In this paper, entirely new discrete-time variants of the super-twisting algorithm are presented. The development of these discrete-time equivalents is based on certain criteria, e.g., the ...approximation of the continuous-time super-twisting algorithm as the discretization time tends to zero. In contrast to the classical explicit Euler discretized super-twisting dynamics, the proposed schemes are exact in the sense that in the unperturbed case, the controllers ensure local convergence to the origin. Oscillations of the system states caused by the discrete-time implementation of the super-twisting algorithm are avoided. The superiority of the developed control laws is demonstrated in simulation examples as well as in a real-world application. These examples reveal that the standard accuracy of the homogeneous second-order sliding mode is preserved and, in contrast to the explicit Euler discretized algorithm, in the presence of exact discrete measurements, the precision of the controlled variable is insensitive to oversized control gains.
Neuroinflammation can be monitored using fluorine-19 (
F)-containing nanoparticles and
F MRI. Previously we studied neuroinflammation in experimental autoimmune encephalomyelitis (EAE) using room ...temperature (RT)
F radiofrequency (RF) coils and low spatial resolution
F MRI to overcome constraints in signal-to-noise ratio (SNR). This yielded an approximate localization of inflammatory lesions. Here we used a new
F transceive cryogenic quadrature RF probe (
F-CRP) that provides the SNR necessary to acquire superior spatially-resolved
F MRI. First we characterized the signal-transmission profile of the
F-CRP. The
F-CRP was then benchmarked against a RT
F/
H RF coil. For SNR comparison we used reference compounds including
F-nanoparticles and ex vivo brains from EAE mice administered with
F-nanoparticles. The transmit/receive profile of the
F-CRP diminished with increasing distance from the surface. This was counterbalanced by a substantial SNR gain compared to the RT coil. Intraparenchymal inflammation in the ex vivo EAE brains was more sharply defined when using 150 μm isotropic resolution with the
F-CRP, and reflected the known distribution of EAE histopathology. At this spatial resolution, most
F signals were undetectable using the RT coil. The
F-CRP is a valuable tool that will allow us to study neuroinflammation with greater detail in future in vivo studies.
•D-cycloserine (DCS) facilitates extinction learning in animals.•Participants received DCS or placebo before extinction in a 3-day fMRI study.•The DCS group showed attenuated amygdala activation ...during recall.•This attenuation might be modulated via enhanced amygdala-vmPFC coupling.
Appetitive Pavlovian conditioning plays a crucial role in the pathogenesis of drug addiction and conditioned reward cues can trigger craving and relapse even after long phases of abstinence. Promising preclinical work showed that the NMDA-receptor partial agonist D-cycloserine (DCS) facilitates Pavlovian extinction learning of fear and drug cues. Furthermore, DCS-augmented exposure therapy seems to be beneficial in various anxiety disorders, while the supposed working mechanism of DCS during human appetitive or aversive extinction learning is still not confirmed.
To test the hypothesis that DCS administration before extinction training improves extinction learning, healthy adults (n=32) underwent conditioning, extinction, and extinction recall on three successive days in a randomized, double-blind, placebo-controlled fMRI design. Monetary wins and losses served as unconditioned stimuli during conditioning to probe appetitive and aversive learning. An oral dose of 50mg of DCS or placebo was administered 1h before extinction training and DCS effects during extinction recall were evaluated on a behavioral and neuronal level.
We found attenuated amygdala activation in the DCS compared to the placebo group during recall of the extinguished appetitive cue, along with evidence for enhanced functional amygdala-vmPFC coupling in the DCS group. While the absence of additional physiological measures of conditioned responses during recall in this study prevent the evaluation of a behavioral DCS effect, our neuronal findings are in accordance with recent theories linking successful extinction recall in humans to modulatory top-down influences from the vmPFC that inhibit amygdala activation. Our results should encourage further translational studies concerning the usefulness of DCS to target maladaptive Pavlovian reward associations.
The posterior parietal cortex (PPC) and the dorsolateral prefrontal cortex (DLPFC) are known to be part of a cortical network involved in visual spatial attention. Top-down control can modulate ...processing at target and distractor positions over a sequence of trials, leading to positive priming at prior target positions and negative priming at prior distractor positions. In order to elucidate the exact time course of this top-down mechanism we here propose a transcranial magnetic stimulation (TMS) protocol. Single-pulses were applied over the right PPC, the right DLPFC or over the vertex (sham stimulation) at five time intervals (50, 100, 150, 200, 250ms) after onset of a probe display during a spatial negative priming paradigm. Both suppression of the negative priming effect at a previous distractor position and enhancement of positive priming at a previous target position was found if a TMS pulse was applied 100ms after the probe display onset either over the right DLPFC or the right PPC. We suggest that top-down mechanisms within the right fronto-parietal attention network are compromised during TMS interference in this time window.
•Top-down control modulates processing at spatial positions over a sequence of trials.•TMS was applied over the rPPC, rDLPFC or the vertex at five time intervals.•Negative priming was reduced for TMS after 100ms over rDLPFC or rPPC.•Positive priming was enhanced for TMS after 100ms over rDLPFC or rPPC.•Top-down processes of the fronto-parietal attention network are disturbed during this specific time window.
Subsurface blood vessels in the cerebral cortex have been identified as a bottleneck in cerebral perfusion with the potential for collateral remodeling. However, valid techniques for non-invasive, ...longitudinal characterization of neocortical microvessels are still lacking. In this study, we validated contrast-enhanced magnetic resonance imaging (CE-MRI) for
characterization of vascular changes in a model of spontaneous collateral outgrowth following chronic cerebral hypoperfusion.
C57BL/6J mice were randomly assigned to unilateral internal carotid artery occlusion or sham surgery and after 21 days, CE-MRI based on T2*-weighted imaging was performed using ultra-small superparamagnetic iron oxide nanoparticles to obtain subtraction angiographies and steady-state cerebral blood volume (ss-CBV) maps. First pass dynamic susceptibility contrast MRI (DSC-MRI) was performed for internal validation of ss-CBV. Further validation at the histological level was provided by
serial two-photon tomography (STP).
Qualitatively, an increase in vessel density was observed on CE-MRI subtraction angiographies following occlusion; however, a quantitative vessel tracing analysis was prone to errors in our model. Measurements of ss-CBV reliably identified an increase in cortical vasculature, validated by DSC-MRI and STP.
Iron oxide nanoparticle-based ss-CBV serves as a robust, non-invasive imaging surrogate marker for neocortical vessels, with the potential to reduce and refine preclinical models targeting the development and outgrowth of cerebral collateralization.
In human adults, voices are processed in specialized brain regions in superior temporal cortices. We examined the development of this cortical organization during infancy by using near-infrared ...spectroscopy. In experiment 1, 7-month-olds but not 4-month-olds showed increased responses in left and right superior temporal cortex to the human voice when compared to nonvocal sounds, suggesting that voice-sensitive brain systems emerge between 4 and 7 months of age. In experiment 2, 7-month-old infants listened to words spoken with neutral, happy, or angry prosody. Hearing emotional prosody resulted in increased responses in a voice-sensitive region in the right hemisphere. Moreover, a region in right inferior frontal cortex taken to serve evaluative functions in the adult brain showed particular sensitivity to happy prosody. The pattern of findings suggests that temporal regions specialize in processing voices very early in development and that, already in infancy, emotions differentially modulate voice processing in the right hemisphere.
► Temporal cortex specializes in processing human voices during infancy ► Emotion specifically enhances voice processing in the right hemisphere in infants ► Deeper evaluation of happy speech in infants' right inferior frontal cortex
Aims
Glioblastomas are high‐grade brain tumours that are characterised by the accumulation of brain‐resident microglia and peripheral macrophages. Recruitment of these myeloid cells can be ...facilitated by CCR2/CCL2 signalling. Besides the well‐known CCR2+ macrophages, we have identified microglia expressing CCR2 in glioma tissues. Thus, we investigated how Ccr2‐deficiency of one of the myeloid cell populations affects the other population and tumour biology.
Methods
We generated four chimeric groups to analyse single and combined Ccr2‐deficiency of microglia and macrophages. On day 21 after tumour cell implantation (GL261), we conducted flow cytometry, immunofluorescence and real‐time polymerase chain reaction analyses. Tumour volume and metabolism were determined by magnetic resonance imaging and magnetic resonance spectroscopy. Moreover, in vitro studies were performed with primary microglia and bone marrow‐derived macrophages.
Results
We demonstrated reduced infiltration of macrophages and microglia depending on the lack of Ccr2. However, the total number of myeloid cells remained constant except for the animals with dual Ccr2‐knockout. Both microglia and macrophages with Ccr2‐deficiency showed impaired expression of proinflammatory molecules and altered phagocytic activity. Despite the altered immunologic phenotype caused by Ccr2‐deficiency, glioma progression and metabolism were hardly affected. Alterations were detected solely in apoptosis and proliferation of tumours from animals with specific Ccr2‐deficient microglia, whereas vessel stability was increased in mice with Ccr2‐knockout in both cell populations.
Conclusion
These results indicate that microglia and macrophages provide a homoeostatic balance within glioma tissue and compensate for the lack of the corresponding counterpart. Moreover, we identified that the CCR2/CCL2 axis is involved in the immunologic function of microglia and macrophages beyond its relevance for migration.
Both macrophages and microglia infiltrate brain tumour tissues in a CCR2‐dependent manner. Immunological functions of macrophages and microglia are impaired by Ccr2‐deficiency. Myeloid cell populations compensate for each other in order to reach a homeostatic balance in glioblastoma.
The present paper focuses on the use of adverbs with an adjectival lexical base in spoken and written presentday Brazilian Portuguese. We compare the frequencies of three different types of ...adverbials: adverbs in -mente (e.g. absolutamente), adjective-adverbs (e.g. alto in falar alto 'speak loudly') and prepositional phrases with adjectives as the postprepositional element (e.g. de novo), the latter being the main focus of this study. The analysis is based on the Discurso & Gramática-corpus, which consists of oral interviews of 170 informants and their written texts on the same topic as the one in the interviews. The data shows that prepositional phrases are less frequent (in terms of type and token frequency) than adjective-adverbs and adverbs ending in -mente. Regarding the difference between spoken and written language, adverbs in -mente occur remarkably more often in written texts while adjective-adverbs are more frequent in spoken language. Prepositional phrases, instead, occur equally in both codes. Finally, we draw the conclusion that prepositional phrases form a small but stable inventory of lexicalised forms, which are not marked for any code.
Background & Aims Dkk1 is a secreted antagonist of the Wnt/β-catenin signaling pathway. It is induced by inflammatory cytokines during colitis and exacerbates tissue damage by promoting apoptosis of ...epithelial cells. However, little is known about the physiologic role of Dkk1 in normal intestinal homeostasis and during wound repair following mucosal injury. We investigated whether inhibition of Dkk1 affects the morphology and function of the adult intestine. Methods We used doubleridge mice (Dkk1d/d ), which have reduced expression of Dkk1, and an inhibitory Dkk1 antibody to modulate Wnt/β-catenin signaling in the intestine. Intestinal inflammation was induced with dextran sulfate sodium (DSS), followed by a recovery period in which mice were given regular drinking water. Animals were killed before, during, or after DSS administration; epithelial homeostasis and the activity of major signaling pathways were investigated by morphometric analysis, bromo-2′-deoxyuridine incorporation, and immunostaining. Results Reduced expression of Dkk1 increased proliferation of epithelial cells and lengthened crypts in the large intestine, which was associated with increased transcriptional activity of β-catenin. Crypt extension was particularly striking when Dkk1 was inhibited during acute colitis. Dkk1d/d mice recovered significantly faster from intestinal inflammation but exhibited crypt architectural irregularities and epithelial hyperproliferation compared with wild-type mice. Survival signaling pathways were concurrently up-regulated in Dkk1d/d mice, including the AKT/β-catenin, ERK/Elk-1, and c-Jun pathways. Conclusions Dkk1, an antagonist of Wnt/β-catenin signaling, regulates intestinal epithelial homeostasis under physiologic conditions and during inflammation. Depletion of Dkk1 induces a strong proliferative response that promotes wound repair after colitis.
The CCNY gene, which encodes cyclin Y, has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Cyclin Y promotes Wnt/β-catenin signaling and autophagy, which are critical for ...intestinal epithelial cell (IEC) homeostasis, and may thereby contribute to wound repair in colitis. However, whether cyclin Y has an essential function in IECs is unknown. We, therefore, investigated the epithelial injury response and mucosal regeneration in mice with conditional knock-out of Ccny in the intestinal epithelium. We observed that Ccny-deficient mice did not exhibit any differences in cell proliferation and disease activity compared to wild-type littermates in the dextran sulfate sodium (DSS) colitis model. Complementary in vitro experiments showed that loss of CCNY in model IECs did not affect Wnt signaling, cell proliferation, or autophagy. Additionally, we observed that expression of the cyclin-Y-associated cyclin-dependent kinase (CDK) 14 is exceedingly low specifically in IEC. Collectively, these results suggest that cyclin Y does not contribute to intestinal epithelial homeostasis, possibly due to low levels of specific CDKs in these cells. Thus, it is unlikely that CCNY mutations are causatively involved in IBD pathogenesis.
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