150 research outputs found
Algebraic Presentations of Dependent Type Theories
No full textC-systems were defined by Cartmell as models of generalized algebraic
theories. B-systems were defined by Voevodsky in his quest to formulate and
prove an initiality conjecture for type theories. They play a crucial role in
Voevodsky's construction of a syntactic C-system from a term monad. In this
work, we construct an equivalence between the category of C-systems and the
category of B-systems, thus proving a conjecture by Voevodsky. We construct
this equivalence as the restriction of an equivalence between more general
structures, called CE-systems and E-systems, respectively. To this end, we
identify C-systems and B-systems as "stratified" CE-systems and E-systems,
respectively; that is, systems whose contexts are built iteratively via context
extension, starting from the empty context.Comment: v2: changed title, added some example
Electroencephalogram paroxysmal θ characterizes cataplexy in mice and children.
No full textAstute control of brain activity states is critical for adaptive behaviours and survival. In mammals and birds, electroencephalographic recordings reveal alternating states of wakefulness, slow wave sleep and paradoxical sleep (or rapid eye movement sleep). This control is profoundly impaired in narcolepsy with cataplexy, a disease resulting from the loss of orexin/hypocretin neurotransmitter signalling in the brain. Narcolepsy with cataplexy is characterized by irresistible bouts of sleep during the day, sleep fragmentation during the night and episodes of cataplexy, a sudden loss of muscle tone while awake and experiencing emotions. The neural mechanisms underlying cataplexy are unknown, but commonly thought to involve those of rapid eye movement-sleep atonia, and cataplexy typically is considered as a rapid eye movement sleep disorder. Here we reassess cataplexy in hypocretin (Hcrt, also known as orexin) gene knockout mice. Using a novel video/electroencephalogram double-blind scoring method, we show that cataplexy is not a state per se, as believed previously, but a dynamic, multi-phased process involving a reproducible progression of states. A knockout-specific state and a stereotypical paroxysmal event were introduced to account for signals and electroencephalogram spectral characteristics not seen in wild-type littermates. Cataplexy almost invariably started with a brief phase of wake-like electroencephalogram, followed by a phase featuring high-amplitude irregular theta oscillations, defining an activity profile distinct from paradoxical sleep, referred to as cataplexy-associated state and in the course of which 1.5-2 s high-amplitude, highly regular, hypersynchronous paroxysmal theta bursts (∼7 Hz) occurred. In contrast to cataplexy onset, exit from cataplexy did not show a predictable sequence of activities. Altogether, these data contradict the hypothesis that cataplexy is a state similar to paradoxical sleep, even if long cataplexies may evolve into paradoxical sleep. Although not exclusive to overt cataplexy, cataplexy-associated state and hypersynchronous paroxysmal theta activities are highly enriched during cataplexy in hypocretin/orexin knockout mice. Their occurrence in an independent narcolepsy mouse model, the orexin/ataxin 3 transgenic mouse, undergoing loss of orexin neurons, was confirmed. Importantly, we document for the first time similar paroxysmal theta hypersynchronies (∼4 Hz) during cataplexy in narcoleptic children. Lastly, we show by deep recordings in mice that the cataplexy-associated state and hypersynchronous paroxysmal theta activities are independent of hippocampal theta and involve the frontal cortex. Cataplexy hypersynchronous paroxysmal theta bursts may represent medial prefrontal activity, associated in humans and rodents with reward-driven motor impulse, planning and conflict monitoring
Irenische Fiktion in polemischer Absicht. Der spätantike Disputationsroman De Gestis in Perside als Widerspruch gegen die Religionspolitik in Byzanz
No full textThis contribution deals with the Greek fictional text De gestis in Perside which was widely received in medieval Byzantium and beyond, but has been hardly noticed by modern research. The confrontation between Christians, Hellenes, Zoroastrians and Jews at the Court of the Sassanians turns out in favor of Christianity, but peacefully and with a plea for peaceful coexistence by the arbiter Aphroditian. The paper methodically explores the relationship between fiction and facts in three steps. It argues that the anonymous, probably Christian author of this disputation novel chose Persia as the setting for an ideal, peaceful debate in order to express his criticism of Justinian’s religious policy as well as his criticism of the discord among the Christians of his time
Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids: implications for multicellular resistance to alkylating agents
No full textSimilar to other anticancer agents, intrinsic or acquired resistance to DNA-damaging chemotherapeutics is a major obstacle for cancer therapy. Current strategies aimed at overcoming this problem are mostly based on the premise that tumor cells acquire heritable genetic mutations that contribute to drug resistance. Here, we present evidence for an epigenetic, tumor cell adhesion-mediated, and reversible form of drug resistance that is associated with a reduction of DNA mismatch repair proteins PMS2 and/or MLH1 as well as other members of this DNA repair process. Growth of human breast cancer, human melanoma, and murine EMT-6 breast cancer cell lines as multicellular spheroids in vitro, which is associated with increased resistance to many chemotherapeutic drugs, including alkylating agents, is shown to lead to a reproducible down-regulation of PMS2, MLH1, or, in some cases, both as well as MHS6, MSH3, and MSH2. The observed down-regulation is in part reversible by treatment of tumor spheroids with the DNA-demethylating agent, 5-azacytidine. Thus, treatment of EMT-6 mouse mammary carcinoma spheroids with 5-azacytidine resulted in reduced and/or disrupted cell-cell adhesion, which in turn sensitized tumor spheroids to cisplatin-mediated killing in vitro. Our results suggest that antiadhesive agents might sensitize tumor spheroids to alkylating agents in part by reversing or preventing reduced DNA mismatch repair activity and that the chemosensitization properties of 5-azacytidine may conceivably reflect its role as a potential antiadhesive agent as well as reversal agent for MLH1 gene silencing in human tumors
„Zucht und lehr“ – Johann Wilhelm Simlers Teutsche Gedichte (1648)
No full textSwiss literature between Niklaus Manuel as an example of a 16th century poet and
Albrecht von Haller as a writer of the Age of Enlightenment has been little researched –
despite the fact that a large body of literature dealing with a particularly ‘Swiss’
language, culture, and poetry can be linked to the political status of the sovereign
confederation in the 17th century. This article presents the book Teutsche Gedichte
by the Zurich author Johann Wilhelm Simler in the context of its creation as well
as its reception. The work was first published in 1648, the year of the separation of
the Confederate cantons from the Holy Roman Empire of the German Nation and at
the end of the Thirty Years’ War. Due to its resounding success, it was reprinted three
times until 1688. In addition to various epigrams, doctrinal and occasional poems, the
collection consists mainly of sacred and secular songs, printed in four-part notation.
The melodies were written by various composers. As well as working with musicians,
Simler also collaborated closely with the Zurich engraver Conrad Meyer. We would like
to highlight Simler’s work as a cultural broker in the cultural scene of his city and for
Swiss poetry in the German-speaking world
Scale-up activation of carbon fibres for hydrogen storage
No full textIn a previous study, we investigated, at a laboratory scale, the chemical activation of two different carbon fibres (CF), their porosity characterization, and their optimization for hydrogen storage [1]. In the present work, this study is extended to: (i) a larger range of KOH activated carbon fibres, (ii) a larger range of hydrogen adsorption measurements at different temperatures and pressures (i.e. at room temperature, up to 20 MPa, and at 77 K, up to 4 MPa), and (iii) a scaling-up activation approach in which the obtained activated carbon fibres (ACF) are compared with those from laboratory-scale activation. The prepared samples cover a large range of porosities, which is found to govern their ability for hydrogen adsorption. The hydrogen uptake capacities of all the prepared samples have been analysed both in volumetric and in gravimetric bases. Thus, maximum adsorption capacities of around 5 wt% are obtained at 77 K, and 1.1 wt% at room temperature, respectively. The packing densities of the materials have been measured, turning out to play an important role in order to estimate the total storage capacity of a tank volume. Maximum values of 17.4 g/l at 298 K, and 38.6 g/l at 77 K were obtained.Osaka Gas Co., Ltd. supplied the two precursor materials. Financial help was received from the European Union (Marie Curie Research Training Network-HyTRAIN-Project reference: 512443), MEC (ENE2005-23824-E/CON), the Generalitat Valenciana (ACOMP06/089 and PROMETEO/2009/047), as well as MEC-CTQ2006-08958/PPQ
Homeostatic and circadian contribution to EEG and molecular state variables of sleep regulation.
No full textSTUDY OBJECTIVES: Besides their well-established role in circadian rhythms, our findings that the forebrain expression of the clock-genes Per2 and Dbp increases and decreases, respectively, in relation to time spent awake suggest they also play a role in the homeostatic aspect of sleep regulation. Here, we determined whether time of day modulates the effects of elevated sleep pressure on clock-gene expression. Time of day effects were assessed also for recognized electrophysiological (EEG delta power) and molecular (Homer1a) markers of sleep homeostasis.
DESIGN: EEG and qPCR data were obtained for baseline and recovery from 6-h sleep deprivation starting at ZT0, -6, -12, or -18.
SETTING: Mouse sleep laboratory.
PARTICIPANTS: Male mice.
INTERVENTIONS: Sleep deprivation.
RESULTS: The sleep-deprivation induced changes in Per2 and Dbp expression importantly varied with time of day, such that Per2 could even decrease during sleep deprivations occurring at the decreasing phase in baseline. Dbp showed similar, albeit opposite dynamics. These unexpected results could be reliably predicted assuming that these transcripts behave according to a driven damped harmonic oscillator. As expected, the sleep-wake distribution accounted for a large degree of the changes in EEG delta power and Homer1a. Nevertheless, the sleep deprivation-induced increase in delta power varied also with time of day with higher than expected levels when recovery sleep started at dark onset.
CONCLUSIONS: Per2 and delta power are widely used as exclusive state variables of the circadian and homeostatic process, respectively. Our findings demonstrate a considerable cross-talk between these two processes. As Per2 in the brain responds to both sleep loss and time of day, this molecule is well positioned to keep track of and to anticipate homeostatic sleep need. CITATION: Curie T; Mongrain V; Dorsaz S; Mang GM; Emmenegger Y; Franken P. Homeostatic and circadian contribution to EEG and molecular state variables of sleep regulation. SLEEP 2013;36(3):311-323
Evaluation of a piezoelectric system as an alternative to electroencephalogram/ electromyogram recordings in mouse sleep studies.
No full textSTUDY OBJECTIVES: Traditionally, sleep studies in mammals are performed using electroencephalogram/electromyogram (EEG/EMG) recordings to determine sleep-wake state. In laboratory animals, this requires surgery and recovery time and causes discomfort to the animal. In this study, we evaluated the performance of an alternative, noninvasive approach utilizing piezoelectric films to determine sleep and wakefulness in mice by simultaneous EEG/EMG recordings. The piezoelectric films detect the animal's movements with high sensitivity and the regularity of the piezo output signal, related to the regular breathing movements characteristic of sleep, serves to automatically determine sleep. Although the system is commercially available (Signal Solutions LLC, Lexington, KY), this is the first statistical validation of various aspects of sleep.
DESIGN: EEG/EMG and piezo signals were recorded simultaneously during 48 h.
SETTING: Mouse sleep laboratory.
PARTICIPANTS: Nine male and nine female CFW outbred mice.
INTERVENTIONS: EEG/EMG surgery.
MEASUREMENTS AND RESULTS: The results showed a high correspondence between EEG/EMG-determined and piezo-determined total sleep time and the distribution of sleep over a 48-h baseline recording with 18 mice. Moreover, the piezo system was capable of assessing sleep quality (i.e., sleep consolidation) and interesting observations at transitions to and from rapid eye movement sleep were made that could be exploited in the future to also distinguish the two sleep states.
CONCLUSIONS: The piezo system proved to be a reliable alternative to electroencephalogram/electromyogram recording in the mouse and will be useful for first-pass, large-scale sleep screens for genetic or pharmacological studies.
CITATION: Mang GM, Nicod J, Emmenegger Y, Donohue KD, O'Hara BF, Franken P. Evaluation of a piezoelectric system as an alternative to electroencephalogram/electromyogram recordings in mouse sleep studies
Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice
No full textProlonged, frequently administered low-dose metronomic
chemotherapy (LDM) is being explored (pre)clinically as a
promising antiangiogenic antitumor strategy. Although
appealing because of a favorable side effect profile and
mostly oral dosing, LDM involves new challenges different
from conventional maximum tolerated dose chemotherapy.
These include possible altered pharmacokinetic
characteristics due to long-term drug exposure potentially
resulting in acquired resistance and increased risk of
unfavorable drug interactions. We therefore compared the
antitumor and antivascular effects of LDM cyclophosphamide
(CPA) given to mice that had been pretreated
with either LDM CPA or normal saline, obtained blood
4-hydroxy-CPA (activated CPA) concentrations using
either gas chromatography/mass spectrometry or liquid
chromatography/tandem mass spectrometry in mice
treated with LDM CPA, and measured hepatic and intratumoral
activity of enzymes involved in the biotransformation
of CPA and many other drugs [i.e., cytochrome
P450 3A4 (CYP3A4) and aldehyde dehydrogenase].
Exposure of mice to LDM CPA for z8 weeks did not
compromise subsequent activity of LDM CPA therapy, and
biologically active 4-hydroxy-CPA levels were maintained
during long-term LDM CPA administration. Whereas the
effects on CYP3A4 were complex, aldehyde dehydrogenase
activity was not affected. In summary, our findings
suggest that acquired resistance to LDM CPA is unlikely
accounted for by altered CPA biotransformation. In the
absence of reliable pharmacodynamic surrogate markers,
pharmacokinetic parameters might become helpful to
individualize/optimize LDM CPA therapy. LDM CPA-associated
changes of CYP3A4 activity point to a potential risk
of unfavorable drug interactions when compounds that are
metabolized by CYP3A4 are coadministered with LDM
CPA
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