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The present work describes the detailed design and operational capabilities of a general purpose test facility developed to evaluate the dynamics and performance of gas lubricated journal bearings. The component level test facility was developed to serve as an initial tollgate test platform for certifying gas lubricated journal bearings into aircraft engine applications. A rotating test rig was engineered to test 70-120 mm diameter bearings at 40,000-80,000 rpm and 1200[degrees]F. The test rig described in this paper possesses design elements that enable the simultaneous application of dynamic and static load profiles of up to 1000 lb while monitoring and measuring the bearing torque. This capability allows for the characterization of several critical metrics such as bearing lift off speed characteristics, load capacity, and frequency dependent rotordynamic force coefficients. This paper discusses the functionality of the test facility and presents sample test measurements from several experiments. [DOI: 10.1115/1.2979004]

Cardiac activity and anaerobic metabolism were analyzed in zebrafish larvae raised under normoxia (P[O.sub.2] = 20 kPa) and under chronic hypoxia (P[O.sub.2] = 10 kPa) at three different temperatures (25, 28, and 31[degrees]C). Heart rate increased with development and with temperature. Under normoxia, cardiac output increased significantly at high temperature (31[degrees]C), but not at 28 or at 25[degrees]C. Under chronic hypoxia, however, heart rate as well as cardiac output increased at all temperatures in larvae at about hatching time or shortly thereafter. Cardiac activity of larvae raised for 2 wk after fertilization with a reduced hemoglobin oxygen-carrying capacity in their blood (hypoxemia; due to the presence of CO or of phenylhydrazine in the incubation water) was not different from control animals. Whole body lactate content of these animals did not increase. Thus there was no indication of a stimulated anaerobic energy metabolism. The increase in cardiac activity observed during hypoxia suggests that at about hatching time receptors are present that sense hypoxic conditions, and this information can be used to induce a stimulation of convective oxygen transport to compensate for a reduction in bulk oxygen diffusion in the face of a reduced oxygen gradient between environmental water and tissues. Under normoxia, however, the P[O.sub.2] gradient between environmental water and tissues and diffusional oxygen transport assure sufficient oxygen supply even if hemoglobin oxygen transport in the blood is severely impaired. Thus, under normoxic conditions and with a normal metabolic rate of the tissues, convective oxygen transport is not required until ~2 wk after fertilization. anaerobic metabolism; cardiac output; convective oxygen transport

Several experimental modal analysis techniques fit resonance peaks to the response curves of a single degree of freedom system in order to identify the natural frequencies and modal damping ratios. The present study identifies a fundamental property of frequency response curves that allows the natural frequency to be identified from a simple characteristic of the curve, independently of the damping ratio. After the natural frequency has been determined, the damping ratio can be computed directly. The fundamental property holds for all values of damping, which eliminates the need to approximate either the natural frequency or damping ratio. [DOI: 10.1115/1.1376122]

This work was prompted by a study performed by Strasberg [7] in which numerous small spring-mass-damper systems are attached to a large suspended mass representing the master structure. The isolated natural frequency of each attached system was selected to match in average the natural frequency of the isolated master structure. Strasberg found that the critical issue when an impulse excitation is applied to the master structure is the bandwidth of the isolated attached systems in comparison to the spacing between the natural frequencies of the system. Modal overlap, which corresponds to bandwidths that exceed the spacing of those frequencies, was shown to greatly influence the response of the master structure. Light damping, for which there is little or no modal overlap, corresponds to an impulse response that consists of a sequence of nearly periodic exponentially decaying pulses, and the transfer function for harmonic excitation of the master structure indicates that the substructure acts as a vibration absorber for the master structure. Increased damping leads to modal overlap, with the result that the impulse response consists of a single decaying pulse. The frequency domain transfer function indicates that the vibration absorber effect is enhanced. The present work explores these issues for continuous systems by replacing the one degree of freedom master structure with a cantilever beam. The system parameters are selected to match Strasberg's model, with the suspended oscillators placed randomly along the beam. The beam displacement is represented as a Ritz series whose basis functions are the cantilever beam modes. The coupled equations are solved by a state-space eigenmode analysis that yields a closed form representation of the response in terms of the complex eigenmode properties. The continuous fuzzy structure is shown not to display the transfer of energy between the master structure and the substructure that was exhibited by the discrete fuzzy structure, apparently because of the asynchronous motion of the attachment points resulting from the spatial variability of the beam's motion. The vibration absorber effect for harmonic excitation is only obtained for the heavy damping in the case of a beam. [DOI: 10.1115/1.1340624]

Abstract: Traumatic brain injury (TBI) is a risk factor for the development of epilepsy, which can occur months to years after the insult. The hippocampus is particularly vulnerable to the pathophysiological effects of TBI. Here, we determined whether there are long-term changes in inhibition in the dentate gyrus that could contribute to the progressive susceptibility to seizures after TBI. We used severe lateral-fluid percussion brain injury to induce TBI in rats. In this model, spontaneous seizure activity, which involves the hippocampus, appears after a long latent period, resembling the human condition. We demonstrate that synaptic GABAA receptor-mediated inhibition is profoundly reduced in ipsilateral dentate granule cells 1 month after TBI. Moreover, synaptic inhibition decreases over time, and by 6 months after TBI, it is also significantly decreased contralaterally. Progressive loss of synaptic inhibition is paralleled by a decline in the number of parvalbumin-positive interneurons, but, in contrast to status epilepticus models, GABAA receptor subunit expression is largely unaltered. At both time points, the magnitude of tonic GABAA receptor-mediated currents after TBI is maintained, indicating a preservation of the inhibitory constraint of granule cells through tonic inhibition. Our results extend the time window during which strategies to target epileptogenesis may be effective. [Copyright &y& Elsevier]

The circuitry underlying the initiation, maintenance, and coordination of wakefulness, rapid eye movement sleep, and non-rapid eye movement sleep is not thoroughly understood. Sleep is thought to arise due to decreased activity in the ascending reticular arousal system, which originates in the brainstem and awakens the thalamus and cortex during wakefulness. Despite the conventional association of sleep-wake states with hippocampal rhythms, the mutual influence of the hippocampal formation in regulating vigilance states has been largely neglected. Here, we focus on the subiculum, the main output region of the hippocampal formation. The subiculum, particulary the ventral part, sends extensive monosynaptic projections to crucial regions implicated in sleep-wake regulation, including the thalamus, lateral hypothalamus, tuberomammillary nucleus, basal forebrain, ventrolateral preoptic nucleus, ventrolateral tegmental area, and suprachiasmatic nucleus. Additionally, second-order projections from the subiculum are received by the laterodorsal tegmental nucleus, locus coeruleus, and median raphe nucleus, suggesting the potential involvement of the subiculum in the regulation of the sleep-wake cycle. We also discuss alterations in the subiculum observed in individuals with sleep disorders and in sleep-deprived mice, underscoring the significance of investigating neuronal communication between the subiculum and pathways promoting both sleep and wakefulness., (© 2024 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Workplace Health Promotion (WHP) can sustainably impact organizations by improving employee health and strengthening legitimization. Digital Workplace Health Promotion (DWHP) may have even more impact thanks to its scope. This study reports on a hospital in Austria wherein DWPH was introduced into the existing WHP structure in combination with a digitalization effort for the entire organization. The approach was mainly quantitative with a few open questions and included a survey before and an evaluation after the project with about 240 respondents each. The use, intentions, barriers and benefits of DWHP from the employees' perspectives were reported on to evaluate the potentials of DWHP for furthering sustainable developments within organizations. While DHWP is perceived as positive, current use is low. Nevertheless, intended future use is promising and perceived benefits are higher after implementation. However, perceived barriers are still high, requiring organizational efforts., Competing Interests: E.N. declares there are no conflicts of interest. M.D. is employed at the organization reported on. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

The subiculum, a key output region of the hippocampus, is increasingly recognized as playing a crucial role in seizure initiation and spread. The subiculum consists of glutamatergic pyramidal cells, which show alterations in intrinsic excitability in the course of epilepsy, and multiple types of GABAergic interneurons, which exhibit varying characteristics in epilepsy. In this study, we aimed to assess the role of the vasoactive intestinal peptide interneurons (VIP-INs) of the ventral subiculum in the pathophysiology of temporal lobe epilepsy. We observed that an anatomically restricted inhibition of VIP-INs of the ventral subiculum was sufficient to reduce seizures in the intrahippocampal kainic acid model of epilepsy, changing the circadian rhythm of seizures, emphasizing the critical role of this small cell population in modulating TLE. As we expected, permanent unilateral or bilateral silencing of VIP-INs of the ventral subiculum in non-epileptic animals did not induce seizures or epileptiform activity. Interestingly, transient activation of VIP-INs of the ventral subiculum was enough to increase the frequency of seizures in the acute seizure model. Our results offer new perspectives on the crucial involvement of VIP-INs of the ventral subiculum in the pathophysiology of TLE. Given the observed predominant disinhibitory role of the VIP-INs input in subicular microcircuits, modifications of this input could be considered in the development of therapeutic strategies to improve seizure control., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Rapid eye movement sleep (REMS) is characterized by the appearance of fast, desynchronized rhythms in the cortical electroencephalogram (EEG), similar to wakefulness. The low electromyogram (EMG) amplitude during REMS distinguishes it from wakefulness; therefore, recording EMG signal seems to be imperative for discriminating between the two states. The present study evaluated the high frequency components of the EEG signal from mice (80-500 Hz) to support REMS detection during sleep scoring without an EMG signal and found a strong positive correlation between waking and the average power of 80-120 Hz, 120-200 Hz, 200-350 Hz and 350-500 Hz. A highly negative correlation was observed with REMS. Furthermore, our machine learning approach demonstrated that simple EEG time-series features are enough to discriminate REMS from wakefulness with sensitivity of roughly 98 percent and specificity of around 92 percent. Interestingly, assessing only the higher frequency bands (200-350 Hz as well as 350-500 Hz) gives significantly greater predictive power than assessing only the lower end of the EEG frequency spectrum. This paper proposes an approach that can detect subtle changes in REMS reliably, and future unsupervised sleep-scoring approaches could greatly benefit from it., (© 2023. The Author(s).)

Epileptic seizures result in pronounced over-expression of neuropeptide Y (NPY). In vivo and in vitro studies revealed that NPY exerts potent anticonvulsive actions through presynaptic Y2 receptors by suppressing glutamate release from principal neurons. We now investigated whether seizure-induced over-expression of NPY contributes to epileptic tolerance induced by preceding seizures. We used a previously established animal model based on selective inhibition of GABA release from parvalbumin (PV)-containing interneurons in the subiculum in mice. The animals present spontaneous recurrent seizures (SRS) and clusters of interictal spikes (IS). The frequency of SRS declined after five to six weeks, indicating development of seizure tolerance. In interneurons of the subiculum and sector CA1, SRS induced over-expression of NPY that persisted there for a prolonged time despite of a later decrease in SRS frequency. In contrast to NPY, somatostatin was not overexpressed in the respective axon terminals. Contrary to interneurons, NPY was only transiently expressed in mossy fibers. To demonstrate a protective function of endogenous, over-expressed NPY, we injected the selective NPY-Y2 receptor antagonist JNJ 5207787 simultaneously challenging the mice by a low dose of pentylenetetrazol (PTZ, 30 or 40 mg/kg, i.p.). In control mice, neither PTZ nor PTZ plus JNJ 5207787 induced convulsions. In mice with silenced GABA/PV neurons, PTZ alone only modestly enhanced EEG activity. When we injected JNJ 5207787 together with PTZ (either dose) the number of seizures, however, became significantly increased. In addition, in the epileptic mice CB1 receptor immunoreactivity was reduced in terminal areas of basket cells pointing to reduced presynaptic inhibition of GABA release from these neurons. Our experiments demonstrate that SRS result in overexpression of NPY in hippocampal interneurons. NPY overexpression persists for several weeks and may be related to later decreasing SRS frequency. Injection of the Y2 receptor antagonist JNJ 5207787 prevents this protective action of NPY only when release of the peptide is triggered by injection of PTZ and induces pronounced convulsions. Thus, over-expressed NPY released "on demand" by seizures may help terminating acute seizures and may prevent from recurrent epileptic activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Drexel and Sperk.)

The International League Against Epilepsy/American Epilepsy Society (ILAE/AES) Joint Translational Task Force initiated the TASK3 working group to create common data elements (CDEs) for various aspects of preclinical epilepsy research studies, which could help improve the standardization of experimental designs. This article addresses neuropathological changes associated with seizures and epilepsy in rodent models of epilepsy. We discuss CDEs for histopathological parameters for neurodegeneration, changes in astrocyte morphology and function, mechanisms of inflammation, and changes in the blood-brain barrier and myelin/oligodendrocytes resulting from recurrent seizures in rats and mice. We provide detailed CDE tables and case report forms (CRFs), and with this companion manuscript, we discuss the rationale and methodological aspects of individual neuropathological examinations. The CDEs, CRFs, and companion paper are available to all researchers, and their use will benefit the harmonization and comparability of translational preclinical epilepsy research. The ultimate hope is to facilitate the development of rational therapy concepts for treating epilepsies, seizures, and comorbidities and the development of biomarkers assessing the pathological state of the disease., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Toll-like receptors (TLR) are one of the main constituents of the innate immune system in mammals. They can detect conserved microbial structures (pathogen-associated molecular patterns) and host-derived ligands that are produced during cellular stress and damage (danger-associated molecular patterns) and may then initiate an intracellular signaling cascade leading to the expression of pro-inflammatory cytokines and immediate immune responses. Some TLR (TLR1, 2, 4, 5, and 6) are expressed on the cell surface while others (TLR3, 7, 8 and 9) are present on the surface of endosomes and their ligands require internalization before recognition is possible. Several TLR have also been detected in neurons where they may serve functions that are not related to immune responses. TLR2, 3, and 4 have been described in cortical neurons and, for TLR4, a seizure-promoting role in epilepsies associated with inflammation has been shown. TLR3, 7, and 8 expressed in neurons seem to influence the growth or withdrawal of neurites and robust activation of TLR8 in neurons may even induce neuronal death. The goal of the current study was to investigate the expression of TLR8 in the hippocampus of mice during postnatal development and in adulthood. We focused on three functionally distinct groups of GABAergic interneurons characterized by the expression of the molecular markers parvalbumin, somatostatin, or calretinin, and we applied double fluorescence immunohistochemistry and cell counts to quantify co-expression of TLR8 in the three groups of GABA-interneurons across hippocampal subregions. We found subregion-specific differences in the expression of TLR8 in these interneurons. During postnatal development, TLR8 was detected only in mice older than P5. While only a small fraction of hippocampal calretinin-positive interneurons expressed TLR8, most parvalbumin-positive interneurons in all hippocampal subregions co-expressed TLR8. Somatostatin-positive interneurons co-expressing TLR8 were mainly present in hippocampal sector CA3 but rare in the dentate gyrus and CA1. High expression of TLR8 in parvalbumin-interneurons may contribute to their high vulnerability in human temporal lobe epilepsy., Competing Interests: The authors have declared that no competing interests exist.

The hippocampus proper and the subiculum contain two major populations of somatostatin (SST)-containing interneurons, oriens-lacunosum moleculare (O-LM) cells projecting from the stratum oriens to the stratum lacunosum moleculare and bistratified cells with their cell bodies close to the pyramidal cell layer and axons terminating in the strata radiatum and oriens. Both types of interneurons innervate pyramidal cell dendrites and exert prominent feedback inhibition. We now investigated whether impairing this type of feed-back inhibition by selectively inhibiting GABA release from SST expressing interneurons in hippocampal sector CA1 and subiculum may be sufficient to induce spontaneous recurrent seizures. We injected transgenic mice expressing Cre-recombinase on the SST promoter unilaterally into the ventral CA1 sector and subiculum with an adeno-associated viral (AAV) vector expressing tetanus toxin light chain (TeLC) with its reading frame inverted in a flip-excision (FLEX) cassette. This treatment resulted in specific expression of TeLC and silencing of SST-containing interneurons. We continuously monitored the EEG and behavior of the mice for six weeks. Nine out of eleven mice within 10 days developed series of pre- or interictal spikes (IS, 21.4 ± 6.83 per week) and four mice exposed recurrent spontaneous seizures (SRS, 1.5 ± 0.29 per week). All 23 SRS observed were preceded by IS series. Our data demonstrate a critical role of feed-forward inhibition mediated by SST-containing interneurons suggesting that their sustained malfunctioning can be causatively involved in the development of TLE., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Traumatic brain injury (TBI) causes 10-20% of structural epilepsy, with seizures typically originating in the cortex. Alterations in the neuronal microcircuits in the cortical epileptogenic zone, however, are poorly understood. Here, we assessed TBI-induced changes in perisomatic gamma aminobutyric acid (GABA)-ergic innervation in the perilesional cortex. We hypothesized that TBI will damage parvalbumin (PV)-immunoreactive inhibitory neurons and induce regulation of the associated GABAergic molecular interactome. TBI was induced in adult male Sprague-Dawley rats by lateral fluid-percussion injury. At 1-month post-TBI, the number of PV-positive somata was plotted on unfolded cortical maps and the distribution and density of immunopositive terminals analyzed. Qualitative analysis revealed either patchy microlesions of several hundred micrometers in diameter or diffuse neuronal loss. Quantitative analysis demonstrated a reduction in the number of PV-positive interneurons in patches down to 0% of that in sham-operated controls in the perilesional cortex. In the majority of patches, the cell numbers ranged from 71% to 90% that of the controls. The loss of PV-positive somata was accompanied by decreased axonal labeling. In situ hybridization revealed downregulated PV mRNA expression in the perilesional cortex. Gene Set Enrichment Analysis indicated a robustly downregulated expression profile of PV-related genes, which was confirmed by quantitative reverse transcriptase polymerase chain reaction. Specifically, we found that genes encoding postsynaptic GABA-A receptor genes, Gabrg2 and Gabrd, were downregulated in TBI animals compared with controls. Our data suggests that patchy reduction in PV-positive perisomatic inhibitory innervation contributes to the development of focal cortical inhibitory deficit after TBI., Competing Interests: Conflict of interest Declarations of interest: none., (Copyright © 2021 IBRO. Published by Elsevier Ltd. All rights reserved.)

Epilepsy animal models indicate pronounced changes in the expression and rearrangement of GABA A receptor subunits in the hippocampus and in para-hippocampal areas, including widespread downregulation of the subunits α5 and δ, and upregulation of α4, subunits that mediate tonic inhibition of GABA. In this case-control study, we investigated changes in the expression of subunits α4, α5 and δ in hippocampal specimens of drug resistant temporal lobe epilepsy patients who underwent epilepsy surgery. Using in situ hybridization, immunohistochemistry and α5-specific receptor autoradiography, we characterized expression of the receptor subunits in specimens from patients with and without Ammon's horn sclerosis compared to post-mortem controls. Expression of the α5-subunit was abundant throughout all subfields of the hippocampus, including the dentate gyrus, sectors CA1 and CA3, the subiculum and pre- and parasubiculum. Significant but weaker expression was detected for subunits α4 and δ notably in the granule cell/molecular layer of control specimens, but was faint in the other parts of the hippocampus. Expression of all three subunits was similarly altered in sclerotic and non-sclerotic specimens. Respective mRNA levels were increased by about 50-80% in the granule cell layer compared with post-mortem controls. Subunit α5 mRNA levels and immunoreactivities were also increased in the sector CA3 and in the subiculum. Autoradiography for α5-containing receptors using [ 3 H]L-655,708 as ligand showed significantly increased binding in the molecular layer of the dentate gyrus in non-sclerotic specimens. Increased expression of the α5 and δ subunits is in contrast to the previously observed downregulation of these subunits in different epilepsy models, whereas increased expression of α4 in temporal lobe epilepsy patients is consistent with that in the rodent models. Our findings indicate increased tonic inhibition likely representing an endogenous anticonvulsive mechanism in temporal lobe epilepsy., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

GABA A receptors are composed of five subunits arranged around a central chloride channel. Their subunits originate from different genes or gene families. The majority of GABA A receptors in the mammalian brain consist of two α-, two β- and one γ- or δ-subunit. This subunit organization crucially determines the physiological and pharmacological properties of the GABA A receptors. Using immunohistochemistry, we investigated the distribution of 10 GABA A receptor subunits (α1, α2, α3, α4, α5, β1, β2, β3, γ2, and δ) in the fore brain of three female rhesus monkeys (Macaca mulatta). Within the cerebral cortex, subunits α1, α5, β2, β3, and γ2 were found in all layers, α2, α3, and β1 were more concentrated in the inner and outer layers. The caudate/putamen was rich in α1, α2, α5, all three β-subunits, γ2, and δ. Subunits α3 and α5 were more concentrated in the caudate than in the putamen. In contrast, α1, α2, β1, β2, γ2, and δ were highest in the pallidum. Most dorsal thalamic nuclei contained subunits α1, α2, α4, β2, β3, and γ2, whereas α1, α3, β1, and γ2 were most abundant in the reticular nucleus. Within the amygdala, subunits α1, α2, α5, β1, β3, γ2, and δ were concentrated in the cortical nucleus, whereas in the lateral and basolateral amygdala α1, α2, α5, β1, β3, and δ, and in the central amygdala α1, α2, β3, and γ2 were most abundant. Interestingly, subunit α3-IR outlined the intercalated nuclei of the amygdala. In the hippocampus, subunits α1, α2, α5, β2, β3, γ2, and δ were highly expressed in the dentate molecular layer, whereas α1, α2, α3, α5, β1, β2, β3, and γ2 were concentrated in sector CA1 and the subiculum. The distribution of GABA A receptor subunits in the rhesus monkey was highly heterogeneous indicating a high number of differently assembled receptors. In most areas investigated, notably in the striatum/pallidum, amygdaloid nuclei and in the hippocampus it was more diverse than in the rat and mouse indicating a more heterogeneous and less defined receptor assembly in the monkey than in rodent brain., (© 2020 The Authors. The Journal of Comparative Neurology published by Wiley Periodicals, Inc.)

The durability and serviceability of concrete structures is influenced by both the early-age behavior of concrete as well as its long-term response in terms of shrinkage and creep. Hygro-thermo-chemo-mechanical models, as they are used in the present publication, offer the possibility to consistently model the behavior of concrete from the first hours to several years. However, shortcomings of the formulation based on effective stress, which is usually employed in such multiphase models, were identified. As a remedy, two alternative formulations with a different coupling of shrinkage and creep are proposed in the present publication. Both assume viscous flow creep to be driven by total stress instead of effective stress, while viscoelastic creep is driven either by total or effective stress. Therefore, in contrast to the formulation based on effective stress, they predict a limit value for shrinkage as observed in long-term drying shrinkage tests. Shrinkage parameters for the new formulations are calibrated based on drying shrinkage data obtained from thin slices. The calibration process is straightforward for the new formulations since they decouple shrinkage and viscous flow creep. The different formulations are compared using results from shrinkage tests on sealed and unsealed cylindrical specimens. Shrinkage strain predictions are significantly improved by the new formulations.

During the past decade, piezo-resistive cantilever type silicon microprobes for high-speed roughness measurements inside high-aspect-ratio microstructures, like injection nozzles or critical gas nozzles have been developed. This article summarizes their metrological properties for fast roughness and shape measurements including noise, damping, tip form, tip wear, and probing forces and presents the first results on the measurement of mechanical surface parameters. Due to the small mass of the cantilever microprobes, roughness measurements at very high traverse speeds up to 15 mm/s are possible. At these high scanning speeds, considerable wear of the integrated silicon tips was observed in the past. In this paper, a new tip-testing artefact with rectangular grooves of different width was used to measure this wear and to measure the tip shape, which is needed for morphological filtering of the measured profiles and, thus, for accurate form measurements. To reduce tip wear, the integrated silicon tips were replaced by low-wear spherical diamond tips of a 2 µm radius. Currently, a compact microprobe device with an integrated feed-unit is being developed for high-speed roughness measurements on manufacturing machines. First measurements on sinusoidal artefacts were carried out successfully. Moreover, the first measurements of the elastic modulus of a polymer surface applying the contact resonance measurement principle are presented, which indicates the high potential of these microprobes for simultaneous high-speed roughness and mechanical parameter measurements.

Hygro-thermo-chemo-mechanical modelling of time-dependent concrete behavior requires the accurate determination of a large set of parameters. In this paper, the parameters of a multiphase model are calibrated based on a comprehensive set of experiments for a particular concrete of grade C30/37. The experiments include a calorimetry test, tests for age-dependent mechanical properties, tests for determining the water desorption isotherm, shrinkage tests, and compressive creep tests. The latter two were performed on sealed and unsealed specimens with accompanying mass water content measurements. The multiphase model is based on an effective stress formulation. It features a porosity-dependent desorption isotherm, taking into account the time-dependency of the desorption properties. The multiphase model is shown to yield excellent results for the evolutions of the mechanical parameters. The evolution of the autogenous shrinkage strain and evolutions of the creep compliances for loading at concrete ages of 2 days, 7 days, and 28 days are well predicted together with the respective mass water content evolution. This also holds for the evolution of the drying shrinkage strain, at least for moderate drying up to one year. However, it will be demonstrated that for longer drying times further conceptual thoughts concerning the coupled representation of shrinkage and creep are required.

N-(4-Ethylphenyl)-N'-phenylurea (INH14) is a fragment-like compound that inhibits the toll-like receptor 2 (TLR2)-mediated inflammatory activity and other inflammatory pathways (i.e., TLR4, TNF-R and IL-1R). In this study, we determined the molecular target of INH14. Overexpression of proteins that are part of the TLR2 pathway in cells treated with INH14 indicated that the target lay downstream of the complex TAK1/TAB1. Immunoblot assays showed that INH14 decreased IkBα degradation in cells activated by lipopeptide (TLR2 ligand). These data indicated the kinases IKKα and/or IKKβ as the targets of INH14, which was confirmed with kinase assays (IC 50 IKKα=8.97 μm; IC 50 IKKβ=3.59 μm). Furthermore, in vivo experiments showed that INH14 decreased TNFα formed after lipopeptide-induced inflammation, and treatment of ovarian cancer cells with INH14 led to a reduction of NF-kB constitutive activity and a reduction in the wound-closing ability of these cells. These results demonstrate that INH14 decreases NF-kB activation through the inhibition of IKKs. Optimization of INH14 could lead to potent inhibitors of IKKs that might be used as antiinflammatory drugs., (© 2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

There exists solid evidence that endogenous galanin and galanin agonists exert anticonvulsive actions mediated both by galanin 1 receptor (GAL1-R) and galanin 2 receptor (GAL2-R). We have now investigated whether depletion of the recently identified third galanin receptor, GAL3-R, and that of GAL2-R, alters the threshold to the systemically applied γ-aminobutyric acid (GABA) antagonist pentylenetetrazole (PTZ) or to intrahippocampally administered kainic acid (KA). In neither model, GAL3-KO mice differed in their latency to the first seizure, mean seizure duration, total number of seizures, or time spent in seizures compared to wild-type controls. In addition, consistent with previous data, the response to PTZ was not altered in GAL2-KO mice. In contrast, intrahippocampal KA resulted in a significantly increased number of seizures and time spent in seizures in GAL2-KO mice, although the latency to the first seizure and the duration of individual seizures was not altered. These results are consistent with the previous data showing that GAL2-R knockdown does not affect the number of perforant path stimulations required for initiating status epilepticus but significantly increases the seizure severity during the ongoing status. In conclusion, our data support a specific role of GAL2-R but not of GAL3-R in mediating the anticonvulsive actions of endogenous galanin., (© The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.)

Letermovir is a human cytomegalovirus terminase inhibitor for cytomegalovirus infection prophylaxis in hematopoietic stem cell transplant recipients. Posaconazole (POS), a substrate of glucuronosyltransferase and P-glycoprotein, and voriconazole (VRC), a substrate of CYP2C9/19, are commonly administered to transplant recipients. Because coadministration of these azoles with letermovir is expected, the effect of letermovir on exposure to these antifungals was investigated. Two trials were conducted in healthy female subjects 18 to 55 years of age. In trial 1, single-dose POS 300 mg was administered alone, followed by a 7-day washout; then letermovir 480 mg once daily was given for 14 days with POS 300 mg coadministered on day 14. In trial 2, on day 1 VRC 400 mg was given every 12 hours; on days 2 and 3, VRC 200 mg was given every 12 hours, and on day 4 VRC 200 mg. On days 5 to 8, letermovir 480 mg was given once daily. Days 9 to 12 repeated days 1 to 4 coadministered with letermovir 480 mg once daily. In both trials, blood samples were collected for the assessment of the pharmacokinetic profiles of the antifungals, and safety was assessed. The geometric mean ratios (90%CIs) for POS+letermovir/POS area under the curve and peak concentration were 0.98 (0.83, 1.17) and 1.11 (0.95, 1.29), respectively. Voriconazole+letermovir/VRC area under the curve and peak concentration geometric mean ratios were 0.56 (0.51, 0.62) and 0.61 (0.53, 0.71), respectively. All treatments were generally well tolerated. Letermovir did not affect POS pharmacokinetics to a clinically meaningful extent but decreased VRC exposure. These results suggest that letermovir may be a perpetrator of CYP2C9/19-mediated drug-drug interactions., (© 2018, The American College of Clinical Pharmacology.)

The present contribution deals with the experimental investigation of the time-dependent behavior of a typical overlay concrete subjected to tensile stresses. The latter develop in concrete overlays, which are placed on existing concrete structures as a strengthening measure, due to the shrinkage of the young overlay concrete, which is restrained by the substrate concrete. Since the tensile stresses are reduced by creep, creep in tension is investigated on sealed and unsealed specimens, loaded at different concrete ages. The creep tests as well as the companion shrinkage tests are performed in a climatic chamber at constant temperature and constant relative humidity. Since shrinkage depends on the change of moisture content, the evolution of the mass water content is determined at the center of each specimen by means of an electrolytic resistivity-based system. Together with the experimental results for compressive creep from a previous study, a consistent set of time-dependent material data, determined for the same composition of the concrete mixture and on identical specimens, is now available. It consists of the hygral and mechanical properties, creep and shrinkage strains for both sealed and drying conditions, the respective compliance functions, and the mass water contents in sealed and unsealed, loaded and load-free specimens.

A new experimental program, focusing on the evolution of the Young's modulus, uniaxial compressive strength, shrinkage and creep of shotcrete is presented. The laboratory tests are, starting at very young ages of the material, conducted on two different types of specimens sampled at the site of the Brenner Basetunnel. The experimental results are evaluated and compared to other experiments from the literature. In addition, three advanced constitutive models for shotcrete, i.e., the model by Meschke, the model by Schädlich and Schweiger, and the model by Neuner et al., are validated on the basis of the test data, and the capabilities of the models to represent the observed shotcrete behavior are assessed. Hence, the gap between the the outdated experimental data on shotcrete available in the literature on the one hand and the nowadays available advanced shotcrete models, on the other hand, is closed.

Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsies and is generally associated with malfunctioning of the hippocampal formation. Recently, a preferential loss of parvalbumin (PV) neurons has been observed in the subiculum of TLE patients and in animal models of TLE. To demonstrate a possible causative role of defunct PV neurons in the generation of TLE, we permanently inhibited GABA release selectively from PV neurons of the ventral subiculum by injecting a viral vector expressing tetanus toxin light chain in male mice. Subsequently, mice were subjected to telemetric EEG recording and video monitoring. Eighty-eight percent of the mice presented clusters of spike-wave discharges (C-SWDs; 40.0 ± 9.07/month), and 64% showed spontaneous recurrent seizures (SRSs; 5.3 ± 0.83/month). Mice injected with a control vector presented with neither C-SWDs nor SRSs. No neurodegeneration was observed due to vector injection or SRS. Interestingly, mice that presented with only C-SWDs but no SRSs, developed SRSs upon injection of a subconvulsive dose of pentylenetetrazole after 6 weeks. The initial frequency of SRSs declined by ∼30% after 5 weeks. In contrast to permanent silencing of PV neurons, transient inhibition of GABA release from PV neurons through the designer receptor hM4Di selectively expressed in PV-containing neurons transiently reduced the seizure threshold of the mice but induced neither acute nor recurrent seizures. Our data demonstrate a critical role for perisomatic inhibition mediated by PV-containing interneurons, suggesting that their sustained silencing could be causally involved in the development of TLE. SIGNIFICANCE STATEMENT Development of temporal lobe epilepsy (TLE) generally takes years after an initial insult during which maladaptation of hippocampal circuitries takes place. In human TLE and in animal models of TLE, parvalbumin neurons are selectively lost in the subiculum, the major output area of the hippocampus. The present experiments demonstrate that specific and sustained inhibition of GABA release from parvalbumin-expressing interneurons (mostly basket cells) in sector CA1/subiculum is sufficient to induce hyperexcitability and spontaneous recurrent seizures in mice. As in patients with nonlesional TLE, these mice developed epilepsy without signs of neurodegeneration. The experiments highlight the importance of the potent inhibitory action mediated by parvalbumin cells in the hippocampus and identify a potential mechanism in the development of TLE., (Copyright © 2017 the authors 0270-6474/17/378166-14$15.00/0.)

Neuropeptide Y (NPY)-Y2 receptors are G-protein coupled receptors and, upon activation, induce opening of potassium channels or closing of calcium channels. They are generally presynaptically located. Depending on the neuron in which they are expressed they mediate inhibition of release of NPY and of the neuron's classical transmitter GABA, glutamate or noradrenaline, respectively. Here we provide evidence that Y2 receptor binding is inhibited dose-dependently by GTPγS along Schaffer collaterals, the stria terminalis and the fimbria indicating that Y2 receptors are functionally coupled to G-proteins along these fiber tracts. Double immune fluorescence revealed coexistence of Y2-immunoreactivity with β-tubulin, a marker for axons in the stria terminalis, but not with synaptophysin labeling presynaptic terminals, supporting the localization of Y2 receptors along axonal tracts. After kainic acid-induced seizures in rats, GTPγS-induced inhibition of Y2 receptor binding is facilitated in the Schaffer collaterals but not in the stria terminalis. Our data indicate that Y2 receptors are not only located at nerve terminals but also along fiber tracts and are there functionally coupled to G-proteins., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The objective of this study was to evaluate sleep electrophysiology in healthy subjects after bedtime administration of therapeutic doses of two insomnia treatments - the orexin receptor antagonist suvorexant or the GABAergic agonist zolpidem. Eighteen healthy men received single bedtime doses of suvorexant 20mg, zolpidem 10mg, or placebo in a double-blinded, randomized, balanced 3-period crossover study. EEG power spectral densities during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep were recorded in a polysomnography (PSG) laboratory using a 19-lead EEG recording array. Spectral density was analyzed for each lead for frequencies between 1-32Hz. During NREM and REM sleep, zolpidem treatment reduced spectral density across theta and alpha frequency bands in all leads. In contrast, suvorexant had no significant effects on spectral density in any frequency band during NREM sleep, and modestly increased spectral density in the theta frequency band during REM sleep. Although the study was not designed to detect effects on PSG sleep endpoints in healthy subjects, both suvorexant and zolpidem increased mean total sleep time and sleep efficiency. Zolpidem reduced latency to persistent sleep whereas suvorexant did not. Suvorexant decreased wake after sleep onset, whereas zolpidem did not. These findings suggest that EEG power spectral density profile after administration of suvorexant in healthy subjects more closely approximates placebo sleep physiology than after zolpidem treatment., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

Epigenetic mechanisms like altered histone acetylation may have a crucial role in epileptogenesis. In two mouse models of temporal lobe epilepsy, we investigated changes in the expression of class II histone deacetylases (HDAC), a group of signal transducers that shuttle between nucleus and cytoplasm. Intrahippocampal injection of kainic acid (KA) induced a status epilepticus, development of spontaneous seizures (after 3 days), and finally chronic epilepsy and granule cell dispersion. Expression of class II HDAC mRNAs was investigated at different time intervals after KA injection in the granule cell layers and in sectors CA1 and CA3 contralateral to the site of KA injection lacking neurodegeneration. Increased expression of HDAC5 and 9 mRNAs coincided with pronounced granule cell dispersion in the KA-injected hippocampus at late intervals (14-28 days after KA) and equally affected both HDAC9 splice variants. In contrast, in the pilocarpine model (showing no granule cell dispersion), we observed decreases in the expression of HDAC5 and 9 at the same time intervals. Beyond this, striking similarities between both temporal lobe epilepsy models such as fast decreases in HDAC7 and 10 mRNAs during the acute status epilepticus were observed, notably also in the contralateral hippocampus not affected by neurodegeneration. The particular patterns of HDAC mRNA expression suggest a role in epileptogenesis and granule cell dispersion. Reduced expression of HDACs may result in increased expression of pro- and anticonvulsive proteins. On the other hand, export of HDACs from the nucleus into the cytoplasm could allow for deacetylation of cytoplasmatic proteins involved in axonal and dendritic remodeling, like granule cell dispersion. HDAC 5 and HDAC 9 expression is highly increased in granule cells of the KA-injected hippocampus and parallels granule cell dispersion. Both HDACs are thought to be targeted to the cytoplasm and to act there by deacetylating cytoplasmatic (e.g. cytosceleton-related) proteins., (© 2015 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)

A prominent role of epigenetic mechanisms in manifestation of epilepsy has been proposed. Thus altered histone H3 and H4 acetylation has been demonstrated in experimental models of temporal lobe epilepsy (TLE). We now investigated changes in the expression of the class I and class IV histone deacetylases (HDAC) in two complementary mouse TLE models. Unilateral intrahippocampal injection of kainic acid (KA) induced a status epilepticus lasting 6 to 24h, development of spontaneous limbic seizures (2 to 3 days after KA injection) and chronic epilepsy, as revealed by telemetric recordings of the EEGs. Mice were killed at different intervals after KA injection and expression of HDAC mRNAs was investigated by in situ hybridization. We observed marked decreases in the expression of HDACs 1, 2 and 11 (by up to 75%) in the granule cell and pyramidal cell layers of the hippocampus during the acute status epilepticus (2 to 6h after KA injection). This was followed by increased expression of all class I HDAC mRNAs in all principal cell layers of the hippocampus after 12 to 48 h. In the chronic phase, 14 and 28 days after KA, only modest increases in the expression of HDAC1 mRNA were observed in granule and pyramidal cells. Immunohistochemistry using an antibody detecting HDAC2 revealed results consistent with the mRNA data and indicates also expression in glial cells on the injection side. Similar changes as seen in the KA model were observed after a pilocarpine-induced status epilepticus except that decreases in HDACs 2, 3 and 8 were also seen at the chronic 28 day interval. The prominent decreases in HDAC expression during status epilepticus are consistent with the previously demonstrated increased expression of numerous proteins and with the augmented acetylation of histone H4. It is suggested that respective putative gene products could facilitate proconvulsive as well as anticonvulsive mechanisms. The increased expression of all class I HDACs during the "silent phase", on the other hand, may be related to decreased histone acetylation, which could cause a decrease in expression of certain proteins, a mechanism that could also promote epileptogenesis. Thus, addressing HDAC expression may have a therapeutic potential in interfering with a status epilepticus and with the manifestation of TLE., (Copyright © 2015. Published by Elsevier Inc.)