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In homeostatic scaling at central synapses, the depth and breadth of cellular mechanisms that detect the offset from the set-point, detect the duration of the offset and implement a cellular response are not well understood. To understand the time-dependent scaling dynamics we treated cultured rat hippocampal cells with either TTX or bicucculline for 2 hr to induce the process of up- or down-scaling, respectively. During the activity manipulation we metabolically labeled newly synthesized proteins using BONCAT. We identified 168 newly synthesized proteins that exhibited significant changes in expression. To obtain a temporal trajectory of the response, we compared the proteins synthesized within 2 hr or 24 hr of the activity manipulation. Surprisingly, there was little overlap in the significantly regulated newly synthesized proteins identified in the early- and integrated late response datasets. There was, however, overlap in the functional categories that are modulated early and late. These data indicate that within protein function groups, different proteomic choices can be made to effect early and late homeostatic responses that detect the duration and polarity of the activity manipulation.
In the latest contribution to the Democracy Papers, Thomas Zittel explores when and how polarization becomes a cause for democratic anxiety. He argues that polarization over traditional policy issues is not in itself harmful, and can even be beneficial for democracies. However, he warns that polarization in which parties become divided over the acceptable rules of the game is a problem for democracies. Unfortunately, this latter type of division is increasingly common on both sides of the Atlantic today.
The individual parameter
(2018)
The present thesis tackles the unification of two-dimensional semantic systems, which are designed to deal with context-dependency of a certain kind i.e. indexicality, with dynamic theories of meaning, designed to capture facts about anaphoricity and the distribution of definite and indefinite articles. The need for a more principled look at this unification is twofold. Firstly, there is an overlap of these two families of theories in terms of empirical data, namely third person personal pronouns, as well as definite descriptions. Both kinds of expressions have anaphoric as well as non-anaphoric usages, whereas some of the latter ones can be captured in terms of indexicality. But, on the other hand, no language, especially not German and English, the main sources of data in this thesis, seems to distinguish these two usages formally, i.e. by employing different expressions. Hence the need for a unified framework in which this sort of ambiguity can be treated. Secondly, the theoretical state is dissatisfactory in the sense that the families of theories take very disparate forms that are not easy to relate conceptually.
The overlap in empirical area of application strongly suggests that this dichotomy is an artifact of the way these theories traditionally are developed and justified. This thesis seeks to overcome this state of the field. It proceeds as follows.
The first chapter discusses the way in which theories indexicality are designed. After taking a closer look some hallmarks of these theories such as the notions of index- and context-dependency themselves, double indexing, etc., it develops a notion of index dependency that makes use of a more complex individual parameter than the one that is usually assumed in the literature. Apart from agents and addressees, the two standard components of indices that represent contexts, additional objects are assumed. This leads to a variant of the semantics of deictically used third person expression that is called ‘indexical theory of demonstratives’, which is then investigated further.
The second chapter discusses the classics of dynamic semantics: DRT, DPL, and FCS. It arrives at the common core of all of these theories that consists in the assumption of a novel sort of variable namely active variables as opposed to free and bound ones that are intended to model the behavior of (in)definite descriptions and pronouns. The projection behavior of these variables or discourse referents is described either in (discourse-)syntactic or semantic terms. The chapter also arrives at a new formulation of the uniqueness condition that is thought to be part of the semantics of definite descriptions and sketches an account of transparent negation.
The third chapter then combines the insights of the previous ones by developing the notion of representation that connects the entities of evaluation of the first chapter i.e. indices with those of the second namely sets of assignments, a.k.a. files. The formal language that emerged in the second chapter is endowed with two kinds of variables for situations to allow for double indexing within a dynamic setting. A novel interpretation mechanism for the so designed language is proposed, which is shown to capture not only those aspects that are known to exist in two-dimensional frameworks, but also certain other index-index interactions that are described in yet another body of literature.
The final chapter discusses potential flaws of the theory and sketches an account of allegedly bound indexicals that is compatible with Kaplan’s infamous ban on monsters.
Application of a developed tool to visualize newly synthesized AMPA receptor components in situ
(2018)
The information flow between neurons happens at contact points, the synapses. One underlying mechanism of learning and memory is the change in the strength of information flow in selected synapses. In order to match the huge demand in membranes and proteins to build and maintain the neurites' complex architecture, neurons use decentralized protein synthesis. Many candidate proteins for local synthesis are known, and the need of de novo synthesis for memory formation is well established. The underlying mechanisms of how somatic versus dendritic synthesis is regulated are yet to be elucidated. Which proteins are newly synthesized in order to allow learning?
In this thesis protein synthesis is studied in hippocampal neurons. The fractional distribution of somatic and dendritic synthesis for candidate proteins and their subsequent transport to their destination are investigated using a newly developed technique. In the first part of this study we describe the development of this technique and use it in the second part to answer biological questions.
We focus here on AMPA receptor subunits, the key players in fast excitatory transmission. AMPA receptors contain multiple subunits with diverse functions. It remains to be understood, when and where in a neuron these subunits come together to form a protein complex and how the choice of subunits is regulated.
The investigation of the subunits' site of synthesis and redistribution kinetics in this study will help us to understand how neurons are able to change their synaptic strength in an input specific manner which eventually allows learning and memory.
Key questions which are addressed in this study:
How can specific newly synthesized endogenous proteins be visualized in situ? What are the neuron's abilities to locally synthesize and fully assemble AMPA receptor complexes?
How fast do different AMPA receptor subunits redistribute within neurons after synthesis?
Regulation of protein turnover allows cells to react to their environment and maintain homeostasis. Proteins can show different turnover rates in different tissue, but little is known about protein turnover in different brain cell types. We used dynamic SILAC to determine half-lives of over 5100 proteins in rat primary hippocampal cultures as well as in neuron-enriched and glia-enriched cultures ranging from <1 to >20 days. In contrast to synaptic proteins, membrane proteins were relatively shorter-lived and mitochondrial proteins were longer-lived compared to the population. Half-lives also correlate with protein functions and the dynamics of the complexes they are incorporated in. Proteins in glia possessed shorter half-lives than the same proteins in neurons. The presence of glia sped up or slowed down the turnover of neuronal proteins. Our results demonstrate that both the cell-type of origin as well as the nature of the extracellular environment have potent influences on protein turnover.
Cardiac sarcoidosis is a rare immunologic disease causing heart involvement in 5% of patients. Cardiac sarcoidosis may manifest clinically as a cardiomyopathy with impaired left ventricular (LV) function or as tachyarrhythmias or bradyarrhythmias. On autopsy, cardiac granulomas can be found in approximately 25% of patients. The most common location for granulomas and scars is the LV free wall, followed by the intraventricular septum, often with involvement of the conduction system. ...
α-ketoglutarate dehydrogenase inhibition counteracts breast cancer-associated lung metastasis
(2018)
Metastasis formation requires active energy production and is regulated at multiple levels by mitochondrial metabolism. The hyperactive metabolism of cancer cells supports their extreme adaptability and plasticity and facilitates resistance to common anticancer therapies. In spite the potential relevance of a metastasis metabolic control therapy, so far, limited experience is available in this direction. Here, we evaluated the effect of the recently described α-ketoglutarate dehydrogenase (KGDH) inhibitor, (S)-2-[(2,6-dichlorobenzoyl) amino] succinic acid (AA6), in an orthotopic mouse model of breast cancer 4T1 and in other human breast cancer cell lines. In all conditions, AA6 altered Krebs cycle causing intracellular α-ketoglutarate (α-KG) accumulation. Consequently, the activity of the α-KG-dependent epigenetic enzymes, including the DNA demethylation ten-eleven translocation translocation hydroxylases (TETs), was increased. In mice, AA6 injection reduced metastasis formation and increased 5hmC levels in primary tumours. Moreover, in vitro and in vivo treatment with AA6 determined an α-KG accumulation paralleled by an enhanced production of nitric oxide (NO). This epigenetically remodelled metabolic environment efficiently counteracted the initiating steps of tumour invasion inhibiting the epithelial-to-mesenchymal transition (EMT). Mechanistically, AA6 treatment could be linked to upregulation of the NO-sensitive anti-metastatic miRNA 200 family and down-modulation of EMT-associated transcription factor Zeb1 and its CtBP1 cofactor. This scenario led to a decrease of the matrix metalloproteinase 3 (MMP3) and to an impairment of 4T1 aggressiveness. Overall, our data suggest that AA6 determines an α-KG-dependent epigenetic regulation of the TET–miR200–Zeb1/CtBP1–MMP3 axis providing an anti-metastatic effect in a mouse model of breast cancer-associated metastasis.
Department of British and American Studies in cooperation with SKASE (The Slovak Association for the Study of English) organized the Word-Formation Theories III & Typology and Universals in Word-Formation IV Conference. The Conference took place at P.J. Šafárik University in Košice, Slovakia, from 27 June to 30 June 2018. The event was organized by Slávka Tomaščíková, Lívia Körtvélyessy and Pavol Štekauer (P.J. Šafárik University in Košice, Slovakia) and with the support of the APVV project No: APVV-16–0035 Research into extralinguistic factors of word-formation and word-interpretation. The program and the book of abstracts are available at the conference homepage http://kaa.ff.upjs.sk/en/alumni-club/33/word-formation-theories-iii-typology-and-universals-in-word-formation-iv.
Four new species of Xiphocentron (Antillotrichia) Brauer, 1870 from the Atlantic forest are diagnosed, described and illustrated. All of them have a small mesal sclerite and a set of spines, differing in size, density and position, on the inner face of the inferior appendage. Moreover, tergum IX varies mostly in the shape of the posterior margin. Four species are described as new for science. Xiphocentron (Antillotrichia) copacabana sp. nov. is distinguished mainly by the projected basoventral margin of the inferior appendage, the spines are clustered in two regions and the quadrate posterior region of tergum IX. Xiphocentron (Antillotrichia) maracanan sp. nov is differentiated by the inferior appendage, with a strongly angled apical region of 90º. Xiphocentron (Antillotrichia) redentor sp. nov. differs by the inferior appendage, with a linear row of thick spines, and the tergum IX, with a posterior margin forming smoothly rounded lobes. Xiphocentron (Antillotrichia) tijuca sp. nov. is diagnosed by the subbasal region of the preanal appendage, which is markedly projected medially, and by the inferior appendage, which is thin subapically, enlarged apically and strongly bent dorsad.
Using recent lattice data on the thermodynamics of QCD in the presence of a background magnetic field, we show that the ratio of transverse to longitudinal pressure exhibits, to good accuracy, a simple scaling behavior over a wide range of temperature and magnetic field, essentially depending only on the ratio T/B $$ T/\sqrt{B} $$. We compare this QCD response to the corresponding magnetoresponse in maximally supersymmetric Yang Mills theory. Given suitable calibrations defining the comparison, we find excellent agreement. This may be viewed as a further test of the applicability of holographic models for hot QCD.