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Using articulatory data from five German speakers, we study how segmental sequences under different syllabic organizations respond to perturbations of phonetic parameters in the segments that compose them. Target words contained stop-lateral sequences /bl, gl, kl, pl/ in word-initial and cross-word contexts and were embedded in carrier phrases with different prosodic boundaries, i.e., no phrase boundary versus an utterance phrase boundary preceded the target word in the case of word-initial clusters, or separated the consonants in the case of cross-word sequences. For word-initial cluster (CCV) onsets, we find that increasing C1 stop duration or the lag between two consonants leads to earlier vowel initiation and reduced local timing stability across CV, CCV. Furthermore, as the inter-consonantal lag increases, C2 duration decreases. In contrast, for cross-word C#CV sequences, increasing inter-consonantal lag does not lead to earlier vowel initiation and robust local timing stability is maintained across CV, C#CV. In other words, in CCV sequences within words, local perturbations to segments have effects that ripple through the rest of the sequence. Instead, in cross-word C#CV sequences, local perturbations stay local. Overall, the findings indicate that the effects of phonetic perturbations on coordination patterns depend on the syllabic organization superimposed on these clusters.
Background
Cytochrome P450 (CYP) 3A contributes to the metabolism of many approved drugs. CYP3A perpetrator drugs can profoundly alter the exposure of CYP3A substrates. However, effects of such drug-drug interactions are usually reported as maximum effects rather than studied as time-dependent processes. Identification of the time course of CYP3A modulation can provide insight into when significant changes to CYP3A activity occurs, help better design drug-drug interaction studies, and manage drug-drug interactions in clinical practice.
Objective
We aimed to quantify the time course and extent of the in vivo modulation of different CYP3A perpetrator drugs on hepatic CYP3A activity and distinguish different modulatory mechanisms by their time of onset, using pharmacologically inactive intravenous microgram doses of the CYP3A-specific substrate midazolam, as a marker of CYP3A activity.
Methods
Twenty-four healthy individuals received an intravenous midazolam bolus followed by a continuous infusion for 10 or 36 h. Individuals were randomized into four arms: within each arm, two individuals served as a placebo control and, 2 h after start of the midazolam infusion, four individuals received the CYP3A perpetrator drug: voriconazole (inhibitor, orally or intravenously), rifampicin (inducer, orally), or efavirenz (activator, orally). After midazolam bolus administration, blood samples were taken every hour (rifampicin arm) or every 15 min (remaining study arms) until the end of midazolam infusion. A total of 1858 concentrations were equally divided between midazolam and its metabolite, 1'-hydroxymidazolam. A nonlinear mixed-effects population pharmacokinetic model of both compounds was developed using NONMEM (R). CYP3A activity modulation was quantified over time, as the relative change of midazolam clearance encountered by the perpetrator drug, compared to the corresponding clearance value in the placebo arm.
Results
Time course of CYP3A modulation and magnitude of maximum effect were identified for each perpetrator drug. While efavirenz CYP3A activation was relatively fast and short, reaching a maximum after approximately 2-3 h, the induction effect of rifampicin could only be observed after 22 h, with a maximum after approximately 28-30 h followed by a steep drop to almost baseline within 1-2 h. In contrast, the inhibitory impact of both oral and intravenous voriconazole was prolonged with a steady inhibition of CYP3A activity followed by a gradual increase in the inhibitory effect until the end of sampling at 8 h. Relative maximum clearance changes were +59.1%, +46.7%, -70.6%, and -61.1% for efavirenz, rifampicin, oral voriconazole, and intravenous voriconazole, respectively.
Conclusions
We could distinguish between different mechanisms of CYP3A modulation by the time of onset. Identification of the time at which clearance significantly changes, per perpetrator drug, can guide the design of an optimal sampling schedule for future drug-drug interaction studies. The impact of a short-term combination of different perpetrator drugs on the paradigm CYP3A substrate midazolam was characterized and can define combination intervals in which no relevant interaction is to be expected.
Ionic liquid crystals (ILCs), that is, ionic liquids exhibiting mesomorphism, liquid crystalline phases, and anisotropic properties, have received intense attention in the past years. Among others, this is due to their special properties arising from the combination of properties stemming from ionic liquids and from liquid crystalline arrangements. Besides interesting fundamental aspects, ILCs have been claimed to have tremendous application potential that again arises from the combination of properties and architectures that are not accessible otherwise, or at least not accessible easily by other strategies. The current review highlights recent developments in ILC research, starting with some key fundamental aspects. Further subjects covered include the synthesis and variations of modern ILCs, including the specific tuning of their mesomorphic behavior. The review concludes with reflections on some applications that may be within reach for ILCs and finally highlights a few key challenges that must be overcome prior and during true commercialization of ILCs.
A volcanic eruption is usually preceded by seismic precursors, but their interpretation and use for forecasting the eruption onset time remain a challenge. A part of the eruptive processes in open conduits of volcanoes may be similar to those encountered in geysers. Since geysers erupt more often, they are useful sites for testing new forecasting methods. We tested the application of Permutation Entropy (PE) as a robust method to assess the complexity in seismic recordings of the Strokkur geyser, Iceland. Strokkur features several minute-long eruptive cycles, enabling us to verify in 63 recorded cycles whether PE behaves consistently from one eruption to the next one. We performed synthetic tests to understand the effect of different parameter settings in the PE calculation. Our application to Strokkur shows a distinct, repeating PE pattern consistent with previously identified phases in the eruptive cycle. We find a systematic increase in PE within the last 15 s before the eruption, indicating that an eruption will occur. We quantified the predictive power of PE, showing that PE performs better than seismic signal strength or quiescence when it comes to forecasting eruptions.
Flood risk management in Germany follows an integrative approach in which both private households and businesses can make an important contribution to reducing flood damage by implementing property-level adaptation measures. While the flood adaptation behavior of private households has already been widely researched, comparatively less attention has been paid to the adaptation strategies of businesses. However, their ability to cope with flood risk plays an important role in the social and economic development of a flood-prone region. Therefore, using quantitative survey data, this study aims to identify different strategies and adaptation drivers of 557 businesses damaged by a riverine flood in 2013 and 104 businesses damaged by pluvial or flash floods between 2014 and 2017. Our results indicate that a low perceived self-efficacy may be an important factor that can reduce the motivation of businesses to adapt to flood risk. Furthermore, property-owners tended to act more proactively than tenants. In addition, high experience with previous flood events and low perceived response costs could strengthen proactive adaptation behavior. These findings should be considered in business-tailored risk communication.
The motility of adherent eukaryotic cells is driven by the dynamics of the actin cytoskeleton. Despite the common force-generating actin machinery, different cell types often show diverse modes of locomotion that differ in their shape dynamics, speed, and persistence of motion. Recently, experiments in Dictyostelium discoideum have revealed that different motility modes can be induced in this model organism, depending on genetic modifications, developmental conditions, and synthetic changes of intracellular signaling. Here, we report experimental evidence that in a mutated D. discoideum cell line with increased Ras activity, switches between two distinct migratory modes, the amoeboid and fan-shaped type of locomotion, can even spontaneously occur within the same cell. We observed and characterized repeated and reversible switchings between the two modes of locomotion, suggesting that they are distinct behavioral traits that coexist within the same cell. We adapted an established phenomenological motility model that combines a reaction-diffusion system for the intracellular dynamics with a dynamic phase field to account for our experimental findings.
Background
There is evidence that in older adults the combination of strength training (ST) and endurance training (ET) (i.e., concurrent training [CT]) has similar effects on measures of muscle strength and cardiorespiratory endurance (CRE) compared with single-mode ST or ET, respectively. Therefore, CT seems to be an effective method to target broad aspects of physical fitness in older adults.
Objectives
The aim was to examine the effects of CT on measures of physical fitness (i.e., muscle strength, power, balance and CRE) in healthy middle-aged and older adults aged between 50 and 73 years. We also aimed to identify key moderating variables to guide training prescription.
Study Design
We conducted a systematic review with meta-analysis of randomized controlled trials.
Data Sources
The electronic databases PubMed, Web of Science Core Collection, MEDLINE and Google Scholar were systematically searched until February 2022.
Eligibility Criteria for Selecting Studies We included randomized controlled trials that examined the effects of CT versus passive controls on measures of physical fitness in healthy middle-aged and older adults aged between 50 and 73 years.
Results
Fifteen studies were eligible, including a total of 566 participants. CT induced moderate positive effects on muscle strength (standardized mean difference [SMD] = 0.74) and power (SMD = 0.50), with a small effect on CRE (SMD = 0.48). However, no significant effects were detected for balance (p > 0.05). Older adults > 65 years (SMD = 1.04) and females (SMD = 1.05) displayed larger improvements in muscle strength compared with adults <= 65 years old (SMD = 0.60) and males (SMD = 0.38), respectively. For CRE, moderate positive effects (SMD = 0.52) were reported in those <= 65 years old only, with relatively larger gains in females (SMD = 0.55) compared with males (SMD = 0.45). However, no significant differences between all subgroups were detected. Independent single training factor analysis indicated larger positive effects of 12 weeks (SMD = 0.87 and 0.88) compared with 21 weeks (SMD = 0.47 and 0.29) of CT on muscle strength and power, respectively, while for CRE, 21 weeks of CT resulted in larger gains (SMD = 0.62) than 12 weeks (SMD = 0.40). For CT frequency, three sessions per week produced larger beneficial effects (SMD = 0.91) on muscle strength compared with four sessions (SMD = 0.55), whereas for CRE, moderate positive effects were only noted after four sessions per week (SMD = 0.58). A session duration of > 30-60 min generated larger improvements in muscle strength (SMD = 0.99) and power (SMD = 0.88) compared with > 60-90 min (SMD = 0.40 and 0.29, respectively). However, for CRE, longer session durations (i.e., > 60-90 min) seem to be more effective (SMD = 0.61) than shorter ones (i.e., > 30-60 min) (SMD = 0.34). ET at moderate-to-near maximal intensities produced moderate (SMD = 0.64) and small positive effects (SMD = 0.49) on muscle strength and CRE, respectively, with no effects at low intensity ET (p > 0.05). Finally, intra-session ST before ET produced larger gains in muscle strength (SMD = 1.00) compared with separate sessions (SMD = 0.55), whereas ET and ST carried out separately induced larger improvements in CRE (SMD = 0.58) compared with intra-session ET before ST (SMD = 0.49).
Conclusions
CT is an effective method to improve measures of physical fitness (i.e., muscle strength, power, and CRE) in healthy middle-aged and older adults aged between 50 and 73 years, regardless of sex. Results of independent single training factor analysis indicated that the largest effects on muscle strength were observed after 12 weeks of training, > 30-60 min per session, three sessions per week, higher ET intensities and when ST preceded ET within the same session. For CRE, the largest effects were noted after 21 weeks of training, four sessions per week, > 60-90 min per session, higher ET intensities and when ET and ST sessions were performed separately. Regarding muscle power, the largest effects were observed after 12 weeks of training and > 30-60 min per session.
The purpose of the present study was to investigate the moderating effect of perceived social support from friends in the associations between self-isolation practices during the COVID-19 pandemic and adolescents' mental health (i.e., depression, subjective health complaints, self-harm), measured six months later (Time 2). Participants were 1,567 7(th) and 8(th) graders (51% female; 51% white; M age = 13.67) from the United States. They completed questionnaires on perceived social support from friends, depression, subjective health complaints, and self-harm at Time 1, and self-isolation practices during COVID-19, depression, subjective health complaints, and self-harm at Time 2. The findings revealed that self-isolation practices during COVID-19 was related positively to Time 1 perceived social support from friends, and negatively to Time 2 depression, subjective health complaints, and self-harm, while accounting for Time 1 mental health outcomes. Higher perceived social support from friends at Time 1 buffered against the negative impacts on adolescents' mental health outcomes at Time 2 when they practiced greater self-isolation during COVID-19, while lower perceived social support at Time 1 had the opposite effects on Time 2 mental health outcomes.
We present the first systematic literature review on stress and burnout in K-12 teachers during the COVID-19 pandemic. Based on a systematic literature search, we identified 17 studies that included 9,874 K-12 teachers from around the world. These studies showed some indication that burnout did increase during the COVID-19 pandemic. There were, however, almost no differences in the levels of stress and burnout experienced by K-12 teachers compared to individuals employed in other occupational fields. School principals' leadership styles emerged as an organizational characteristic that is highly relevant for K-12 teachers' levels of stress and burnout. Individual teacher characteristics associated with burnout were K-12 teachers' personality, self-efficacy in online teaching, and perceived vulnerability to COVID-19. In order to reduce stress, there was an indication that stress-management training in combination with training in technology use for teaching may be superior to stress-management training alone. Future research needs to adopt more longitudinal designs and examine the interplay between individual and organizational characteristics in the development of teacher stress and burnout during the COVID-19 pandemic and beyond.
We show that local deformations, near closed subsets, of solutions to open partial differential relations can be extended to global deformations, provided all but the highest derivatives stay constant along the subset. The applicability of this general result is illustrated by a number of examples, dealing with convex embeddings of hypersurfaces, differential forms, and lapse functions in Lorentzian geometry.
The main application is a general approximation result by sections that have very restrictive local properties on open dense subsets. This shows, for instance, that given any K is an element of Double-struck capital R every manifold of dimension at least 2 carries a complete C-1,C- 1-metric which, on a dense open subset, is smooth with constant sectional curvature K. Of course, this is impossible for C-2-metrics in general.