Search

The phase field model - a powerful tool - has been well established to simulate the fatigue crack evolution behavior. However, it is still hard to understand how each energy component in the phase field model contributes to crack evolution since the phase field method is based on an energetic criterion. In this work, we borrow the concept of configurational forces and show a straightforward way to examine the energetic driving forces in the phase field fatigue model. Results show that different parts of the configurational forces provide different energetic contributions during crack propagation.

This paper captures a better understanding of the career development of people leading megaprojects through the use of biographical research method. The characteristics of megaprojects cause serious and diverse challenges for their leaders, but programs where they are trained to overcome these challenges are not easily available around the world. We used a biographic research to gather sixteen life histories of megaproject leaders from ten different countries. This approach helps to explore megaproject leaders as people and how they have learned to become leaders. Findings show that leaders learned to manage megaprojects through a lifetime interaction of: (1) personal characteristics of leaders, (2) turning points in their lives, (3) value orientations stemming from their family, region or religion, (4) their relationship to the project team, and (5) their professionalization through a diversity of projects. These findings add to our knowledge on leaders’ career development that this not only depends on individual agency but also on contextual influences which span a lifetime. Furthermore, the findings contribute to the debate on narrative inquiry methods by demonstrating the full potential of biographical research method for understanding megaproject leadership. Finally, the findings contribute to the debate on megaprojects leaders with real accounts of how people have become leaders through self-development.

Plants have the potency to regenerate adventitious roots from aerial organs after detachment. In Arabidopsis thaliana, de novo root regeneration (DNRR) from leaf explants is triggered by wounding signaling that rapidly induces the expression of the ETHYLENE RESPONSE FACTOR (ERF) transcription factors ERF109 and ABR1 (ERF111). In turn, the ERFs promote the expression of ASA1, an essential enzyme of auxin biosynthesis, which contributes to rooting by providing high levels of auxin near the wounding side of the leaf. Here, we show that the loss of the epigenetic regulator ULTRAPETALA1 (ULT1), which interacts with Polycomb and Trithorax Group proteins, accelerates and reinforces adventitious root formation. Expression of ERF109 and ASA1 was increased in ult1 mutants, whereas ABR1 was not significantly changed. Cultivation of explants on media with exogenous auxin equates adventitious root formation in wild-type with ult1 mutants, suggesting that ULT1 negatively regulates DNRR by suppressing auxin biosynthesis. Based on these findings, we propose that ULT1 is involved in a novel mechanism that prevents overproliferation of adventitious roots during DNRR.

Ice flow dynamics in Greenland’s outlet glaciers are influenced by elastic deformation, both in the area of tidal influence up to 14 km inland from the grounding line and further upstream, suggest analyses of GPS observations and numerical simulations.

Pluripotent stem-cells are slowly dividing cells giving rise to daughter cells that can either differentiate to new tissues and organs, or remain stem-cells. In plants, stem-cells are located in specific niches of the shoot and root apical meristems (SAMs and RAMs). After ablation of stem-cell niches, pluripotent meristematic cells can establish new stem-cells, whereas the removal of the whole meristem destructs the regeneration process. In tissue cultures, after detached plant organs are transferred to rooting or callus induction medium (G5 or CIM), vasculature-associated pluripotent cells (VPCs) immediately start proliferation to form adventitious roots or callus, respectively, while other cell types of the organ explants basically play no part in the process. Hence, in contrast to the widely-held assumption that all plant cells have the ability to reproduce a complete organism, only few cell types are pluripotent in practice, raising the question how pluripotent stem-cells differ from differentiated cells. It is now clear that, in addition to gene regulatory networks of pluripotency factors and phytohormone signaling, epigenetics play a crucial role in initiation, maintenance and determination of plant stem-cells. Although, more and more epigenetic regulators have been shown to control plant stem-cell fate, only a few studies demonstrate how they are recruited and how they change the chromatin structure and transcriptional regulation of pluripotency factors. Here, we highlight recent breakthroughs but also revisited classical studies of epigenetic regulation and chromatin dynamics of plant stem-cells and their pluripotent precursor-cells, and point out open questions and future directions.

Glasses in the systems Me2O-ZnO-B2O3 with Me = Li, Na, K, Rb (MeZB), Na2O-ZnO-CuO-B2O3 (NZCuB), CaO-ZnO-B2O3 (CaZB), and Li2O-PbO-B2O3 (LPbB) as a reference, were studied by differential thermal analysis, dilatometry, rotational viscometry, and heating microscopy. A decrease of viscosity and sintering range was found with decreasing number of fourfold coordinated boron. The viscosity of the alkali zinc borate glasses varies only slightly. LPbB and CaZB stand out by their reduced and increased viscosities, respectively. Sodium, potassium, and calcium zinc borate glasses possess a fragility above 76. All glasses were sintered to full density before crystallization. Mostly binary zinc borate phases govern crystallization. A ternary crystalline phase was detected only in the potassium containing sample. The Weinberg glass stability parameter ranges between 0.07 and 0.12. This is caused by the presence of several crystalline phases and varying melting points of even the same crystalline phase in different glass matrices.

YIN YANG 1 (YY1) encodes a dual-function transcription factor, evolutionary conserved between the animal and plant kingdom. In Arabidopsis thaliana, AtYY1 is a negative regulator of ABA responses and floral transition. Here, we report the cloning and functional characterization of the two AtYY1 paralogs, YIN and YANG (also named PtYY1a and PtYY1b) from Populus (Populus trichocarpa). Although the duplication of YY1 occurred early during the evolution of the Salicaceae, YIN and YANG are highly conserved in the willow tree family. In the majority of Populus tissues, YIN was more strongly expressed than YANG. Subcellular analysis showed that YIN-GFP and YANG-GFP are mainly localized in the nuclei of Arabidopsis. Stable and constitutive expression of YIN and YANG resulted in curled leaves and accelerated floral transition of Arabidopsis plants, which was accompanied by high expression of the floral identity genes AGAMOUS (AG) and SEPELLATA3 (SEP3) known to promote leaf curling and early flowering. Furthermore, the expression of YIN and YANG had similar effects as AtYY1 overexpression to seed germination and root growth in Arabidopsis. Our results suggest that YIN and YANG are functional orthologues of the dual-function transcription factor AtYY1 with similar roles in plant development conserved between Arabidopsis and Populus.

Controlled oriented crystallization of glass surfaces is desired for high precision applications, since the uppermost crystal layer significantly influences the properties of the material. In contrast to previous studies, the data presented here deal with separated crystals growing at defect-free surfaces in four atmospheres with different degrees of humidity (ambient/dry air, argon and vacuum). A glass with the composition 2 BaO–TiO2–2.75 SiO2 was heat-treated at 825 °C until fresnoite (Ba2TiSi2O8) grew to a significant size. The crystal growth rate is found to increase with increasing humidity. The morphology of the crystals changes from highly distorted dendrites in the driest atmosphere (vacuum) to circular/spear-head-shaped crystals in the wettest atmosphere (ambient air), which we attribute to a decrease in viscosity of the glass surface due to water uptake. The least distorted crystals appear in the form of depressions of up to 6 µm. This has an influence on the observed crystal orientation, as measured by electron backscatter diffraction (EBSD). The pulled-in crystals change the orientation during growth relative to the flat glass surface due to an enrichment in SiO2 at the crystal fronts. This confirms that the orientation of crystals is not fixed following nucleation.

Considerable confusion prevails in the mutual positioning and relationship of concepts like management, leadership, governance and governmentality in projects. This article first develops a framework to distinguish these terms conceptually by use of Archer’s structure and human agency philosophy. This provides for clearer conceptualization and lesser redundancy in the use of terms. Then the interaction between governance and governmentality in the context of projects is assessed, using a contingency theory perspective. This addresses long-standing questions about the nature of the impact of governance and governmentality on each other and on project and organizational performance. The results show that higher levels of project sovereignty (as a measure of governance), are associated with lower levels of authoritarian, but higher levels of neo-liberal governmentality, as well as higher levels of project and organizational performance. The article continues with a discussion of the theoretical implications from different perspectives of causality, which provides for different approaches to improve project performance through deliberate fine-tuning of governance and governmentality.

Balanced leadership has emerged as a contemporary theory of the dynamics in the continuous transfer of leadership authority between project managers and team members in projects. This article addresses the cognitive mechanisms for the coordination of this transfer. Four case studies in three different continents identified the most generic cognitive coordination mechanisms between project managers and team members. By building on and extending the concept of the socio-cognitive space, the study shows that empowerment, self-management, and shared understanding of skills needs govern and legitimize the question of ‘who leads’ at any point in time. The content of these three constructs varies contingent on the type of project management methodology used. A theory about the role of the socio-cognitive space in balanced leadership is developed and discussed.

In the current ice-sheet models calving of ice shelves is based on phenomenological approaches. To obtain physics-based calving criteria, a viscoelastic Maxwell model is required accounting for short-term elastic and long-term viscous deformation. On timescales of months to years between calving events, as well as on long timescales with several subsequent iceberg break-offs, deformations are no longer small and linearized strain measures cannot be used. We present a finite deformation framework of viscoelasticity and extend this model by a nonlinear Glen-type viscosity. A finite element implementation is used to compute stress and strain states in the vicinity of the ice-shelf calving front. Stress and strain maxima of small (linearized strain measure) and finite strain formulations differ by ~ 5% after 1 and by ~ 30% after 10 years, respectively. A finite deformation formulation reaches a critical stress or strain faster, thus calving rates will be higher, despite the fact that the exact critical values are not known. Nonlinear viscosity of Glen-type leads to higher stress values. The Maxwell material model formulation for finite deformations presented here can also be applied to other glaciological problems, for example, tidal forcing at grounding lines or closure of englacial and subglacial melt channels.

Considerable confusion prevails in the mutual positioning and relationship of concepts like management, leadership, governance and governmentality in projects. This article first develops a framework to distinguish these terms conceptually by use of Archer’s structure and human agency philosophy. This provides for clearer conceptualization and lesser redundancy in the use of terms. Then the interaction between governance and governmentality in the context of projects is assessed, using a contingency theory perspective. This addresses long-standing questions about the nature of the impact of governance and governmentality on each other and on project and organizational performance. The results show that higher levels of project sovereignty (as a measure of governance), are associated with lower levels of authoritarian, but higher levels of neo-liberal governmentality, as well as higher levels of project and organizational performance. The article continues with a discussion of the theoretical implications from different perspectives of causality, which provides for different approaches to improve project performance through deliberate fine-tuning of governance and governmentality.

This data article provides raw auditory evoked brainstem responses (ABRs) from controls and Cav2.3 transgenics, i.e. heterozygous Cav2.3+/- and Cav2.3-/- null mutants. Gender specific ABR recordings were performed in age-matched animals under ketamine/xylazine narcosis. Data presented here include ABRs upon both click and tone burst presentation in the increasing SPL mode using a commercially available ABR setup from Tucker Davis Technologies Inc. (TDT, USA). Detailed information is provided for the sound attenuating cubicle, electrical shielding, electrode parameters, stimulus characteristics and architecture, sampling rate, filtering processes and ABR protocol application during the course of data acquisition and recording. The later are important for subsequent analysis of click and tone burst related hearing thresholds, amplitude growth function and peak latencies. Raw data are available at MENDELEY DATA, DIO: 〈DOI:10.17632/g6ygz2spzx.1〉, URL: 〈https://data.mendeley.com/datasets/g6ygz2spzx/1〉).

To explore the impact of ambient and structural water on static fatigue, the initiation and growth of 3279 Vickers induced median radial cracks were automatically recorded and analyzed. We find that humidity is more efficient in initiating cracks and promoting their growth than water, which is dissolved in the glass structure. In particular for slow crack growth (< 3 × 10–6 m s–1), tests in dry nitrogen showed a considerable decrease in the crack growth exponent with increasing water content of the glasses. On the other hand, if tests were performed in humid air, the crack growth exponent was independent of the water content of the hydrous glasses, while stress intensity decreased slightly. These observations indicate that water promotes the processes at the crack-tip regardless of its origin. However, ambient water is more efficient.

To understand the influence of water and alkalis on aluminosilicate glasses, three polymerized glasses with varying ratios of Na/K were synthesized [(22. 5-x)Na2O-xK2O-22.5 Al2O3-55 SiO2 with x = 0, 7.5, and 11.25]. Subsequently, these glasses were hydrated (up to 8 wt% H2O) in an internally heated gas pressure vessel. The density of hydrous glasses linearly decreased with water content above 1 wt%, consistent with the partial molar volume of H2O of 12 cm3/mol. Near-infrared spectroscopy revealed that hydroxyl groups are the dominant species at water content of 5 wt%. The fraction of OH is particularly high in the pure Na-bearing glass compared to the mixed alkali glasses. 27Al magic angle spinning-NMR spectroscopy shows that aluminum is exclusively fourfold coordinated with some variations in the local geometry. It appears that the local structure around Al becomes more ordered with increasing K/Na ratio. The incorporation of H2O reinforces this effect. The differential thermal analysis of hydrous glasses shows a significant mass loss in the range of glass transition already during the first upscan, implying the high mobility of water in the glasses. This observation can be explained by the open structure of the aluminosilicate network and by the low dissociation enthalpy of H2O in the glasses (≈ 8 kJ/mol). The effect of the dissolved H2O on the glass transition temperature is less pronounced than for other aluminosilicate glasses, probably because of the large fraction of Al in the glasses.

Many plant species are able to regenerate adventitious roots either directly from aerial organs such as leaves or stems, in particularly after detachment (cutting), or indirectly, from over-proliferating tissue termed callus. In agriculture, this capacity of de novo root formation from cuttings can be used to clonally propagate several important crop plants including cassava, potato, sugar cane, banana and various fruit or timber trees. Direct and indirect de novo root regeneration (DNRR) originates from pluripotent cells of the pericycle tissue, from other root-competent cells or from non-root-competent cells that first dedifferentiate. Independently of their origin, the cells convert into root founder cells, which go through proliferation and differentiation subsequently forming functional root meristems, root primordia and the complete root. Recent studies in the model plants Arabidopsis thaliana and rice have identified several key regulators building in response to the phytohormone auxin transcriptional networks that are involved in both callus formation and DNRR. In both cases, epigenetic regulation seems essential for the dynamic reprogramming of cell fate, which is correlated with local and global changes of the chromatin states that might ensure the correct spatiotemporal expression pattern of the key regulators. Future approaches might investigate in greater detail whether and how the transcriptional key regulators and the writers, erasers, and readers of epigenetic modifications interact to control DNRR.

Stable crack growth was measured for nominal dry and water-bearing (6 wt%) soda-lime silicate glasses in double cantilever beam geometry and combined with DMA studies on the effects of dissolved water on internal friction and glass transition, respectively. In vacuum, a decreased slope of logarithmic crack growth velocity versus stress intensity factor is evident for the hydrous glass in line with an increase of β-relaxation intensity indicating more energy dissipation during fracture. Further, inert crack growth in hydrous glass is found to be divided into sections of different slope, which indicates different water related crack propagation mechanism. In ambient air, a largely extended region II is observed for the hydrous glass, which indicates that crack growth is more sensitive to ambient water.

BackgroundThe COVID-19 pandemic has already changed our globalised world and its long-term impact is not yet known. It is apparent that businesses and institutions are increasingly affected. COVID-19 discussions often focus on intensive care units in hospitals. However, COVID-19 also effects life-saving and -prolonging radiotherapy for patients suffering from cancer.MethodWe have conducted a structured online survey among medical physicists in Germany, Austria and Switzerland from March 23rd to 26th 2020. In total 154 responses (82 completed, 72 partially completed) were analysed in the context of the COVID-19 dissemination.Results72.4% of the respondent's state that their processes are affected due to COVID-19, while the top three answers are longer processing times (54.2%), patient no-shows (42.5%) and staff reduction (36.7%). 75.8% expect further unavailability of their personnel in the upcoming weeks. All participants have already taken several measures, especially providing information for patients at the entrance (89.6%) or over the phone (73.6%), restricting access for accompanying persons (77.4%) and providing disinfectant at the entrance (72.6%).DiscussionThe results presented in this article aim to support business continuity and risk management for radiotherapy centres to prepare for future challenges. The results show that most radiotherapy centres has implemented initial contingency measures, applying them pragmatically. The main problem however remains, that is the high risk of infection both for patients and medical personnel along with the associated risk of temporarily loss of personnel and ordered closure of business.

Physical storage of gaseous hydrogen under high-pressure in glassy micro-containers such as spheres and capillaries is a promising concept for enhancing safety and the volumetric capacity of mobile hydrogen storage systems. As very low permeation through the container wall is required for storage of compressed hydrogen, development of glasses of minimal hydrogen permeability is needed. For this purpose, one has to understand better the dependence of hydrogen permeability on glass structure. The paper points out that minimizing the accessible free volume is a sound strategy to minimize hydrogen permeability. Based on previously measured and comprehensive literature data, it is shown that permeation is independently controlled by ionic porosity and network modifier content. Thus, ionic porosity in modified and fully polymerized networks can be decreased equally to the lowest hydrogen permeability among the glasses under study. Applying this concept, a drop of up to 30,000 with respect to the permeation of hydrogen molecules through silica glass is attainable.

Abstract Objectives Voltage-gated Ca2+ channels (VGCCs) are of central relevance in regulating Ca2+ influx into living cells. The low-voltage activated (LVA) Cav3 T-type Ca2+ channels are widely distributed throughout the brain including the peripheral auditory system and ascending auditory tract. Their exact role in auditory information processing is still not fully understood. Within the LVA subgroup, Cav3.2 T-type Ca2+ channels seem to be of special importance as qPCR revealed a steady increase in Cav3.2 transcript levels over age, e.g. in the cochlea and spiral ganglion neurons (SGN). Furthermore, pharmacological studies suggested an association between Cav3.2 expression and both age-related and noise-induced hearing loss. Given the potential functional relevance of Cav3.2 VGGCs in sensorineural hearing loss, we recorded gender specific auditory evoked brainstem responses (ABRs) upon both click and tone burst presentation. Here we present auditory brainstem response (ABR) data from Cav3.2+/+, Cav3.2+/− and Cav3.2−/− mice from both genders which are of value for researchers who want to evaluate how Cav3.2 loss affects basic auditory parameters, e.g. click and tone burst based hearing thresholds, amplitude growth function and peak latencies. Data description Information presented here includes ABR data from age-matched female and male Cav3.2+/+, Cav3.2+/− and Cav3.2−/− mice and technical aspects of the auditory recording protocol. Data were recorded using a commercially available ABR setup from Tucker Davis Technologies Inc. (TDT). Raw data files (arf.-file format) were exported as txt.-files with free access for analysis.

Long jumpers with below the knee amputation (BKA) have achieved remarkable performances, yet the underlying biomechanics resulting in these jump distances are unknown. We measured three-dimensional motion and used multi-segment modelling to quantify and compare the centre of mass (COM) and joint kinematics of three long jumpers with BKA and seven non-amputee long jumpers during the take-off step of the long jump. Despite having the same jump distances, athletes with BKA, who used their affected leg for the take-off step, had lower sagittal plane hip and knee joint range of motion and positioned their affected leg more laterally relative to the COM compared to non-amputee athletes. Athletes with BKA had a longer compression phase and greater downward movement of their COM, suggesting that their affected leg (lever) was less rigid compared to the biological leg of non-amputees. Thus, athletes with BKA used a different kinematic mechanism to redirect horizontal to vertical velocity compared to non-amputee athletes. The specific movement patterns of athletes with BKA during the take-off step were constrained by the mechanical properties of the prosthesis. These results provide a basis for coaches and athletes to develop training protocols that improve performance and inform the design of future prostheses.

Indentation into a metastable austenite may induce the phase transformation to the bcc phase. We study this process using atomistic simulation. At temperatures low compared to the equilibrium transformation temperature, the indentation triggers the transformation of the entire crystallite: after starting the transformation, it rapidly proceeds throughout the simulation crystallite. The microstructure of the transformed sample is characterized by twinned grains. At higher temperatures, around the equilibrium transformation temperature, the crystal transforms only locally, in the vicinity of the indent pit. In addition, the indenter produces dislocation plasticity in the remaining austenite. At intermediate temperatures, the crystal continuously transforms throughout the indentation process.

Calving mechanisms are still poorly understood and stress states in the vicinity of ice-shelf fronts are insufficiently known for the development of physically motivated calving laws that match observations. A calving model requires the knowledge of maximum tensile stresses. These stresses depend on different simulation approaches and material models. Therefore, this study compares results of a two-dimensional (2-D) continuum approach using finite elements with results of a one-dimensional (1-D) beam model elaborated in Reeh (1968). A purely viscous model, as well as a viscoelastic Maxwell model, is applied for the 2-D case. The maximum tensile stress usually appears at the top surface of an ice shelf. Its location and magnitude are predominantly influenced by the thickness of the ice shelf and the height of the freeboard, the traction-free part at the ice front. More precisely, doubling the thickness leads to twice the stress maximum, while doubling the freeboard, based on changes of the ice density, results in an increase of the stress maximum by 61%. Poisson's ratio controls the evolution of the maximum stress with time. The viscosity and Young's modulus define the characteristic time of the Maxwell model and thus the time to reach the maximum principal stress.

Surface melt, driven by atmospheric temperatures and albedo, is a strong contribution of mass loss of the Greenland Ice Sheet. In the past, black carbon, algae and other light-absorbing impurities were suggested to govern albedo in Greenland’s ablation zone. Here we combine optical (MODIS/Sentinel-2) and radar (Sentinel-1) remote sensing data with airborne radar and laser scanner data, and engage firn modelling to identify the governing factors leading to dark glacier surfaces in Northeast Greenland. After the drainage of supraglacial lakes, the former lake ground is a clean surface represented by a high reflectance in Sentinel-2 data and aerial photography. These bright spots move with the ice flow and darken by more than 20% over only two years. In contrast, sites further inland do not exhibit this effect. This finding suggests that local deposition of dust, rather than black carbon or cryoconite formation, is the governing factor of albedo of fast-moving outlet glaciers. This is in agreement with a previous field study in the area which finds the mineralogical composition and grain size of the dust comparable with that of the surrounding soils.

Martensite transformation is a complex mechanism in materials that is classically initiated by a suitable heat treatment. This heat treatment process can be optimized based on a better understanding of the physical mechanisms on the length scale of several prior austenite grains. It is therefore appropriate to consider individual process steps of heat treatment in isolation. The aim of this study is to characterize the microstructural size changes caused by a variation of the cooling rate applied during the quenching process. For this purpose, individual martensitic microstructures from different heat treatments are analyzed using the electron backscatter diffraction (EBSD) method. With special orientation relationships between the parent austenite and martensite, the structure of the prior austenite grains and the close packet plane packets can then be reconstructed. The influence of the heat treatments on these characteristics as well as on the martensite blocks is thus quantified. No significant influence of the quenching rate on the sizes of martensite blocks and packets could be found.

Alzheimer's disease (AD) is a multifactorial disorder leading to progressive memory loss and eventually death. In this study, an APPswePS1dE9 AD mouse model has been analyzed for motor cortex theta, beta and gamma frequency alterations using computerized 3D stereotaxic electrode positioning and implantable video-EEG radiotelemetry to perform long-term M1 recordings from both genders considering age, circadian rhythm and activity status of experimental animals. We previously demonstrated that APPswePS1dE9 mice exibit complex alterations in hippocampal frequency power and another recent investigation reported a global increase of alpha, beta and gamma power in APPswePS1dE9 in females of 16-17 weeks of age. In this cortical study in APPswePS1dE9 mice we did not observe any changes in theta, beta and particularly gamma power in both genders at the age of 14, 15, 18 and 19 weeks. Importantly, no activity dependence of theta, beta and gamma activity could be detected. These findings clearly point to the fact that EEG activity, particularly gamma power exhibits developmental changes and spatial distinctiveness in the APPswePS1dE9 mouse model of Alzheimer's disease.

EEG radiotelemetry plays an important role in the neurological characterization of transgenic mouse models of neuropsychiatric and neurodegenerative diseases as well as epilepsies providing valuable insights into underlying pathophysiological mechanisms and thereby facilitating the development of new translational approaches. We elaborate on the major advantages of nonrestraining EEG radiotelemetry in contrast to restraining procedures such as tethered systems or jacket systems containing recorders. Whereas a main disadvantage of the latter is their unphysiological, restraining character, telemetric EEG recording overcomes these disadvantages. It allows precise and highly sensitive measurement under various physiological and pathophysiological conditions. Here we present a detailed description of a straightforward successful, quick, and efficient technique for intraperitoneal as well as subcutaneous pouch implantation of a standard radiofrequency transmitter in mice and rats. We further present computerized 3D-stereotaxic placement of both epidural and deep intracerebral electrodes. Preoperative preparation of mice and rats, suitable anaesthesia, and postoperative treatment and pain management are described in detail. A special focus is on fields of application, technical and experimental pitfalls, and technical connections of commercially available radiotelemetry systems with other electrophysiological setups.

Alzheimer’s disease (AD) is a multifactorial disorder leading to progressive memory loss and eventually death. In this study an APPswePS1dE9 AD mouse model has been analyzed using implantable video-EEG radiotelemetry to perform long-term EEG recordings from the primary motor cortex M1 and the hippocampal CA1 region in both genders. Besides motor activity, EEG recordings were analyzed for electroencephalographic seizure activity and frequency characteristics using a Fast Fourier Transformation (FFT) based approach. Automatic seizure detection revealed severe electroencephalographic seizure activity in both M1 and CA1 deflection in APPswePS1dE9 mice with gender-specific characteristics. Frequency analysis of both surface and deep EEG recordings elicited complex age, gender, and activity dependent alterations in the theta and gamma range. Females displayed an antithetic decrease in theta (θ) and increase in gamma (γ) power at 18-19 weeks of age whereas related changes in males occurred earlier at 14 weeks of age. In females, theta (θ) and gamma (γ) power alterations predominated in the inactive state suggesting a reduction in atropine-sensitive type II theta in APPswePS1dE9 animals. Gender-specific central dysrhythmia and network alterations in APPswePS1dE9 point to a functional role in behavioral and cognitive deficits and might serve as early biomarkers for AD in the future.

Alzheimer’s disease (AD) has been associated with increased phosphorylation of the translation initiation factor 2α (eIF2α) at serine 51. Increased phosphorylation of eIF2α alters translational control and may thereby have adverse effects on synaptic plasticity, learning, and memory. To analyze if increased levels of p-eIF2α indeed promote AD-related neurocognitive impairments, we crossed 5xFAD transgenic mice with an eIF2αS51A knock-in line that expresses the nonphosphorylatable eIF2α variant eIF2αS51A. Behavioral assessment of the resulting mice revealed motor and cognitive deficits in 5xFAD mice that were, with the possible exception of locomotor hyperactivity, not restored by the eIF2αS51A allele. Telemetric intracranial EEG recordings revealed no measurable effects of the eIF2αS51A allele on 5xFAD-associated epileptic activity. Microarray-based transcriptome analyses showed clear transcriptional alterations in 5xFAD hippocampus that were not corrected by the eIF2αS51A allele. In contrast to prior studies, our immunoblot analyses did not reveal increased levels of p-eIF2α in the hippocampus of 5xFAD mice, suggesting that elevated p-eIF2α levels are not a universal feature of AD models. Collectively, our data indicate that 5xFAD-related pathologies do not necessarily require hyperphosphorylation of eIF2α to emerge; they also show that heterozygosity for the nonphosphorylatable eIF2αS51A allele has limited effects on 5xFAD-related disease manifestations.

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by impairment of memory function. The 5XFAD mouse model was analyzed and compared with wild-type (WT) controls for aberrant cortical excitability and hippocampal theta oscillations by using simultaneous video-electroencephalogram (EEG) monitoring. Seizure staging revealed that 5XFAD mice exhibited cortical hyperexcitability whereas controls did not. In addition, 5XFAD mice displayed a significant increase in hippocampal theta activity from the light to dark phase during nonmotor activity. We also observed a reduction in mean theta frequency in 5XFAD mice compared to controls that was again most prominent during nonmotor activity. Transcriptome analysis of hippocampal probes and subsequent qPCR validation revealed an upregulation of Plcd4 that might be indicative of enhanced muscarinic signalling. Our results suggest that 5XFAD mice exhibit altered cortical excitability, hippocampal dysrhythmicity, and potential changes in muscarinic signaling.

In phase field fracture models the value of the order parameter distinguishes between broken and undamaged material. At crack faces the order parameter interpolates smoothly between these two states of the material, which can be regarded as phases. The crack evolution follows implicitly from the time integration of an evolution equation of the order parameter, which is coupled to the mechanical field equations. Among other phenomena phase field fracture models are able to reproduce crack nucleation in initially sound materials. For a 1D setting it has been shown that crack nucleation is triggered by the loss of stability of the unfractured, spatially homogeneous solution, and that the stability point depends on the size of the considered structure. This work numerically investigates to which extend size effects are reproduced by the 2D phase field model. Exemplarily, a finite element study of the hole size effect is performed and the simulation results are compared to experimental data.

p38 mitogen-activated protein kinase (MAPK) is thought to play a central role in acute and chronic inflammatory responses. Whether p38MAPK plays a pathogenic role in crescentic GN (GN) and which of its four isoforms is preferentially involved in kidney inflammation is not definitely known. We thus examined expression and activation of p38MAPK isoforms during anti-glomerular basement membrane (GBM) nephritis. Therefore, p38α conditional knockout mice (MxCre-p38α(Δ/Δ)) were used to examine the role of p38α in anti-GBM induced nephritis. Both wild type and MxCre-p38α(Δ/Δ) mice developed acute renal failure over time. Histological examinations revealed a reduced monocyte influx and less tubular damage in MxCre-p38α(Δ/Δ) mice, whereas glomerular crescent formation and renal fibrosis was similar. Likewise, the levels of pro- and anti-inflammatory cytokines such as TNF, IL-1 and IL-10 were similar, but IL-8 was even up-regulated in MxCre-p38α(Δ/Δ) mice. In contrast, we could detect strong down-regulation of chemotactic cytokines such as CCL-2, -5 and -7, in the kidneys of MxCre-p38α(Δ/Δ) mice. In conclusion, p38α is the primary p38MAPK isoform expressed in anti-GBM nephritis and selectively affects inflammatory cell influx and tubular damage. Full protection from nephritis is however not achieved as renal failure and structural damage still occurs.

In Arabidopsis, mutations in the Pc-G gene CURLY LEAF (CLF) give early flowering plants with curled leaves. This phenotype is caused by mis-expression of the floral homeotic gene AGAMOUS (AG) in leaves, so that ag mutations largely suppress the clf phenotype. Here, we identify three mutations that suppress clf despite maintaining high AG expression. We show that the suppressors correspond to mutations in FPA and FT, two genes promoting flowering, and in SEPALLATA3 (SEP3) which encodes a co-factor for AG protein. The suppression of the clf phenotype is correlated with low SEP3 expression in all case and reveals that SEP3 has a role in promoting flowering in addition to its role in controlling floral organ identity. Genetic analysis of clf ft mutants indicates that CLF promotes flowering by reducing expression of FLC, a repressor of flowering. We conclude that SEP3 is the key target mediating the clf phenotype, and that the antagonistic effects of CLF target genes masks a role for CLF in promoting flowering.

The topology of most experimentally determined protein domains is defined by the relative arrangement of secondary structure elements, i.e. α-helices and β-strands, which make up 50-70% of the sequence. Pairing of β-strands defines the topology of β-sheets. The packing of side chains between α-helices and β-sheets defines the majority of the protein core. Often, limited experimental datasets restrain the position of secondary structure elements while lacking detail with respect to loop or side chain conformation. At the same time the regular structure and reduced flexibility of secondary structure elements make these interactions more predictable when compared to flexible loops and side chains. To determine the topology of the protein in such settings, we introduce a tailored knowledge-based energy function that evaluates arrangement of secondary structure elements only. Based on the amino acid C(β) atom coordinates within secondary structure elements, potentials for amino acid pair distance, amino acid environment, secondary structure element packing, β-strand pairing, loop length, radius of gyration, contact order and secondary structure prediction agreement are defined. Separate penalty functions exclude conformations with clashes between amino acids or secondary structure elements and loops that cannot be closed. Each individual term discriminates for native-like protein structures. The composite potential significantly enriches for native-like models in three different databases of 10,000-12,000 protein models in 80-94% of the cases. The corresponding application, "BCL::ScoreProtein," is available at www.meilerlab.org.

In pemphigus vulgaris (PV), IgG autoantibodies against the ectodomain of desmoglein 3 (Dsg3) have been shown to be directly responsible for the loss of keratinocyteadhesion. The aim of the present study was to study the effect of the B cell depleting anti-CD20 monoclonal antibody, rituximab, on the profile of pathogenic IgG against distinct regions of the Dsg3 ectodomain in 22 PV patients who were followed up clinically and serologically by Dsg3 ELISA over 12-24 months. Prior to rituximab, all the 22 PV patients showed IgG against Dsg3 (Dsc3EC1-5). Specifically, 14/22 showed IgG reactivity against the Dsg3EC1 subdomain, 5/22 patients against Dsg3EC2, 7/22 against Dsg3EC3, 11/22 against Dsg3EC4, and 2/22 against Dsg3EC5. Within 6 months after rituximab, all the patients showed significant clinical improvement and reduced IgG against Dsg3 (5/22) and the various subdomains, that is, Dsg3EC1 (7/22), Dsg3EC2 (3/22), Dsg3EC3 (2/22), sg3EC4 (2/22), and Dsg3EC5 (0/22). During the entire observation period, 6/22 PV patients experienced a clinical relapse which was associated with the reappearance of IgG against previously recognized Dsg3 subdomains, particularly against the Dsg3EC1. Thus, in PV, rituximab only temporarily depletes pathogenic B cell responses against distinct subdomains of Dsg3 which reappear upon clinical relapse.

Es war eines der Aufregerthemen des letzten Jahres: Im April 2019 verabschiedete die EU nach langen Verhandlungen die Urheberrechtsrichtlinie. Art. 17 der Richtlinie schreibt kommerziellen Hosting Providern unter anderem vor, für die von Nutzern hochgeladenen urheberrechtlich geschützten Inhalten Lizenzen von Rechteinhabern zu erwerben. Scheitert der Lizenzerwerb jedoch, so kann der Hosting Provider die Haftung für einen von seinen Nutzern begangenen Urheberrechtsverstoß jedoch dadurch ausschließen, dass er unter Mithilfe der Rechteinhaber „nach Maßgabe hoher branchenüblicher Standards“ – sprich durch den Einsatz von Filtern – die Nicht-Verfügbarkeit geschützter Inhalte sicherstellt.