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This study presents a finite element model (FEM) simulation of optoelectronic stimulation in the rat brain, designed to investigate the effects of this emerging neural stimulation technique. A detailed 3D model of the rat brain and an equivalent circuit representation of the organic semiconductor-based stimulation device was used to simulate the subdural application of optoelectronic stimuli to the rat brain. The model is based on realistic electrode geometries and material properties. The stimulated brain volume is approximately 38 mm3 with a maximal stimulation depth of 2.6 mm. Our results indicate that optoelectronic stimulation can achieve targeted activation of cortical neurons. Further studies will focus on optimizing device parameters, exploring long-term effects, and expand this approach for specific neural bioelectronics to fully exploit its potential in clinical applications.

Interview of Jakub Sirovátka with Maximilian Forschner and Rudolf Langthaler.

Context: Against a backdrop of dwindling oil resources and increasing unemployment rates, the government of Oman has set out to diversify its industry and establish a knowledge-based economy. In this context, forming a highly-skilled Omani workforce is considered to be of crucial importance. Yet, the national TVET system suffers from low social status, poor quality, and limited labour market connectivity. This paper offers an analysis of Oman's TVET system in the socio-economic and cultural context of a rentier state. Approach: We draw on the political economy of skills and socio-cultural approaches that understand TVET systems and the broader skills regimes in which they are embedded as part and expression of particular patterns of the social organisation of work. This helps to locate TVET systems' strengths and weaknesses in the context of their underlying social relations instead of considering them as mere dysfunctionalities at the systemic level. This paper draws on an unpublished study on TVET for industrialisation commissioned by an Omani line ministry in cooperation with an international organisation. For this study, the authors carried out a literature review, undertook two field trips to Oman in 2018 and 2019 and conducted forty semi-structured interviews with stakeholders from government, private companies, business associations, and TVET and higher education institutions. Findings: Our analysis highlights how skill formation in Oman is shaped by the socioeconomic and cultural context of the Omani rentier state. First, the availability of cheap expatriate labour and Omanis' traditional preference for public sector jobs culminate in poor incentives for employing Omani nationals in the private sector. Second, reluctant employer attitudes towards national skill formation deepen quality issues in the TVET system, especially with regard to work-based training. This reinforces negative perceptions of the local workforce, which in turn contribute to biased employment patterns. Both social processes mutually reinforce each other, eventually preventing the emergence of strong national skill formation dynamics. Conclusions: While immediate structural change appears challenging, it is evident that reforms of the TVET system alone will not lead to its sustainable improvement. More research into how skill formation relates to Oman's specific socio-economic structures, how employment dynamics relate to educational credentials and how cultural traditions shape educational and work practices is needed.

BackgroundThe association between education and atherosclerotic cardiovascular disease (ASCVD) has been well described for decades. Nevertheless, most cardiovascular risk models, including SCORE2, still do not take educational status into account even if this factor is easily assessed and costs nothing to acquire. Using carotid plaques as a proxy for ASCVD, we analysed educational status as associated with carotid plaque development, to determine if the relationship remains, how it relates to traditional risk factors and, how it impacts the European cardiovascular risk model, SCORE2. Our study also provides further data on plaque development in a well-characterised population nearly equally weighted by gender.Methods9,083 subjects (51% female, 49% male) from the Paracelsus 10,000 cohort, underwent a carotid doppler duplex as part of thorough screening for subclinical ASCVD. Well over 90% of carotid doppler duplex examinations were performed by the same experienced clinician. Subjects were then classified by educational status using the Generalized International Standard Classification of Education. Plaque absence or presence was dichotomised and variables analysed using regression modelling to examine educational status relative to cardiovascular risk factors and with respect to the SCORE2 model.ResultsUsing medium educational status as a reference, subjects in our cohort with low educational status had higher odds, while subjects with high educational status had lower odds for carotid plaques compared to subjects with medium education (aOR 1.76 95%CI 1.50–2.06; and 0.0.63 95%CI 0.57–0.70, respectively). Even after adjusting for common risk factors including metabolic syndrome and SCORE2, the relationship was maintained. Furthermore, when comparing the potential predictive power of SCORE2 alone and plus educational status using the Akaike information criterion, we showed a ‘better fit’ when educational status was added.ConclusionsMeasuring educational status is cost-free and easy for clinicians to obtain. We believe cardiovascular risk prediction models such as SCORE2 may more accurately reflect individual risk if educational status is also taken into account. Additionally, we believe clinicians need to understand and appropriately address educational status as a risk factor, to better quantify individual risk and take appropriate measures to reduce risk so that the association may finally be broken.

Abstract Intro: Reliable estimates of drug uptake from blood to brain parenchyma are crucial in CNS drug discovery and development. While in vivo Kp,uu,brain estimates are the gold standard for investigating brain drug disposition, animal usage is a limitation to high throughput application. This study investigates an in vitro model using P-gp expressing MDCKII-MDR1 cells for predicting in vivo brain drug penetration. Methods: In vitro equilibrium distribution studies were conducted in apical and basolateral solutions with high protein content to estimate Kp,brain and Kp,uu,brain values. The correlation between in vitro and in vivo Kp,brain values for a set of compounds was examined. Results: We observed a good correlation between in vitro and in vivo Kp,brain values (R2 = 0.69, Slope: 1.6), indicating that the in vitro model could predict in vivo drug brain penetration. The ‘unilateral (Uni-L)’ in vitro setup correctly classified 5 out of 5 unrestricted compounds and 3 out of 5 restricted compounds. Possible reasons for the observed disparities for some compounds have been discussed, such as difference in transport areas between in vitro and in vivo settings and effect of pH changes. Conclusion: The in vitro assay setup developed in this study holds promise for predicting in vivo drug brain penetration in CNS drug discovery. The correlation between in vitro and in vivo Kp,brain values, underscores that the model may have potential for early-stage screening. With minor refinements, this in vitro approach could reduce the reliance on in vivo experiments, accelerating the pace of CNS drug discovery and promoting a more ethical research approach.

Fluid flow in the human body can be modeled using a water-level tank, a commonly used mechanistic approach in mechanical engineering for fluid transport processes. Postoperative fluid data from patients undergoing cardiac surgery is used to estimate fluid flow dynamics and total body water in the human body. This simplified model provide a basic understanding of the dynamics of fluid flow processes in the human body and could aid in modeling distribution of fluids in compartments.

BackgroundPatients with spinal cord injury (SCI) show abnormal cortical excitability that might be caused by deafferentation. We hypothesize a reduced short-interval intracortical inhibition preceding movement in patients with SCI compared with healthy participants. In addition, we expect that neuroplasticity induced by different types of sports can modulate intracortical inhibition during movement preparation in patients with SCI.MethodsWe used a reaction test and paired-pulse transcranial magnetic stimulation to record cortical excitability, assessed by measuring amplitudes of motor-evoked potentials in preparation of movement. The participants were grouped as patients with SCI practicing wheelchair dancing (n = 7), other sports (n = 6), no sports (n = 9), and healthy controls (n = 24).ResultsThere were neither significant differences between healthy participants and the patients nor between the different patient groups. A non-significant trend (p = .238), showed that patients engaged in sports have a stronger increase in cortical excitability compared with patients of the non-sportive group, while the patients in the other sports group expressed the highest increase in cortical excitability.ConclusionThe small sample sizes limit the statistical power of the study, but the trending effect warrants further investigation of different sports on the neuroplasticity in patients with SCI. It is not clear how neuroplastic changes impact the sensorimotor output of the affected extremities in a patient. This needs to be followed up in further studies with a greater sample size.

IntroductionAdvances in molecular targeting of ion channels may open up new avenues for therapeutic approaches in cancer based on the cells’ bioelectric properties. In addition to in-vitro or in-vivo models, in silico models can provide deeper insight into the complex role of electrophysiology in cancer and reveal the impact of altered ion channel expression and the membrane potential on malignant processes. The A549 in silico model is the first computational cancer whole-cell ion current model that simulates the bioelectric mechanisms of the human non-small cell lung cancer cell line A549 during the different phases of the cell cycle. This work extends the existing model with a detailed mathematical description of the store-operated Ca2+ entry (SOCE) and the complex local intracellular calcium dynamics, which significantly affect the entire electrophysiological properties of the cell and regulate cell cycle progression.MethodsThe initial model was extended by a multicompartmental approach, addressing the heterogenous calcium profile and dynamics in the ER-PM junction provoked by local calcium entry of store-operated calcium channels (SOCs) and uptake by SERCA pumps. Changes of cytosolic calcium levels due to diffusion from the ER-PM junction, release from the ER by RyR channels and IP3 receptors, as well as corresponding PM channels were simulated and the dynamics evaluated based on calcium imaging data. The model parameters were fitted to available data from two published experimental studies, showing the function of CRAC channels and indirectly of IP3R, RyR and PMCA via changes of the cytosolic calcium levels.ResultsThe proposed calcium description accurately reproduces the dynamics of calcium imaging data and simulates the SOCE mechanisms. In addition, simulations of the combined A549-SOCE model in distinct phases of the cell cycle demonstrate how Ca2+ - dynamics influence responding channels such as KCa, and consequently modulate the membrane potential accordingly.DiscussionLocal calcium distribution and time evolution in microdomains of the cell significantly impact the overall electrophysiological properties and exert control over cell cycle progression. By providing a more profound description, the extended A549-SOCE model represents an important step on the route towards a valid model for oncological research and in silico supported development of novel therapeutic strategies.

This paper discusses possibilities to explain which Kv channels can be considered as first-order systems. This means that the dynamic behavior of these channels can be described with a first-order differential equation and are the most straightforward dynamical systems. For example, a typical first-order system is an RC circuit, and analogously, Kv channels can be considered with the dynamic behavior of first-order systems following RC circuits. This work represents a family of KV channels that can be described as first-order systems, providing an efficient method of ion channel modeling in computational electrophysiology.

Abstract The detailed mechanisms by which the transferrin receptor (TfR) and associated ligands traffic across brain capillary endothelial cells (BECs) of the CNS-protective blood–brain barrier constitute an important knowledge gap within maintenance and regulation of brain iron homeostasis. This knowledge gap also presents a major obstacle in research aiming to develop strategies for efficient receptor-mediated drug delivery to the brain. While TfR-mediated trafficking from blood to brain have been widely studied, investigation of TfR-mediated trafficking from brain to blood has been limited. In this study we investigated TfR distribution on the apical and basal plasma membranes of BECs using expansion microscopy, enabling sufficient resolution to separate the cellular plasma membranes of these morphological flat cells, and verifying both apical and basal TfR membrane domain localization. Using immunofluorescence-based transcellular transport studies, we delineated endosomal sorting of TfR endocytosed from the apical and basal membrane, respectively, as well as bi-directional TfR transcellular transport capability. The findings indicate different intracellular sorting mechanisms of TfR, depending on the apicobasal trafficking direction across the BBB, with the highest transcytosis capacity in the brain-to-blood direction. These results are of high importance for the current understanding of brain iron homeostasis. Also, the high level of TfR trafficking from the basal to apical membrane of BECs potentially explains the low transcytosis which are observed for the TfR-targeted therapeutics to the brain parenchyma.

Cancer cells typically exhibit altered ion channel expression and membrane potential, wich plays an important role in various processes such as proliferation or apoptosis Hence, therapeutic strategies that modulate ion channel activity or shift the membrane potential prove to be promising for cancer therapy. Since temperature significantly affects ion channel function, deviation from normal body temperture might provide akey factor in electrophysiological progression. In this pilot study, we focused on a first insight into the temperature-induced modulation of A549 cells using an automated patch clamp system. Measurements of 14 cells at hypo-, normo- and hypertermia were accomplished to investigate the temperature-dependent electophysiological behavior. The results revealed that both, temperatures below and above normal body temperature affect the current and potential of A549 cells. In hyperthermia the potential tends to more hyperpolarized values, while conversely, in hypothermic conditions we observer mainly a lower current reponse and thus a depolarization of the membrane potential.

In this paper, we present a control system theory based modeling approach for the voltage-gated ion-channel Kv10.1 at different temperatures. Kv10.1 is expressed in the central nervous system and the brain of healthy humans. The study of the activity of this ion channel is important, because its activity is associated with the occurrence of cancer in different organs or tissues. According to systems and control theory, the voltage-gated channel Kv10.1 was assumed to be a linear time-invariant system and, as such, exhibits dynamic behavior. The experimental results show that Kv10.1 operates as a first-order model based on the input voltage step protocol and the measured macroscopic ion current output.

Background: Hyperferritinemia (HF) is a common finding and can be considered as metabolic HF (MHF) in combination with metabolic diseases. The definition of MHF was heterogenous until a consensus statement was published recently. Our aim was to apply the definition of MHF to provide data on the prevalence and characteristics of MHF in a Central-European cohort. Methods: This study was a retrospective analysis of the Paracelsus 10,000 study, a population-based cohort study from the region of Salzburg, Austria. We included 8408 participants, aged 40–77. Participants with HF were divided into three categories according to their level of HF and evaluated for metabolic co-morbidities defined by the proposed criteria for MHF. Results: HF was present in 13% (n = 1111) with a clear male preponderance (n = 771, 69% of HF). Within the HF group, 81% (n = 901) of subjects fulfilled the metabolic criteria and were defined as MHF, of which 75% (n = 674) were characterized by a major criterion. In the remaining HF cohort, 52% (n = 227 of 437) of subjects were classified as MHF after application of the minor criteria. Conclusion: HF is a common finding in the general middle-aged population and the majority of cases are classified as MHF. The new classification provides useful criteria for defining MHF.

Summary: Background: There is limited data on human papillomaviruses (HPV) prevalence in transpeople due to low acceptance rate of screening methods. HPV tests from self-collected urine are gender-neutral, have a high acceptance, and have a comparable accuracy in females to clinician-collected samples. The aim of this study was to evaluate both the HPV prevalence in the urine in a large cohort of 200 transpeople with common risk profiles and the acceptability of such screening method. Methods: The study was conducted at the outpatient clinic for transpeople at the Department of Obstetrics and Gynaecology, Medical University of Vienna, Austria. 200 transpeople have been enrolled between May and October 2021. Inclusion criteria were gender identity dysphoria, age over 18 years, and adequate language skills.Subjects were asked to answer a survey concerning gender identity, established risk factors for HPV infections as well as their preference regarding urine or provider-collected cytology-/HPV-based screening, and to provide a urine sample. Five patients not able to provide urine were excluded. HPV genotyping was performed using a validated multiplex real-time PCR assay, which simultaneously detects 28 HPV genotypes. This trial is registered at ClinicalTrials.gov, NCT04864951. Findings: Overall HPV positivity was 19·0% (37/195), 24·2% in female to male, 11·8% in male to female, 26·3% in genderqueer/non binary/other subjects, 27·9% in subjects currently having a cervix, and 26·0% in subjects born with cervix. Independent of gender reassignment surgery, being born with a cervix was associated with a higher risk of HPV infections (p = 0·008), yet 42·3% (44/104) have never attended cervical cancer screening. Overall, 79·0% (154/195) of transpeople would prefer urine HPV tests to provider-collected HPV screening. Interpretation: HPV testing in self-collected urine samples provides a unique opportunity for screening of this hard-to-reach population and should be evaluated in further studies. Funding: None.

A search in the GDC Data Portal revealed 304 documented somatic mutations of the KCNJ3 gene in primary tumors (out of 10.202 cases). Most affected tumor types were carcinomas from uterus, skin and lung, while breast cancer exerted the lowest number of somatic mutations. We focused our research on 15 missense mutations within the region between TM1 and TM2, comprising the pore helix and ion selectivity signature. Expression was measured by confocal laser scan microscopy of eGFP tagged GIRK1 subunits, expressed with and without GIRK4 in oocytes of Xenopus laevis. GIRK ion currents were activated via coexpressed m2Rs and measured by the Two Electrode Voltage Clamp technique. Magnitude of the total GIRK current, as well as the fraction of current inducible by the agonist, were measured. Ion selectivity was gauged by assessment of the PNa+/PK+ ratio, calculated by the GIRK current reversal potential in extracellular media at different Na+ and K+ concentrations. None of the tested mutations was able to form functional GIRK1 homooligomeric ion channels. One of the mutations, G145A, which locates directly to the ion selectivity signature, exerted an increased PNa+/PK+ ratio. Generally, the missense mutations studied can be categorized into three groups: (i) normal/reduced expression accompanied by reduced/absent function (S132Y, F136L, E139K, G145A, R149Q, R149P, G178D, S185Y, Q186R), (ii) normal/increased expression as well as increased function (E140M, A142T, M184I) and (iii) miniscule expression but increased function relative to expression levels (I151N, G158S). We conclude, that gain of function mutations, identical or similar to categories (ii) and (iii), may potentially be involved in genesis and progression of malignancies in tissues that exert a high rate of occurrence of somatic mutations of KCNJ3.

The aim of this study was to evaluate the endocervical margin status according to transformation zone (TZ) and high-risk HPV (hr-HPV) subtype in specimens with cone length ≤ 10 mm versus > 10 mm to provide data for informed decision making and patients counseling especially for women wishing to conceive. In this retrospective cohort study, 854 patients who underwent large loop excision of the transformation zone during a nine-year period (2013–2021) for cervical disease were analyzed. The main outcome parameters were excision length, histological result, TZ type, HPV subtype and endocervical margin status. A subgroup analysis was performed according to excision length, with a cut-off value of 10 mm. A two-step surgical procedure was performed in case of an excision length of > 10 mm. The overall rate of positive endocervical margins irrespective of excision length was 17.2%, with 19.3% in specimens with ≤ 10 mm and 15.0% with > 10 mm excision length. Overall, 41.2% of women with a visible TZ and HPV 16/hr infection and 27.0% of women with HPV 18 received an excisional treatment of > 10 mm length without further oncological benefit, respectively. In contrast, assuming that only an excision of ≤ 10 mm length had been performed in women with visible TZ, the rate of clear endocervical margins would have been 63.7% for HPV 16/hr infections and 49.3% for HPV 18 infections. In conclusion, the decision about excision length should be discussed with the patient in terms of oncological safety and the risk of adverse pregnancy events. An excision length > 10 mm increases the number of cases with cervical tissue removed without further oncological benefit, which needs to be taken into account in order to provide an individual therapeutic approach. Furthermore, HPV 18 positivity is related to a higher rate of positive endocervical margins irrespective of TZ.

Background: Minutes after an injury to the spinal cord, structural and functional reorganization of the connected brain areas may be initiated. Exercise enhances this neuroplasticity in the further course of the condition, which might modulate the connectivity patterns in brain regions responsible for movement execution and imagination. However, connectivity patterns have not been analyzed as a correlate for activity effects on neuroplasticity after spinal cord injury (SCI). We hypothesize that wheelchair sport has a modulating effect on the cortical connectivity in patients with SCI, such that distinguished activity patterns can be observed between sportive and non-sportive individuals with SCI and healthy participants. Methods: Sportive (n = 16) and non-sportive (n = 7) patients with SCI as well as sportive (n = 16) and non-sportive (n = 14) healthy participants were instructed to either observe, imagine, or conduct an observed movement while high-density EEG (HD-EEG) was recorded. Functional connectivity was computed from the recorded signals, and the coefficients were compared between groups and conditions using a non-parametric repeated measures analysis. Results: We found that depending on being sportive or not, patients with SCI and controls would react differently to the conditions, but the effects depended on the location in the brain as well as the analyzed frequency range (p < 0.05). Further analysis indicates that non-sportive patients showed higher connectivity received by the right posterior parietal cortex and a lower connectivity received by the left M1 compared to sportive patients. These effects were mainly observed during movement imagination, not during movement. Sportive and non-sportive participants in the healthy control group showed smaller differences than the patients. Conclusions: The results suggest a modulative effect of sports on connectivity patterns during movement imagination and to some extent during movement. This effect was predominantly found in patients with SCI, and to a lesser extent in healthy participants with opposing connectivity patterns. We suggest that this might be due to increased cortical excitability and the elevated brain derived neurotrophic factor (BDNF) level in patients with SCI that is enhanced by exercise.

ObjectiveAccording to Panksepp's hierarchical emotion model, emotion processing relies on three functionally and neuroanatomically distinct levels. These levels comprise subcortical networks (primary level), the limbic system (secondary level), and the neocortex (tertiary level) and are suggested to serve differential emotional processing. We aimed to validate and extend previous evidence of discrete and dimensional emotion processing in patient with juvenile myoclonic epilepsy (JME).MethodsWe recorded brain activity of patients with JME and healthy controls in response to lexical decisions to words reflecting the discrete emotion fear and the affective dimension negativity previously suggested to rely on different brain regions and to reflect different levels of processing. In all study participants, we tested verbal cognitive functions, as well as the relationship of psychiatric conditions, seizure types and duration of epilepsy and emotional word processing.ResultsIn support of the hierarchical emotion model, we found an interaction of discrete emotion and affective dimensional processing in the right amygdala likely to reflect secondary level processing. Brain activity related to affective dimensional processing was found in the right inferior frontal gyrus and is suggested to reflect tertiary level processing. Psychiatric conditions, type of seizure nor mono- vs. polytherapy and duration of epilepsy within patients did not have any effect on the processing of emotional words. In addition, no differences in brain activity or response times between patients and controls were observed, despite neuropsychological testing revealed slightly decreased verbal intelligence, verbal fluency and reading speed in patients with JME.SignificanceThese results were interpreted to be in line with the hierarchical emotion model and to highlight the amygdala's role in processing biologically relevant stimuli, as well as to suggest a semantic foundation of affective dimensional processing in prefrontal cortex. A lack of differences in brain activity of patients with JME and healthy controls in response to the emotional content of words could point to unaffected implicit emotion processing in patients with JME.

Numerous passages in the context of Kant’s philosophy of religion show without doubt his acquaintance with Lessing. But apart from the obvious affinity and agreement between Kant and Lessing with regard to many substantial questions, serious differences cannot be overlooked; the frequently diagnosed closeness and widely suspected “harmony” between the two is probably also the primary reason why important factual differences and controversial aspects have so far usually been neglected or ignored in research, although they still continue to raise problems and controversies in the context of the Enlightenment and the philosophy of religion. Although Lessing and Kant are both committed to the ideas of the Enlightenment and also appear as “related in essence”, above all with regard to religio-philosophical questions, Kant’s “moral determined monotheism” also contains an obvious criticism of Lessing’s religio-philosophical doctrines. This is also obvious in Kant’s — direct and indirect — confrontation with the “Ring Parable” in Lessing’s drama Nathan the Wise. The criticism that becomes apparent there concerns above all the question of “principles” left unclarified by Lessing, the “equal rank” of the monotheistic religions which he claimed, and the asserted “competition of religions.” I investigate some of the main points of this criticism.

Context: Against a backdrop of dwindling oil resources and increasing unemployment rates, the government of Oman has set out to diversify its industry and establish a knowledge-based economy. In this context, forming a highly-skilled Omani workforce is considered to be of crucial importance. Yet, the national TVET system suffers from low social status, poor quality, and limited labour market connectivity. This paper offers an analysis of Oman's TVET system in the socio-economic and cultural context of a rentier state. Approach: We draw on the political economy of skills and socio-cultural approaches that understand TVET systems and the broader skills regimes in which they are embedded as part and expression of particular patterns of the social organisation of work. This helps to locate TVET systems' strengths and weaknesses in the context of their underlying social relations instead of considering them as mere dysfunctionalities at the systemic level. This paper draws on an unpublished study on TVET for industrialisation commissioned by an Omani line ministry in cooperation with an international organisation. For this study, the authors carried out a literature review, undertook two field trips to Oman in 2018 and 2019 and conducted forty semi-structured interviews with stakeholders from government, private companies, business associations, and TVET and higher education institutions. Findings: Our analysis highlights how skill formation in Oman is shaped by the socio-economic and cultural context of the Omani rentier state. First, the availability of cheap expatriate labour and Omanis' traditional preference for public sector jobs culminate in poor incentives for employing Omani nationals in the private sector. Second, reluctant employer attitudes towards national skill formation deepen quality issues in the TVET system, especially with regard to work-based training. This reinforces negative perceptions of the local workforce, which in turn contribute to biased employment patterns. Both social processes mutually reinforce each other, eventually preventing the emergence of strong national skill formation dynamics. Conclusions: While immediate structural change appears challenging, it is evident that reforms of the TVET system alone will not lead to its sustainable improvement. More research into how skill formation relates to Oman's specific socio-economic structures, how employment dynamics relate to educational credentials and how cultural traditions shape educational and work practices is needed.

Summary: Background: Treatment of degenerating tendons still presents a major challenge, since the aetiology of tendinopathies remains poorly understood. Besides mechanical overuse, further known predisposing factors include rheumatoid arthritis, diabetes, obesity or smoking all of which combine with a systemic inflammation. Methods: To determine whether the systemic inflammation accompanying these conditions contributes to the onset of tendinopathy, we studied the effect of a systemic inflammation induced by an allergic episode on tendon properties. To this end, we induced an allergic response in mice by exposing them to a timothy grass pollen allergen and subsequently analysed both their flexor and Achilles tendons. Additionally, we analysed data from a health survey comprising data from more than 10.000 persons for an association between the occurrence of an allergy and tendinopathy. Findings: Biomechanical testing and histological analysis revealed that tendons from allergic mice not only showed a significant reduction of both elastic modulus and tensile stress, but also alterations of the tendon matrix. Moreover, treatment of 3D tendon-like constructs with sera from allergic mice resulted in a matrix-remodelling expression profile and the expression of macrophage-associated markers and matrix metalloproteinase 2 (MMP2) was increased in allergic Achilles tendons. Data from the human health study revealed that persons suffering from an allergy have an increased propensity to develop a tendinopathy. Interpretation: Our study demonstrates that the presence of a systemic inflammation accompanying an allergic condition negatively impacts on tendon structure and function. Funding: This study was financially supported by the Fund for the Advancement of Scientific Research at Paracelsus Medical University (PMU-FFF E-15/22/115-LEK), by the Land Salzburg, the Salzburger Landeskliniken (SALK, the Health Care Provider of the University Hospitals Landeskrankenhaus and Christian Doppler Klinik), the Paracelsus Medical University, Salzburg and by unrestricted grants from Bayer, AstraZeneca, Sanofi-Aventis, Boehringer-Ingelheim.

Lung cancer is still a leading cause of death worldwide. In recent years, knowledge has been obtained of the mechanisms modulating ion channel kinetics and thus of cell bioelectric properties, which is promising for oncological biomarkers and targets. The complex interplay of channel expression and its consequences on malignant processes, however, is still insufficiently understood. We here introduce the first approach of an in-silico whole-cell ion current model of a cancer cell, in particular of the A549 human lung adenocarcinoma, including the main functionally expressed ion channels in the plasma membrane as so far known. This hidden Markov-based model represents the electrophysiology behind proliferation of the A549 cell, describing its rhythmic oscillation of the membrane potential able to trigger the transition between cell cycle phases, and it predicts membrane potential changes over the cell cycle provoked by targeted ion channel modulation. This first A549 in-silico cell model opens up a deeper insight and understanding of possible ion channel interactions in tumor development and progression, and is a valuable tool for simulating altered ion channel function in lung cancer electrophysiology.

Abstract Power system automation is heavily dependent on the reliable interconnection of power system field equipment and centralised control applications. Particularly important to achieve reliability in automated power systems is the redundant connection of field equipment controllers. Today, the fundamental redundancy management and switch-over processes are handled by the power system control applications itself. This, however, increases the complexity of the control systems and leads to an intersection of concerns. Consequently, the design and the implementation of field equipment controller redundancy is time-consuming and cost-intensive. In this paper, we propose the implementation of a redundancy virtualisation layer for power system controllers based on software-defined networking (SDN). The goal is to relieve the control applications from managing field level redundancy. Thus, our SDN approach allows to detect gateway failures and to perform transparent switch-overs. This significantly simplifies the configuration of the control application with redundant components and finally leads to more flexible and simplified redundancy design, deployment and operation. Arbitrary redundancy topologies, such as triple-controller-redundancy can be implemented without modifying the control applications.

Abstract Optimizing energy consumption in local energy communities is one of the key contributions to the so-called smart grid. Such communities are equipped with rooftop photovoltaic power plants or other forms of small power plants for local energy production. In addition, a number of appliances allow for shiftable energy consumption, e.g., heat pumps or electric vehicle charging stations. The ability to shift is, however, dependent on customer preferences. In this paper, we present a trust-less approach for optimizing the electricity consumption in a local energy community given forecasts of energy production and customer demands, along with constraints for shiftable loads. In larger communities, appointing a single party for managing load curtailment requires a high level of trust. In the proposed trust-less approach, all parties can independently propose optimal solutions for this optimization problem and then globally agree one one solution that meets the defined requirements to the greatest extent.

The role of the ipsilaterally descending motor pathways in the recovery mechanisms after unilateral hemispheric damage is still poorly understood. Motor output reorganization was investigated in a 56-year-old male patient with acquired unilateral hemispheric atrophy due to Rasmussen encephalitis. In particular, the ipsilateral corticospinal pathways were explored using focal transcranial magnetic stimulation. In the first dorsal interosseous and wrist extensors muscles, the median amplitudes of the ipsilateral motor evoked potentials induced by transcranial magnetic stimulation in the patient were higher than those of 10 age-matched healthy control subjects. In the biceps brachii muscle, the median amplitudes of the ipsilateral motor evoked potentials were the second largest in the patient compared to the controls. This study demonstrated a reinforcement of ipsilateral motor projections from the unaffected motor cortex to the hemiparetic hand in a subject with acquired unihemispheric cortical damage.

Background. Bodily self-perception is an important concept for several neurological disorders, including spinal cord injury (SCI). Changing one’s bodily self-perception, e.g., via rubber hand illusion (RHI), induces alterations of bottom-up and top-down pathways and with this the connectivity between involved brain areas. We aim to examine whether (1) this process can be manipulated by changing cortical excitability, (2) connectivity between relevant brain areas differ when the RHI cannot be evoked, and (3) how this projection differs in a patient with SCI. Method. We applied RHI and facilitatory theta burst stimulation (TBS) on the right primary somatosensory cortex (S1) of 18 healthy participants and one patient with incomplete, cervical SCI. During RHI, we recorded high-density electroencephalography (HD-EEG) and extracted directed and nondirected connectivity measures. Results. There is no difference in connectivity between sham and real TBS or in the effectivity of RHI. We observed a higher laterality in the patient, i.e., higher connectivity of the right and lower of the left hemisphere. Besides this, connectivity patterns do not differ between healthy participants and the patient. Conclusion. This connectivity pattern might represent a neuroplastic response in the attempt to overcome the functional impairment of the patient resulting in a similar overall connectivity pattern to the healthy participants, yet with a higher sensitivity towards RHI and a higher laterality. The cortico-cortical communication was not altered depending on whether the illusion was provoked or not; hence, the perceptory illusion could not be observed in the EEG analysis.

The use of nanoelectromechanical systems or nanorobots offers a new concept for sensing and controlling subcellular structures, such as ion channels. We present here a novel method for mathematical modeling of ion channels based on control system theory and system identification. We investigated the use of nanoelectromechanical devices to control the activity of ion channels, particularly the activity of the voltage-gated ion channel Kv10.1, an important channel in cancer development and progression. A mathematical model of the dynamic behavior of the selected ion channel Kv10.1 in the Laplace (s) domain was developed, which is given in the representation of a transfer function. In addition, we addressed the possibilities of controlling ion channel activity by nanoelectromechanical devices and nanorobots and finally presented a control algorithm for the Kv10.1 as a control object. A use case demonstrates the potential of a Kv10.1 controlled nanorobot for cancer treatment at a single-cell level.

Background: High frequency oscillations (HFOs) have attracted great interest among neuroscientists and epileptologists in recent years. Not only has their occurrence been linked to epileptogenesis, but also to physiologic processes, such as memory consolidation. There are at least two big challenges for HFO research. First, detection, when performed manually, is time consuming and prone to rater biases, but when performed automatically, it is biased by artifacts mimicking HFOs. Second, distinguishing physiologic from pathologic HFOs in patients with epilepsy is problematic. Here we automatically and manually detected HFOs in intracranial EEGs (iEEG) of patients with epilepsy, recorded during a visual memory task in order to assess the feasibility of the different detection approaches to identify task-related ripples, supporting the physiologic nature of HFOs in the temporal lobe.Methods: Ten patients with unclear seizure origin and bilaterally implanted macroelectrodes took part in a visual memory consolidation task. In addition to iEEG, scalp EEG, electrooculography (EOG), and facial electromyography (EMG) were recorded. iEEG channels contralateral to the suspected epileptogenic zone were inspected visually for HFOs. Furthermore, HFOs were marked automatically using an RMS detector and a Stockwell classifier. We compared the two detection approaches and assessed a possible link between task performance and HFO occurrence during encoding and retrieval trials.Results: HFO occurrence rates were significantly lower when events were marked manually. The automatic detection algorithm was greatly biased by filter-artifacts. Surprisingly, EOG artifacts as seen on scalp electrodes appeared to be linked to many HFOs in the iEEG. Occurrence rates could not be associated to memory performance, and we were not able to detect strictly defined “clear” ripples.Conclusion: Filtered graphoelements in the EEG are known to mimic HFOs and thus constitute a problem. So far, in invasive EEG recordings mostly technical artifacts and filtered epileptiform discharges have been considered as sources for these “false” HFOs. The data at hand suggests that even ocular artifacts might bias automatic detection in invasive recordings. Strict guidelines and standards for HFO detection are necessary in order to identify artifact-derived HFOs, especially in conditions when cognitive tasks might produce a high amount of artifacts.

Am Rande des XVIII. World Economic History Congress 2018 in Boston, USA, luden Rolf Bauer und Ernst Langthaler den an der Harvard University als Laird Bell Professor of History tätigen Historiker Sven Beckert zu einem Gespräch. Sein 2014 erschienenes Buch "Empire of Cotton" ist ein internationaler Bestseller geworden, dessen Lesepublikum weit über die Fachkreise hinausreicht. Das Buch hat unter Forscher*innen in mehrfacher Weise für Diskussion gesorgt: als Beitrag zur "new history of capitalism", die gegenüber struktur- und systemorientierten Zugängen die Praxis von Akteur*innen stärker ins Licht rückt; als Ansatz einer Globalgeschichte, die sich aus weiträumigen Verflechtungen zwischen Ländern, Regionen und Orten konstituiert; als Versuch, zeit- und raumübergreifende Entwicklungen im Prisma eines bestimmten Produkts zu betrachten. Das Gespräch fand am 3. August 2018 in Cambridge, Massachusetts in Simon's Coffee Shop statt – jenem Café, in dem Sven Beckert einen Teil seines Baumwoll-Buches geschrieben hat.

This article assesses the ongoing South American soy expansion from a world-historical perspective, comparing the case of Brazil with the cases of China and the USA. For this purpose, it applies the concept of commodity frontier, involving both external and internal modes of capitalist incorporation. The Chinese soy expansion (1900s–1930s) shows a predominant shift of the external frontier, associated with the peasant mode of farming. The US soy expansion (1930s–1970s) represents a predominant shift of the internal frontier, connected to the entrepreneurial mode of farming. The Brazilian soy expansion (1970s–2010s) reveals a flexible combination of extensive and intensive frontier shifts, corresponding with the capitalist mode of farming. These commodity booms were driven not only by nation states, capitalist enterprises and social movements, but also by the potentials and limitations of the soybean plant itself. Shifts of commodity frontiers often disrupted society and nature and, hence, were contested among diverse actors, both human and non-human.

Introduction: Single-pulse transcranial magnetic stimulation (TMS) and high-frequency repetitive TMS (rTMS) over Wernicke's area were found to facilitate language functions in right-handed healthy subjects. We aimed at investigating the effects of excitatory rTMS, given as intermittent theta burst stimulation (iTBS) over left Wernicke's area, on auditory comprehension in patients suffering from fluent aphasia after stroke of the left temporal lobe.Methods: We studied 13 patients with chronic fluent aphasia after an ischemic stroke involving Wernicke's area. iTBS was applied in random order to Wernicke's area, the right-hemisphere homologous of Wernicke's area, and the primary visual cortex. Auditory comprehension was blind assessed using the Token test before (T0), 5 (T1), and 40 min (T2) after a single session of iTBS.Results: At the first evaluation (T1) after iTBS on left Wernike's area, but not on the contralateral homologous area nor on the primary visual cortex, the scores on the Token test were significantly increased. No significant effects were observed at T2.Conclusion: We demonstrated that a single session of excitatory iTBS over Wernicke's area was safe and led to a transient facilitation of auditory comprehension in chronic stroke patients with lesions in the same area. Further studies are needed to establish whether TBS-induced modulation can be enhanced and transformed into longer-lasting effects by means of repeated TBS sessions and by combining TBS with speech and language therapy.

The mathematical modeling of ion channel kinetics is an important tool for studying the electrophysiological mechanisms of the nerves, heart, or cancer, from a single cell to an organ. Common approaches use either a Hodgkin–Huxley (HH) or a hidden Markov model (HMM) description, depending on the level of detail of the functionality and structural changes of the underlying channel gating, and taking into account the computational effort for model simulations. Here, we introduce for the first time a novel system theory-based approach for ion channel modeling based on the concept of transfer function characterization, without a priori knowledge of the biological system, using patch clamp measurements. Using the shaker-related voltage-gated potassium channel Kv1.1 (KCNA1) as an example, we compare the established approaches, HH and HMM, with the system theory-based concept in terms of model accuracy, computational effort, the degree of electrophysiological interpretability, and methodological limitations. This highly data-driven modeling concept offers a new opportunity for the phenomenological kinetic modeling of ion channels, exhibiting exceptional accuracy and computational efficiency compared to the conventional methods. The method has a high potential to further improve the quality and computational performance of complex cell and organ model simulations, and could provide a valuable new tool in the field of next-generation in silico electrophysiology.

Taking as point of departure soy’s omnipresence in everyday life, this article investigates agro-food globalization in the twentieth century through the lens of soy as a commodity. From an exogenous view, soy’s commodification was driven by state and corporate projects, widening and deepening the regional frontiers of global food regimes. From an endogenous view, soy as a versatile crop rich in fat and protein drove these projects as industrial raw material, animal feed, and human food. The cases of Northeast China and the US and Brazilian Midwest highlight various modes, systemic forces, and actors as well as socio-natural impacts of soy expansions as regional sites of globalization. Soy was not only passively transformed into a global commodity but also played an active albeit paradoxical role as both protagonist and antagonist of the prevailing food regime.

The presented data are related to the research article entitled “Characterization of the IPEC-J2 MDR1 (iP-gp) cell line as a tool for identification of P-gp substrates” by Ozgur et al. (2017) [1]. This data report describes the challenges of investigating the concentration-dependent transport of P-glycoprotein (P-gp) substrates with relatively low aqueous solubility. Thus, we provide solubility data on two prototypical P-gp substrates, digoxin and rhodamine 123, representing P-gp substrates with a relatively low- and high-aqueous solubility, respectively. We present a hypothetical Michaelis-Menten curve of the P-gp mediated transport of digoxin to demonstrate that the maximal donor concentration, which can be reached in the experimental transport buffer, is too low to yield transport data in the saturable range of the Michaelis-Menten relationship. Furthermore, we present data on the bidirectional transport of digoxin and rhodamine 123 across cell monolayers of the MDCK II MDR1 cell line and iP-pg cell line in the presence of the selective P-gp inhibitor, zosuquidar/LY335979.