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Chemical and Biological Mechanisms Relevant to the Rescue of MG-132-Treated Neurons by Cysteine
No full textProteasome dysfunctions are observed in many human pathologies. To study their role and potential treatment strategies, models of proteasome inhibition are widely used in biomedical research. One frequently used tool is the proteasome inhibitor MG-132. It triggers the degeneration of human neurons, and several studies show protection from pathological events by glutathione or its precursors. It has therefore been concluded that glutathione protects cells from proteasome dysfunction. However, an alternative explanation is that MG-132, which is a peptide aldehyde, is chemically inactivated by thiols, and the apparent protection by glutathione from proteasome dysfunction is an artefact. To clarify this issue, we examined the chemical inactivation of MG-132 by thiols and the role of such reactions for neuroprotection. Using mass spectrometry and nuclear magnetic resonance spectroscopy, we found that MG-132 reacted with L-cysteine to form a stable end product and with glutathione to form an unstable intermediate. Using a cell-free proteasome inhibition assay, we found that high concentrations of L-cysteine can scavenge a substantial fraction of MG-132 and thus reduce proteasome inhibition. Glutathione (or N-acetyl-cysteine) did not alter proteasome inhibition (even at high concentrations). In a final step, we studied human neuronal cultures. We exposed them to MG-132, supplemented the culture medium with various thiols, and assessed intracellular L-cysteine concentrations. The transcriptome response pattern also indicated an inhibition of the proteasome by MG-132 in the presence of L-cysteine. We conclude that thiol concentrations that can be reached in cells do not inactivate MG-132 in pathological models. They rather act in a cytoprotective way as antioxidants.publishe
Form-meaning relationships in the lab and in the mountains
No full textWe present a brief overview of form-meaning relationships investigated in controlled laboratory experiments and discuss whether and how the results generalize to form-meaning relationships “in the wild”. As a case study for non-laboratory situations, we use mountain hikes, which, like intonation, also involve peaks and slopes. Mountain hikes are exhausting for the hiker and have an influence on breathing and hence speech production. We investigate the prosodic realization of some typical illocution types found on mountain hikes (self-addressed questions, information-seeking questions, surprise questions) in two conditions, in a normal laboratory condition and in a simulated mountain hike condition. The results show no differences across recording conditions in speaking rate. In regard to pitch characteristics, self-addressed questions were produced with a lower f0-range and shallower slope in the lab than in the mountains, while information-seeking questions and surprise questions showed the opposite patterns. These differences are discussed in terms of the prosody-semantic interface and phonetic constraints. We further discuss the larger context, which also plays a pivotal role, and discuss ideas for future research, in the lab and in the mountains.publishe
Multilayer MoS<sub>2</sub> Schottky Barrier Field Effect Transistor
No full textThe miniaturization of electronic components remains a critical focus in electronics, particularly in transistor design, with research exploring new solutions such as the use of two-dimensional materials in Schottky Barrier Field Effect Transistors (SB-FETs). Following the trend, this study presents two-dimensional MoS₂ SB-FETs, configured with back-gate and van der Pauw contacts, and analyses their electrical behaviour through output and transfer characteristics. The consequences that local inhomogeneities due to fabrication processes have on Schottky barriers height and electrical behaviour of the device are underlined. A hierarchy of the Schottky barrier heights at the contacts is established, and a band model is developed to elucidate the underlying conduction mechanisms. This model combines thermionic emission and tunnelling to explain the operation of the studied MoS₂ devices and can be broadly applied to other SB-FETs.publishe
SNP-RFLP Markers for the Study of Arabidopsis lyrata
No full textArabidopsis lyrata has become a useful system for the study of comparative genomics, hybridization, polyploidization, and evolutionary transitions from outcrossing to selfing. Previous studies of its mating system have used microsatellite loci, but low allelic diversity, particularly in self-compatible populations characterized by low levels of outcrossing, reduces the utility of these markers for more detailed studies. Here, we aimed to develop population-level SNP markers for A. lyrata ssp. lyrata sampled from a self-compatible population at Rondeau Provincial Park, Ontario, Canada. We performed de novo SNP discovery and identified 6808 putative SNPs from genome-wide sequences of 22 individuals originating from a highly selfing population. Further filtering and marker validation enabled the development of 17 SNP marker loci that can be visualized using standard PCR-RFLP protocols. These markers had average minor-allele frequencies of 0.40 in the target population, and four of seven markers were variable in a small sample from nine other A. lyrata populations. These PCR-RFLP markers have the potential to be useful for the analysis of mating patterns within and beyond the inbred self-compatible populations of A. lyrata studied here and enable the continued development of A. lyrata as a model for studying evolutionary transitions from outcrossing to selfing.publishe
Effects of Stress on Physiological Synchrony
No full textA need for connectedness is balanced with a striving for individuality when navigating the social environment. Feelings of belongingness are shaped by interpersonal synchronization, i.e., the temporal correspondence of processes between individuals. On a physiological level, physiological synchrony (PS) quantifies the interrelation of autonomic or endocrinological processes between interaction partners. However, research gaps remain regarding PS and its emergence and consequences. Stress, a ubiquitous part of human experiences, could influence the degree to which people synchronize physiologically, thus providing insights into when and how PS arises. Stressors elicit a multifaceted stress response with far-reaching effects on the organism. Stress effects reach beyond the individuals and may extend to physiological synchronization, potentially influencing social connections. A prerequisite for analyzing the effects of stress on PS is choosing an appropriate methodology for quantifying synchrony. Various approaches are used in the literature, but it is unclear which approach is suited for what situation. The first project of this thesis provides an introduction to selected methods and their implementation. The overview reveals the assumptions and areas of application for different approaches, including guidance on which method is suitable for which type of research question and data. The second and third projects of the thesis investigated whether acute stress influences PS using different biomarkers (cortisol and heart rate). The second project focused on synchrony of the endocrine system, i.e., cortisol data, to examine the effect of a laboratory stressor on cortisol PS in groups of strangers. N = 44 groups (138 participants; mean age = 23.48 ± 3.99, 47.1% female) underwent a stress induction or nonstressful control paradigm. Cortisol PS, determined by stability-and-influence modeling, was attenuated in the stress condition, showing that stress reduces group-level physiological connectedness. An exploratory analysis revealed no significant sympathetic nervous system synchrony within groups. The third project investigated the effect of one-sided stress on post-stress autonomic PS (i.e., PS in parasympathetic and sympathetic components of heart rate) in romantic couples (N = 75 dyads; mean age = 22.66 ±2.99, 51% female). Partners separately underwent either a laboratory stressor or a nonstressful control paradigm. When reunited, they were not informed about each other’s stress state while completing three nonstressful tasks together. Heart rate synchrony was measured via a time-frequency analysis of PS, i.e., cross-wavelet power. Couples with a stressed partner showed lower synchrony than nonstressed couples, indicating that stress reduces couples’ physiological connection even after an acute stressor. Across projects, stress reduced PS, implying an interplay between the two phenomena. The mechanisms behind this effect are not yet identified, but multiple explanations are possible. Stress effects on PS may be related to attentional or physiological processes that could hinder synchronization. However, reduced PS in a stressful context may also be protective to avoid the spread of stress in the collective. While a short-term reduction in PS may be adaptive, chronic stress might lead to a long-term attenuation of synchrony with potential detrimental consequences. Stress can be described as an interpersonal phenomenon that may affect the fundamental building blocks of belonging and individuation.publishe
Structural and functional analysis of DNA polymerases in the interplay of artificial substrates
No full textpublishe
Mapping out strategies to further develop human-relevant, new approach methodology (NAM)-based developmental neurotoxicity (DNT) testing
No full textOn occasion of the DNT5 meeting in Konstanz, Germany (April-2024), participants brainstormed on future challenges concerning a regulatory implementation of the developmental neurotoxicity (DNT) in vitro test battery (DNT-IVB). The five discussion topics below outline some of the key issues, opportunities and research directions for the next several years: (1) How to contextualize DNT hazard with information on potential maternal toxicity or other toxicity domains (non-DNT)? Several approaches on how to use cytotoxicity data from NAMs were discussed. (2) What opportunities exist for an immediate or near-future application of the DNT-IVB, e.g. as a prioritisation step or add-on to other information? Initial examples are already emerging; the data can be used even if the battery is not converted to a defined approach. (3) How to establish data interpretation procedures for multi-dimensional endpoints that reduce dimensionality and are suitable for classification? A decision framework is required on how to use the DNT-IVB in a regulatory context. Machine-learning (AI-approaches) may provide novel classification models. (4) How can a battery of molecular initiating events (MIEs) be smartly linked to the DNT-IVB? If decisions are required, at what tier of an overall strategy would MIEs be evaluated, and how would optimally balance cost vs information yield. (5) What is the way forward to scientific validation of DNT NAMs and the DNT-IVB? A large set of animal data would be required for conventional approaches, while mechanistic information may establish relevance in other ways.publishe
Migratory Birds Advance Spring Arrival and Egg‐Laying in the Arctic, Mostly by Travelling Faster
No full textIn the current warming climate, many organisms in seasonal environments advance their timing of reproduction to benefit from resource peaks earlier in spring. For migrants, the potential to advance reproduction may be constrained by their migration strategies, notably their ability to advance arrival at the breeding grounds. Recent studies show various changes in migration strategies, including wintering closer to the breeding grounds, earlier departure from the wintering grounds or faster travels by spending less time at stopover sites. However, whether such changes lead to earlier arrival or earlier breeding remains an open question. We studied changes in migration and reproduction timing in 12 populations of nine migratory birds, including seabirds, shorebirds, birds of prey and waterfowl breeding at Arctic sites bordering the Greenland and Barents Sea, a region undergoing rapid climate warming. The timing of migration and reproduction was derived from tracking and field data and analysed to study (1) how timing has changed in response to the changing moment of snowmelt at the breeding grounds and (2) what adjustments in migration strategies this involved. We found that in years with early snowmelt, egg‐laying in multiple populations advanced, but only two waterfowl populations also advanced arrival in the Arctic. In contrast, arrival in the Arctic generally advanced with time, even when snowmelt or egg‐laying dates did not advance. Earlier arrival with time was mostly explained by populations traveling to the Arctic faster, likely spending less time at stopover sites. Inability to forecast conditions in the Arctic may limit birds to adjust migration timing to annually varying snowmelt, but we show that several species, particularly waterfowl, are able to travel faster and advance the timing of migration over the years. The question remains whether this reflects adaptations to Arctic climate change or other factors, for example, environmental changes along the migratory route.publishe
Partial Landau-Zener transitions and applications to qubit shuttling
No full textThe transition dynamics of two-state systems with time-dependent energy levels, first considered by Landau, Zener, Majorana, and Stückelberg, is one of the basic models in quantum physics and has been used to describe various physical systems. We propose here a generalization of the Landau-Zener (LZ) problem characterized by distinct paths of the instantaneous eigenstates as the system evolves in time while keeping the instantaneous eigenenergies exactly as in the standard LZ model. We show that these paths play an essential role in the transition probability between the two states, and can lead to a substantial reduction of , being possible even to achieve =0 in an instructive extreme case, and also to large even in the absence of any anticrossing point. The partial LZ model can describe valley transition dynamics during charge and spin shuttling in semiconductor quantum dots.publishe
