Ambivalence has been deployed in positive ways, as offering political promise, while, at the same time, being regarded with suspicion.
In 1989 the triumphant discourse on the 'end of history' brought the death of socialism and the expansion of liberal democracy. The proclamation of the end of history could also be read literally, as the death of 'history' as a discipline with a homogenized narrative. It is in the same year that Pierra Nora wrote a groundbreaking article, which disentangled the fundamental opposition between history and memory, and at the end assumed the standpoint of memory. The article departs from the diagnosis of post-Yugoslav contemporary accounts of Yugoslav and partisan events. The critique of nationalist and Yugonostalgic discourses discloses shared assumptions that are based on the 'romantic' temporality of Nation and on history as a closed process. In the main part of the article the author works on the special, multiple temporality of partisan poetry that emerged during the WWII partisan struggle. The special temporality hinges on the productive and tensed relationship between the 'not yet existing' - the position of the new society free of foreign occupation, but also in a radically transformed society - and the contemporary struggle within war, which is also marked by the fear that the rupture of the struggle might not be remembered rightly, if at all. The memory of the present struggle remains to be the task to be realized not only for poets, but for everyone participating in the struggle. This is where the revolutionary temporality of the unfinished process comes to its fore, relating poetry to struggle, but again producing a form of poetry in the struggle.
Identity politics redux
(2014)
Pornography reappropriated by feminist and queer pornographers is being reimagined as a site of activist productions, be it through the reshaping of desire or engaging with wider discussions of representational politics. Here, K. Heintzman takes up Shine Louise Houston's feature length film, "The Wild Search", as a unique case study for addressing the relationship between debates of identity politics and queer activist practice.
In his major theoretical work on experimentation, "Towards a History of Epistemic Things" (1997), Hans-Jörg Rheinberger writes: 'If experimental systems have a life of their own, precisely what kind of life they have remains to be determined.' Rheinberger is alluding to the slogan Ian Hacking gave to the post-Kuhnian 'practical turn' in the history and epistemology of science.
This paper deals with the general topic of subjectivity and subjectivation, considered through a philosophical tradition opposed to the 'philosophies of consciousness': that is, a philosophical tradition, from Spinoza to Althusser, that rejects as a myth the supposed primacy and presocial character of subjective identity.
The Rubin vase and duck-rabbit have two things in common: not only are they famous multistable figures, or 'Kippbilder', but before being discovered by scientists and philosophers, they both started their career as simple jokes. In contrast to usual understandings of 'Kippbilder', this paper will try to demonstrate that 'Kippbilder' can be a helpful model for understanding better dramatic, existential, and even religious events and their consequences. Multistable figures or 'Kippbilder' combine reversibility and irreversibility in an interesting way. While the so called first aspect change introduces an irreversible split, all subsequent aspect changes can be understood as an endless chain of reversible changes. After discussing the specificity of the Rubin vase and its aspect changes and focussing then on the distinction between first and further aspect changes, Di Blasi suggests the productive potential of the multistable figure as model for eventful events in discussing the conversion of Paul and his 'hōs mē' ('as if not').
Aspects and abstracta
(2014)
Philosophers of perception and psychologists first studied 'multistable' or 'reversible' figures, 'Kippbilder', in the nineteenth century. The earliest description of the phenomenon of a 'sudden and involuntary change in the apparent position' of a represented object occurred in a letter written by Louis Albert Necker in Geneva to Sir David Brewster on 24 May 1832 and published six months later in the "Philosophical Magazine". The picture in question would become known as the Necker cube.
KippCity
(2014)
On 28 April 2011, on the Rathausplatz of Neukölln, Christine Hentschel's puzzlement vis-à-vis Neukölln's liberation met the neighbourhood's flickering urbanity, which she seeks to capture in a project called KippCity. KippCity is an experiment in tracing urban change while it happens. If space is the 'event of place', as Doreen Massey holds, the space of KippCity is the transformation of Neukölln. This chapter explores the potentials of multistable figures (Kippbilder) for conceptualizing urban change. This potential, Hentschel argues, lies in the flip-moment itself, in the space-time of urban transformation. In Berlin-Neukölln, a neighbourhood long branded as poor and failing, multiple and partly conflicting flip-scenarios have begun to inspire and haunt the neighbourhood and its self-reflective talk. KippCity Neukölln is thus a flickering figure. But unlike an artefact Kippbild, which flickers between duck and rabbit, for example, KippCity Neukölln does not simply tip into a new pre-fabricated form, but rather wavers between different future scenarios. Neukölln's flickering urbanity is thus nervous, full of uncertainty, frustration and enthusiasm. The article shows how the neighbourhood seeks escape from the dystopia of two dominant flip scenarios of ghettoization and gentrification by digging its claws into its 'Now'.
Introduction
(2014)
The experience of multistable figures or so-called Kippbilder - the sudden and repeated 'kippen' of perception as the same object is seen under different aspects - is fascinating in its own right. However, what animated the year-long discussion leading to this volume was a critical exploration of the proposition that such figures may offer a helpful model for thinking through the intercultural and interdisciplinary effort of productively negotiating between conflicting positions.
Halobacillus halophilus, a moderately halophilic bacterium isolated from salt marshes, produces various compatible solutes to cope with osmotic stress. Glutamate and glutamine are dominant compatible solutes at mild salinities. Glutamine synthetase activity in cell suspensions of Halobacillus halophilus wild type was shown to be salt dependent and chloride modulated. A possible candidate to catalyze glutamine synthesis is glutamine synthetase A2, whose transcription is stimulated by chloride. To address the role of GlnA2 in the biosynthesis of the osmolytes glutamate and glutamine, a deletion mutant (ΔglnA2) was generated and characterized in detail. We compared the pool of compatible solutes and performed transcriptional analyses of the principal genes controlling the solute production in the wild type strain and the deletion mutant. These measurements did not confirm the hypothesized role of GlnA2 in the osmolyte production. Most likely the presence of another, yet to be identified enzyme has the main contribution in the measured activity in crude extracts and probably determines the total chloride-modulated profile. The role of GlnA2 remains to be elucidated.
The article aims to investigate, under the aspect of translation, the process of legal appropriation and reproduction of international law during the course of the 19th century. An occidental understanding of translation played an important role in the so-called process of universalization in the 19th century, as it made the complexity of global circulation of ideas invisible. Approaches proposed by scholars of Postcolonial, Cultural and Translation Studies are useful for re-reading histories of the circulation of European ideas, particularly the international law doctrines, from a different perspective. The great strides made in Translation and Cultural Studies in the last decades, as well as the discernment practiced in the scholarship of Postcolonial Studies, are important for a broader and more differentiated understanding of the processes of appropriation and reproduction of the doctrines of international law during the 19th century. The present article begins by tracing the connection between translation and universalization of concepts in 19th century international law; after a short excursus on the Western idea of translation, the attention is focused on the translation of international law textbooks. The conclusive section is dedicated to a comparison between Emer de Vattel’s Droit des gens and Andrés Bello’s Principios de Derecho de Jentes.
During embryonic development a large number of widely differing and specialized cell types with identical genomes are generated from a single totipotent zygote. Tissue specific transcription factors cooperate with epigenetic modifiers to establish cellular identity in differentiated cells and epigenetic regulatory mechanisms contribute to the maintenance of distinct chromatin states and cell-type specific gene expression patterns, a phenomenon referred to as epigenetic memory. This is accomplished via the stable maintenance of various epigenetic marks through successive rounds of cell division. Preservation of DNA methylation patterns is a well-established mechanism of epigenetic memory, but more recently it has become clear that many other epigenetic modifications can also be maintained following DNA replication and cell division. In this review, we present an overview of the current knowledge regarding the role of histone lysine methylation in the establishment and maintenance of stable epigenetic states.
The morphology of presynaptic specializations can vary greatly ranging from classical single-release-site boutons in the central nervous system to boutons of various sizes harboring multiple vesicle release sites. Multi-release-site boutons can be found in several neural contexts, for example at the neuromuscular junction (NMJ) of body wall muscles of Drosophila larvae. These NMJs are built by two motor neurons forming two types of glutamatergic multi-release-site boutons with two typical diameters. However, it is unknown why these distinct nerve terminal configurations are used on the same postsynaptic muscle fiber. To systematically dissect the biophysical properties of these boutons we developed a full three-dimensional model of such boutons, their release sites and transmitter-harboring vesicles and analyzed the local vesicle dynamics of various configurations during stimulation. Here we show that the rate of transmission of a bouton is primarily limited by diffusion-based vesicle movements and that the probability of vesicle release and the size of a bouton affect bouton-performance in distinct temporal domains allowing for an optimal transmission of the neural signals at different time scales. A comparison of our in silico simulations with in vivo recordings of the natural motor pattern of both neurons revealed that the bouton properties resemble a well-tuned cooperation of the parameters release probability and bouton size, enabling a reliable transmission of the prevailing firing-pattern at diffusion-limited boutons. Our findings indicate that the prevailing firing-pattern of a neuron may determine the physiological and morphological parameters required for its synaptic terminals.
Local active information storage as a tool to understand distributed neural information processing
(2014)
Every act of information processing can in principle be decomposed into the component operations of information storage, transfer, and modification. Yet, while this is easily done for today's digital computers, the application of these concepts to neural information processing was hampered by the lack of proper mathematical definitions of these operations on information. Recently, definitions were given for the dynamics of these information processing operations on a local scale in space and time in a distributed system, and the specific concept of local active information storage was successfully applied to the analysis and optimization of artificial neural systems. However, no attempt to measure the space-time dynamics of local active information storage in neural data has been made to date. Here we measure local active information storage on a local scale in time and space in voltage sensitive dye imaging data from area 18 of the cat. We show that storage reflects neural properties such as stimulus preferences and surprise upon unexpected stimulus change, and in area 18 reflects the abstract concept of an ongoing stimulus despite the locally random nature of this stimulus. We suggest that LAIS will be a useful quantity to test theories of cortical function, such as predictive coding.
Top-down influences on ambiguous perception: the role of stable and transient states of the observer
(2014)
The world as it appears to the viewer is the result of a complex process of inference performed by the brain. The validity of this apparently counter-intuitive assertion becomes evident whenever we face noisy, feeble or ambiguous visual stimulation: in these conditions, the state of the observer may play a decisive role in determining what is currently perceived. On this background, ambiguous perception and its amenability to top-down influences can be employed as an empirical paradigm to explore the principles of perception. Here we offer an overview of both classical and recent contributions on how stable and transient states of the observer can impact ambiguous perception. As to the influence of the stable states of the observer, we show that what is currently perceived can be influenced (1) by cognitive and affective aspects, such as meaning, prior knowledge, motivation, and emotional content and (2) by individual differences, such as gender, handedness, genetic inheritance, clinical conditions, and personality traits and by (3) learning and conditioning. As to the impact of transient states of the observer, we outline the effects of (4) attention and (5) voluntary control, which have attracted much empirical work along the history of ambiguous perception. In the huge literature on the topic we trace a difference between the observer's ability to control dominance (i.e., the maintenance of a specific percept in visual awareness) and reversal rate (i.e., the switching between two alternative percepts). Other transient states of the observer that have more recently drawn researchers' attention regard (6) the effects of imagery and visual working memory. (7) Furthermore, we describe the transient effects of prior history of perceptual dominance. (8) Finally, we address the currently available computational models of ambiguous perception and how they can take into account the crucial share played by the state of the observer in perceiving ambiguous displays.
Evaluating model fit in nonlinear multilevel structural equation models (MSEM) presents a challenge as no adequate test statistic is available. Nevertheless, using a product indicator approach a likelihood ratio test for linear models is provided which may also be useful for nonlinear MSEM. The main problem with nonlinear models is that product variables are non-normally distributed. Although robust test statistics have been developed for linear SEM to ensure valid results under the condition of non-normality, they have not yet been investigated for nonlinear MSEM. In a Monte Carlo study, the performance of the robust likelihood ratio test was investigated for models with single-level latent interaction effects using the unconstrained product indicator approach. As overall model fit evaluation has a potential limitation in detecting the lack of fit at a single level even for linear models, level-specific model fit evaluation was also investigated using partially saturated models. Four population models were considered: a model with interaction effects at both levels, an interaction effect at the within-group level, an interaction effect at the between-group level, and a model with no interaction effects at both levels. For these models the number of groups, predictor correlation, and model misspecification was varied. The results indicate that the robust test statistic performed sufficiently well. Advantages of level-specific model fit evaluation for the detection of model misfit are demonstrated.
Families are central to the social and emotional development of youth, and most families engage in musical activities together, such as listening to music or talking about their favorite songs. However, empirical evidence of the positive effects of musical family rituals on social cohesion and emotional well-being is scarce. Furthermore, the role of culture in the shaping of musical family rituals and their psychological benefits has been neglected entirely. This paper investigates musical rituals in families and in peer groups (as an important secondary socialization context) in two traditional/collectivistic and two secular/individualistic cultures, and across two developmental stages (adolescence vs. young adulthood). Based on cross-sectional data from 760 young people in Kenya, the Philippines, New Zealand, and Germany, our study revealed that across cultures music listening in families and in peer groups contributes to family and peer cohesion, respectively. Furthermore, the direct contribution of music in peer groups on well-being appears across cultural contexts, whereas musical family rituals affect emotional well-being in more traditional/collectivistic contexts. Developmental analyses show that musical family rituals are consistently and strongly related to family cohesion across developmental stages, whereas musical rituals in peer groups appear more dependent on the developmental stage (in interaction with culture). Contributing to developmental as well as cross-cultural psychology, this research elucidated musical rituals and their positive effects on the emotional and social development of young people across cultures. The implications for future research and family interventions are discussed.
In self-organized critical (SOC) systems avalanche size distributions follow power-laws. Power-laws have also been observed for neural activity, and so it has been proposed that SOC underlies brain organization as well. Surprisingly, for spiking activity in vivo, evidence for SOC is still lacking. Therefore, we analyzed highly parallel spike recordings from awake rats and monkeys, anesthetized cats, and also local field potentials from humans. We compared these to spiking activity from two established critical models: the Bak-Tang-Wiesenfeld model, and a stochastic branching model. We found fundamental differences between the neural and the model activity. These differences could be overcome for both models through a combination of three modifications: (1) subsampling, (2) increasing the input to the model (this way eliminating the separation of time scales, which is fundamental to SOC and its avalanche definition), and (3) making the model slightly sub-critical. The match between the neural activity and the modified models held not only for the classical avalanche size distributions and estimated branching parameters, but also for two novel measures (mean avalanche size, and frequency of single spikes), and for the dependence of all these measures on the temporal bin size. Our results suggest that neural activity in vivo shows a mélange of avalanches, and not temporally separated ones, and that their global activity propagation can be approximated by the principle that one spike on average triggers a little less than one spike in the next step. This implies that neural activity does not reflect a SOC state but a slightly sub-critical regime without a separation of time scales. Potential advantages of this regime may be faster information processing, and a safety margin from super-criticality, which has been linked to epilepsy.
Changes in vitamin D serum levels have been associated with inflammatory diseases, such as inflammatory bowel disease (IBD), rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis (MS), atherosclerosis, or asthma. Genome- and transcriptome-wide studies indicate that vitamin D signaling modulates many inflammatory responses on several levels. This includes (i) the regulation of the expression of genes which generate pro-inflammatory mediators, such as cyclooxygenases or 5-lipoxygenase, (ii) the interference with transcription factors, such as NF-κB, which regulate the expression of inflammatory genes and (iii) the activation of signaling cascades, such as MAP kinases which mediate inflammatory responses. Vitamin D targets various tissues and cell types, a number of which belong to the immune system, such as monocytes/macrophages, dendritic cells (DCs) as well as B- and T cells, leading to individual responses of each cell type. One hallmark of these specific vitamin D effects is the cell-type specific regulation of genes involved in the regulation of inflammatory processes and the interplay between vitamin D signaling and other signaling cascades involved in inflammation. An important task in the near future will be the elucidation of the regulatory mechanisms that are involved in the regulation of inflammatory responses by vitamin D on the molecular level by the use of techniques such as chromatin immunoprecipitation (ChIP), ChIP-seq, and FAIRE-seq.
Symbiotic nitrogen fixation (SNF) in root nodules of grain legumes such as chickpea is a highly complex process that drastically affects the gene expression patterns of both the prokaryotic as well as eukaryotic interacting cells. A successfully established symbiotic relationship requires mutual signaling mechanisms and a continuous adaptation of the metabolism of the involved cells to varying environmental conditions. Although some of these processes are well understood today many of the molecular mechanisms underlying SNF, especially in chickpea, remain unclear. Here, we reannotated our previously published transcriptome data generated by deepSuperSAGE (Serial Analysis of Gene Expression) to the recently published draft genome of chickpea to assess the root- and nodule-specific transcriptomes of the eukaryotic host cells. The identified gene expression patterns comprise up to 71 significantly differentially expressed genes and the expression of twenty of these was validated by quantitative real-time PCR with the tissues from five independent biological replicates. Many of the differentially expressed transcripts were found to encode proteins implicated in sugar metabolism, antioxidant defense as well as biotic and abiotic stress responses of the host cells, and some of them were already known to contribute to SNF in other legumes. The differentially expressed genes identified in this study represent candidates that can be used for further characterization of the complex molecular mechanisms underlying SNF in chickpea.
High resolution gamma spectroscopy with sophisticated detector arrays significantly contributes to nuclear structure physics. The Advanced Gamma Tracking Array (AGATA) combines gamma tracking and pulse shape analysis to achieve an efficiency and quality of the spectra that could not be reached with spectrometers of the previous generation. Tracking of the photons interacting in the detector requires a precise knowledge of the individual interaction positions. The task of the pulse shape analysis is to provide a position resolution of better than $5mm$ FWHM, a value that could not be achieved by segmentation of the detector alone. As the signals induced on the electrodes of the detectors depends on the position of interaction, the charge pulses can be used to infer the interaction position. To be able to handle high rates, algorithms that are used have to be optimized to be able to process the data in real-time. Pulse shape analysis is the most involved part of the real-time processing and requires further improvement. This work is dealing with optimizations and improvements of pulse shape analysis algorithms. The Grid Search algorithm localizes the interaction position by comparing the measured pulse shape with precomputed shapes in a database to find the best fit. Two linear filters based on orthogonal transformations have been compared and it could be concluded that the one based on a singular value decomposition of the pulse shapes works best. It speeds up the pulse shape analysis by a factor of roughly $2-3$ (depending on how it is combined with the other modifications). Further, a new method to exclude most signals from the database as best fit has been developed based on the principle of lateration. Most interaction positions can be excluded by means of a fast check and for single interactions on average only $34.8\%$ of all signals from the database have to be compared to the measured one. The overhead introduced by the method is negligible and the reduced number of comparisons almost direclty translates into increased efficiency of the algorithm. A similar method could also be applied for double interactions. Two or more interactions taking place in the same segment require special treatment as the measured signals cannot be directly compared to signals from the database. A new method to calculate the figure of merit that quantifies the fit in case of a double interaction has been introduced. Compared to the unmodified algorithm the new method finds the best fit for double interactions roughly two orders of magnitude faster. Actually, the time required to localize double interactions is almost the same as for single interactions. Apart from optimizing the algorithm, also the achievable position resolution was investigated. It strongly varies inside the volume of the detector and it crucially depends on the shape of all signals in the database and the amplitude of the noise present in the measured signals. As a first step towards a precise analytic expression for the position resolution, an estimate for the probability to find the correct position has been derived.
Understanding the role of structure and social aspects regarding heat stress of people in urban areas requires an interdisciplinary scientific approach that connects methods from both natural sciences and social sciences. In this study, we combine three approaches to provide an interdisciplinary analysis of the structure and social components of heat stress in the city of Aachen, Germany. First, we assess the overall spatial structure of the urban heat island using spatially distributed measurements from mobile air temperature recordings on public transport units combined with spatially distributed geo-statistical data. The results indicate that the time of day matters: During the afternoon, areas with a relative low building density, like the industrial area northeast of the inner city, are the warmest, while surfaces in high-building-density areas like the inner city heat up faster during the evening. Second, we combine these measurements with place-based survey data collected in 2010 from residents aged 50 to 92 regarding their individual housing conditions, medical history and social integration to examine the match among heat-based stress of older residents, social conditions and elevated temperatures in their residential quarter. We identify disadvantaged areas for specific already-disadvantaged demographic groups in the city, pointing to a cumulation of inequalities, including heat stress among the most vulnerable. Third, we compare data of biometeorological measurements on urban public squares during the afternoon with results of the micrometeorological model ENVI-met to examine the spatial variability of the inner-city heat load. We complement the modelling results with on-site interviews to evaluate people’s heat perception at the same public places. A simulation shows that additional vegetation would increase thermal comfort at these public places, whereby the heat load assessed using the predicted mean vote (PMV) value would decrease by approximately 60 %. Furthermore, we demonstrate the strengths and weaknesses of heat stress simulation. ENVI-met allows for an overall reasonable representation of heat load during stable atmospheric conditions. However, due to the setup and structure of ENVI-met, large-scale atmospheric changes that occur during the day cannot readily be integrated into ENVI-met simulations.
Aim. To compare the efficacy, safety, and patient’s perception of two prostaglandin E2 application methods for induction of labour.
Method. Above 36th weeks of gestation, all women, who were admitted to hospital for induction of labour, were prospectively randomised to intravaginal 1 mg or intracervical 0.5 mg irrespective of cervical Bishop score. The main outcome variables were induction-to-delivery interval, number of foetal blood samples, PDA rate, rate of oxytocin augmentation, rate of vaginal delivery, and patient’s perception using semantic differential questionnaire.
Results. Thirty-nine patients were enrolled in this study. There was no statistical significant difference between the two groups in regard to perceptions of induction. The median induction delivery time using intravaginal versus intracervical administration was 29.9 versus 12.8 hours, respectively (). No statistically difference between the groups was detected in regard to parity, gestation age, cervical Bishop score, number of foetal blood samples, PDA rate, rate of oxytocin augmentation, and mode of birth.
Summary. Irrespective of the cervical Bishop Score, intracervical gel had a shorter induction delivery time without impingement on the women’s perception of induction.
Altered microRNA (miRNA) expression is a hallmark of many cancer types. The combined analysis of miRNA and messenger RNA (mRNA) expression profiles is crucial to identifying links between deregulated miRNAs and oncogenic pathways. Therefore, we investigated the small non-coding (snc) transcriptomes of nine clear cell renal cell carcinomas (ccRCCs) and adjacent normal tissues for alterations in miRNA expression using a publicly available small RNA-Sequencing (sRNA-Seq) raw-dataset. We constructed a network of deregulated miRNAs and a set of differentially expressed genes publicly available from an independent study to in silico determine miRNAs that contribute to clear cell renal cell carcinogenesis. From a total of 1,672 sncRNAs, 61 were differentially expressed across all ccRCC tissue samples. Several with known implications in ccRCC development, like the upregulated miR-21-5p, miR-142-5p, as well as the downregulated miR-106a-5p, miR-135a-5p, or miR-206. Additionally, novel promising candidates like miR-3065, which i.a. targets NRP2 and FLT1, were detected in this study. Interaction network analysis revealed pivotal roles for miR-106a-5p, whose loss might contribute to the upregulation of 49 target mRNAs, miR-135a-5p (32 targets), miR-206 (28 targets), miR-363-3p (22 targets), and miR-216b (13 targets). Among these targets are the angiogenesis, metastasis, and motility promoting oncogenes c-MET, VEGFA, NRP2, and FLT1, the latter two coding for VEGFA receptors.
Physics at its core is an experimental pursuit. If one theory does not agree with experimental results, then the theory is wrong. However, it is becoming harder and harder to directly test some theories of fundamental physics at the high energy/small distance frontier exactly because this frontier is becoming technologically harder to reach. The Large Hadron Collider is getting near the limit of what we can do with present accelerator technology in terms of directly reaching the energy frontier. The motivation for this special issue was to try and collect together ideas and potential approaches to experimentally probe some of our ideas about physics at the high energy/small distance frontier. Some of the papers in this special issue directly deal with the issue of what happens to spacetime at small distance scales. In the paper by A. Aurilia and E. Spallucci a picture of quantum spacetime is given based on the effects of ultrahigh velocity length contractions on the structure of the spacetime. The work of P. Nicolini et al. further pursues the idea that spacetime has a minimal length. The consequences of this minimal length are investigated in terms of the effects it would have on the gravitational collapse of a star to form a black hole. In the article by G. Amelino-Camelia et al. the quantum structure of spacetime is studied through the Fermi LAT data on the Gamma Ray Burst GRB130427A. The article by S. Hossenfelder addressed the question of whether spacetime is fundamentally continuous or discrete and postulates that in the case when spacetime is discrete it might have defects which would have important observational consequences. ...
This paper studies the geometry and the thermodynamics of a holographic screen in the framework of the ultraviolet self-complete quantum gravity. To achieve this goal we construct a new static, neutral, nonrotating black hole metric, whose outer (event) horizon coincides with the surface of the screen. The spacetime admits an extremal configuration corresponding to the minimal holographic screen and having both mass and radius equalling the Planck units. We identify this object as the spacetime fundamental building block, whose interior is physically unaccessible and cannot be probed even during the Hawking evaporation terminal phase. In agreement with the holographic principle, relevant processes take place on the screen surface. The area quantization leads to a discrete mass spectrum. An analysis of the entropy shows that the minimal holographic screen can store only one byte of information, while in the thermodynamic limit the area law is corrected by a logarithmic term.
Background. Depression is the most common type of mental disorder in Germany. It is associated with a high level of suffering for individuals and imposes a significant burden on society. The aim of this study was to estimate the depression related costs in Germany taking a societal perspective.
Materials and Methods. Data were collected from the primary care monitoring for depressive patients trial (PRoMPT) of patients with major depressive disorder who were treated in a primary care setting. Resource utilisation and days of sick leave were observed and analysed over a 1-year period.
Results. Average depression related costs of €3813 were calculated. Significant differences in total costs due to sex were demonstrated. Male patients had considerable higher total costs than female patients, whereas single cost categories did not differ significantly. Further, differences in costs according to severity of disease and age were observed. The economic burden to society was estimated at €15.6 billion per year.
Conclusion. The study results show that depression poses a significant economic burden to society. There is a high potential for prevention, treatment, and patient management innovations to identify and treat patients at an early stage.
Diabetic retinopathy (DR) is an important cause of vision loss around the world, being the leading cause in the population between 20 and 60 years old. Among patients with DR, diabetic macular edema (DME) is the most frequent cause of vision impairment and represents a significant public health issue. Macular photocoagulation has been the standard treatment for this condition reducing the risk of moderate visual loss by approximately 50%. The role of vascular endothelial growth factor (VEGF) in DR and DME pathogenesis has been demonstrated in recent studies. This review addresses and summarizes data from the clinical trials that investigated anti-VEGF for the management of DME and evaluates their impact on clinical practice. The literature searches were conducted between August and October 2013 in PubMed and Cochrane Library with no date restrictions and went through the most relevant studies on pegaptanib, ranibizumab, bevacizumab, and aflibercept for the management of DME. The efficacy and safety of intravitreal anti-VEGF as therapy for DME have recently been proved by various clinical trials providing significantly positive visual and anatomical results. Regarding clinical practice, those outcomes have placed intravitreal injection of anti-VEGF as an option that must be considered for the treatment of DME.
In this article, I review select institutional and analytical traditions of Legal History in 20th century Germany, in order to put forth some recommendations for the future development of our discipline. A careful examination of the evolution of Legal History in Germany in the last twenty-five years, in particular, reveals radical transformations in the research framework: Within the study of law, there has been a shift in the internal reference points for Legal History. While the discipline is opening up to new understandings of law and to its neighboring disciplines, its institutional position at the law departments has become precarious. Research funding is being allocated in new ways and the German academic system is witnessing ever more internal differentiation. Internationally, German contributions and analytic traditions are receiving less attention and are being marginalized as new regions enter into a global dialogue on law and its history. The German tradition of research in Legal History had for long been setting benchmarks internationally; now it has to reflect upon and react to new global knowledge systems that have emerged in light of the digital revolution and the transnationalization of legal and academic systems. If legal historians in Germany accept the challenge these changing conditions pose, thrilling new intellectual and also institutional opportunities emerge. Especially the transnationalization of law and the need for a transnational legal scholarship offers fascinating perspectives for Legal History.
For centuries, it may have seemed as if standards of normative thinking now valid across the globe had first been instituted in Europe. These normative orders form the foundations of our verdicts that define and distinguish right and wrong, good and bad or even beautiful and ugly. But in order to better understand the global presence of such normative orders that evolved from within the European horizon, the history and implications of European expansion in the early modern era cannot be swept under the rug. ...
Complexin-1 and foxp1 expression changes are novel brain effects of
alpha-synuclein pathology
(2014)
As the second most frequent neurodegenerative disorder of the aging population, Parkinson’s disease (PD) is characterized by progressive deficits in spontaneous movement, atrophy of dopaminergic midbrain neurons and aggregation of the protein alpha-synuclein (SNCA). To elucidate molecular events before irreversible cell death, we studied synucleinopathy-induced expression changes in mouse brain and identified 49 midbrain/brainstem-specific transcriptional dysregulations. In particular complexin-1 (Cplx1), Rabl2a and 14-3-3epsilon (Ywhae) downregulation, as well as upregulation of the midbrain-specific factor forkhead box P1 (Foxp1) and of Rabgef1, were interesting as early mRNA level effects of alpha-synuclein triggered pathology. The protein levels of complexin-1 were elevated in midbrain/brainstem tissue of mice with A53T-SNCA overexpression and of mice with SNCA-knockout. The response of CPLX1 and Foxp1 levels to SNCA deficiency supports the notion that these factors are regulated by altered physiological function of alpha-synuclein. Thus, their analysis might be useful in PD stages before the advent of Lewy pathology. Because both alpha-synuclein and complexin-1 modulate vesicle release, our findings support presynaptic dysfunction as an early event in PD pathology.
Reciprocal exchanges can be understood as the updating of an initial belief about a partner. This initial level of trust is essential when it comes to establishing cooperation with an unknown partner, as cooperation cannot arise without a minimum of trust not justified by previous successful exchanges with this partner. Here we demonstrate the existence of a representation of the initial trust level before an exchange with a partner has occurred. Specifically, we can predict the Investor’s initial investment—i.e. his initial level of trust toward the unknown trustee in Round 1 of a standard 10-round Trust Game—from resting-state functional connectivity data acquired several minutes before the start of the Trust Game. Resting-state functional connectivity is, however, not significantly associated with the level of trust in later rounds, potentially mirroring the updating of the initial belief about the partner. Our results shed light on how the initial level of trust is represented. In particular, we show that a person’s initial level of trust is, at least in part, determined by brain electrical activity acquired well before the beginning of an exchange.
Talking about emotion and sharing emotional experiences is a key component of human interaction. Specifically, individuals often consider the reactions of other people when evaluating the meaning and impact of an emotional stimulus. It has not yet been investigated, however, how emotional arousal ratings and physiological responses elicited by affective stimuli are influenced by the rating of an interaction partner. In the present study, pairs of participants were asked to rate and communicate the degree of their emotional arousal while viewing affective pictures. Strikingly, participants adjusted their arousal ratings to match up with their interaction partner. In anticipation of the affective picture, the interaction partner’s arousal ratings correlated positively with activity in anterior insula and prefrontal cortex. During picture presentation, social influence was reflected in the ventral striatum, that is, activity in the ventral striatum correlated negatively with the interaction partner’s ratings. Results of the study show that emotional alignment through the influence of another person’s communicated experience has to be considered as a complex phenomenon integrating different components including emotion anticipation and conformity.