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Background: Modulation of cortical excitability by transcranial magnetic stimulation (TMS) is used for investigating human brain functions. A common observation is the high variability of long-term depression (LTD)-like changes in human (motor) cortex excitability. This study aimed at analyzing the response subgroup distribution after paired continuous theta burst stimulation (cTBS) as a basis for subject selection.
Methods: The effects of paired cTBS using 80% active motor threshold (AMT) in 31 healthy volunteers were assessed at the primary motor cortex (M1) corresponding to the representation of the first dorsal interosseous (FDI) muscle of the left hand, before and up to 50 min after plasticity induction. The changes in motor evoked potentials (MEPs) were analyzed using machine-learning derived methods implemented as Gaussian mixture modeling (GMM) and computed ABC analysis.
Results: The probability density distribution of the MEP changes from baseline was tri-modal, showing a clear separation at 80.9%. Subjects displaying at least this degree of LTD-like changes were n = 6 responders. By contrast, n = 7 subjects displayed a paradox response with increase in MEP. Reassessment using ABC analysis as alternative approach led to the same n = 6 subjects as a distinct category.
Conclusion: Depressive effects of paired cTBS using 80% AMT endure at least 50 min, however, only in a small subgroup of healthy subjects. Hence, plasticity induction by paired cTBS might not reflect a general mechanism in human motor cortex excitability. A mathematically supported criterion is proposed to select responders for enrolment in assessments of human brain functional networks using virtual brain lesions.
Based on accumulating evidence of a role of lipid signaling in many physiological and pathophysiological processes including psychiatric diseases, the present data driven analysis was designed to gather information needed to develop a prospective biomarker, using a targeted lipidomics approach covering different lipid mediators. Using unsupervised methods of data structure detection, implemented as hierarchal clustering, emergent self-organizing maps of neuronal networks, and principal component analysis, a cluster structure was found in the input data space comprising plasma concentrations of d = 35 different lipid-markers of various classes acquired in n = 94 subjects with the clinical diagnoses depression, bipolar disorder, ADHD, dementia, or in healthy controls. The structure separated patients with dementia from the other clinical groups, indicating that dementia is associated with a distinct lipid mediator plasma concentrations pattern possibly providing a basis for a future biomarker. This hypothesis was subsequently assessed using supervised machine-learning methods, implemented as random forests or principal component analysis followed by computed ABC analysis used for feature selection, and as random forests, k-nearest neighbors, support vector machines, multilayer perceptron, and naïve Bayesian classifiers to estimate whether the selected lipid mediators provide sufficient information that the diagnosis of dementia can be established at a higher accuracy than by guessing. This succeeded using a set of d = 7 markers comprising GluCerC16:0, Cer24:0, Cer20:0, Cer16:0, Cer24:1, C16 sphinganine, and LacCerC16:0, at an accuracy of 77%. By contrast, using random lipid markers reduced the diagnostic accuracy to values of 65% or less, whereas training the algorithms with randomly permuted data was followed by complete failure to diagnose dementia, emphasizing that the selected lipid mediators were display a particular pattern in this disease possibly qualifying as biomarkers.
The Gini index is a measure of the inequality of a distribution that can be derived from Lorenz curves. While commonly used in, e.g., economic research, it suffers from ambiguity via lack of Lorenz dominance preservation. Here, investigation of large sets of empirical distributions of incomes of the World’s countries over several years indicated firstly, that the Gini indices are centered on a value of 33.33% corresponding to the Gini index of the uniform distribution and secondly, that the Lorenz curves of these distributions are consistent with Lorenz curves of log-normal distributions. This can be employed to provide a Lorenz dominance preserving equivalent of the Gini index. Therefore, a modified measure based on log-normal approximation and standardization of Lorenz curves is proposed. The so-called UGini index provides a meaningful and intuitive standardization on the uniform distribution as this characterizes societies that provide equal chances. The novel UGini index preserves Lorenz dominance. Analysis of the probability density distributions of the UGini index of the World’s counties income data indicated multimodality in two independent data sets. Applying Bayesian statistics provided a data-based classification of the World’s countries’ income distributions. The UGini index can be re-transferred into the classical index to preserve comparability with previous research.
Persistent and, in particular, neuropathic pain is a major healthcare problem with still insufficient pharmacological treatment options. This triggered research activities aimed at finding analgesics with a novel mechanism of action. Results of these efforts will need to pass through the phases of drug development, in which experimental human pain models are established components e.g. implemented as chemical hyperalgesia induced by capsaicin. We aimed at ranking the various readouts of a human capsaicin–based pain model with respect to the most relevant information about the effects of a potential reference analgesic. In a placebo‐controlled, randomized cross‐over study, seven different pain‐related readouts were acquired in 16 healthy individuals before and after oral administration of 300 mg pregabalin. The sizes of the effect on pain induced by intradermal injection of capsaicin were quantified by calculating Cohen's d. While in four of the seven pain‐related parameters, pregabalin provided a small effect judged by values of Cohen's d exceeding 0.2, an item categorization technique implemented as computed ABC analysis identified the pain intensities in the area of secondary hyperalgesia and of allodynia as the most suitable parameters to quantify the analgesic effects of pregabalin. Results of this study provide further support for the ability of the intradermal capsaicin pain model to show analgesic effects of pregabalin. Results can serve as a basis for the designs of studies where the inclusion of this particular pain model and pregabalin is planned.
An easy-to-use model to evaluate conductivities at high and middle latitudes in the height range 70–100 km is presented. It is based on electron density profiles obtained with the EISCAT VHF radar during 11 years and on the neutral atmospheric model MSIS95. The model uses solar zenith angle, geomagnetic activity and season as input parameters. It was mainly constructed to study the properties of Schumann resonances that depend on such conductivity profiles.
Dual-task paradigms encompass a broad range of approaches to measure cognitive load in instructional settings. As a common characteristic, an additional task is implemented alongside a learning task to capture the individual’s unengaged cognitive capacities during the learning process. Measures to determine these capacities are, for instance, reaction times and interval errors on the additional task, while the performance on the learning task is to be maintained. Opposite to retrospectively applied subjective ratings, the continuous assessment within a dual-task paradigm allows to simultaneously monitor changes in the performance related to previously defined tasks. Following the Cognitive Load Theory, these changes in performance correspond to cognitive changes related to the establishment of permanently existing knowledge structures. Yet the current state of research indicates a clear lack of standardization of dual-task paradigms over study settings and task procedures. Typically, dual-task designs are adapted uniquely for each study, albeit with some similarities across different settings and task procedures. These similarities range from the type of modality to the frequency used for the additional task. This results in a lack of validity and comparability between studies due to arbitrarily chosen patterns of frequency without a sound scientific base, potentially confounding variables, or undecided adaptation potentials for future studies. In this paper, the lack of validity and comparability between dual-task settings will be presented, the current taxonomies compared and the future steps for a better standardization and implementation discussed.
Este artigo tem por objetivo analisar comparativamente as semelhanças contidas nas críticas à democracia liberal presentes em alguns trabalhos selecionados de Carl Schmitt (1888-1985) e Robert Kurz (1943-2012). A despeito da estreita associação do primeiro autor com o regime nazista após 1933 e do segundo ser normalmente caracterizado como um pensador marxista (embora bastante crítico ao marxismo “ortodoxo”), são verificáveis inúmeras similitudes entre ambos quando se propõem a analisar as características do liberalismo parlamentar das democracias do século XX. Uma hipótese que pode explicar tais semelhanças seria a influência exercida por Schmitt sobre diversos teóricos da escola de Frankfurt, com os quais Kurz frequentemente dialoga em seus escritos e que foram inspiradores de algumas de suas reflexões – em especial, Walter Benjamin, Theodor Adorno e Max Horkheimer, embora Schmitt também tenha influenciado Franz Neumann, Otto Kirchheimer, Karl Korsch e Herbert Marcuse. Outra via de interpretação abordada aqui se refere à possibilidade de Schmitt ter encontrado, em suas teorias sobre o Estado e sobre o direito, os limites epistemológicos do liberalismo moderno, o que constitui o principal objeto de pesquisa de Kurz e foi tema recorrente nos escritos dos teóricos de Frankfurt.
Este artigo analisa a crítica de Adorno à ontologia de Heidegger. Para tal, utiliza como leitmotiv a interpretação heideggeriana de Kant. Procuraremos mostrar que para Adorno a edificação da ontologia fundamental a partir da filosofia de Kant é uma interpretação indevida desta. Por fim, procura apontar uma possível saída na filosofia de Adorno para o problema da necessidade de fundamentação do discurso filosófico. Tal saída passa pela constatação da importância da arte para a construção da universalidade na filosofia.
A critical role for VEGF and VEGFR2 in NMDA receptor synaptic function and fear-related behavior
(2016)
Vascular endothelial growth factor (VEGF) is known to be required for the action of antidepressant therapies but its impact on brain synaptic function is poorly characterized. Using a combination of electrophysiological, single-molecule imaging and conditional transgenic approaches, we identified the molecular basis of the VEGF effect on synaptic transmission and plasticity. VEGF increases the postsynaptic responses mediated by the N-methyl-d-aspartate type of glutamate receptors (GluNRs) in hippocampal neurons. This is concurrent with the formation of new synapses and with the synaptic recruitment of GluNR expressing the GluN2B subunit (GluNR-2B). VEGF induces a rapid redistribution of GluNR-2B at synaptic sites by increasing the surface dynamics of these receptors within the membrane. Consistently, silencing the expression of the VEGF receptor 2 (VEGFR2) in neural cells impairs hippocampal-dependent synaptic plasticity and consolidation of emotional memory. These findings demonstrated the direct implication of VEGF signaling in neurons via VEGFR2 in proper synaptic function. They highlight the potential of VEGF as a key regulator of GluNR synaptic function and suggest a role for VEGF in new therapeutic approaches targeting GluNR in depression.
Rezension zu: Psychology of Retention:Theory, Research and Practice / Melinde Coetzee, Ingrid L. Potgieter and Nadia Ferreira (Eds.), ISBN:978-3-319-98919-8 Publisher:Springer Nature, 2018, R1600 (Preis SA)
Background: Invasive off- or on-pump cardiac surgery (elective and emergency procedures, excluding transplants are routinely performed to treat complications of ischaemic heart disease. Randomised controlled trials (RCT) evaluate the effectiveness of treatments in the setting of cardiac surgery. However, the impact of RCTs is weakened by heterogeneity in outcome measuring and reporting, which hinders comparison across trials. Core outcome sets (COS, a set of outcomes that should be measured and reported, as a minimum, in clinical trials for a specific clinical field) help reduce this problem. In light of the above, we developed a COS for cardiac surgery effectiveness trials.
Methods: Potential core outcomes were identified a priori by analysing data on 371 RCTs of 58,253 patients. We reached consensus on core outcomes in an international three-round eDelphi exercise. Outcomes for which at least 60% of the participants chose the response option "no" and less than 20% chose the response option "yes" were excluded.
Results: Eighty-six participants from 23 different countries involving adult cardiac patients, cardiac surgeons, anaesthesiologists, nursing staff and researchers contributed to this eDelphi. The panel reached consensus on four core outcomes: 1) Measure of mortality, 2) Measure of quality of life, 3) Measure of hospitalisation and 4) Measure of cerebrovascular complication to be included in adult cardiac surgery trials.
Conclusion: This study used robust research methodology to develop a minimum core outcome set for clinical trials evaluating the effectiveness of treatments in the setting of cardiac surgery. As a next step, appropriate outcome measurement instruments have to be selected.
Commercialization of consumers’ personal data in the digital economy poses serious, both conceptual and practical, challenges to the traditional approach of European Union (EU) Consumer Law. This article argues that mass-spread, automated, algorithmic decision-making casts doubt on the foundational paradigm of EU consumer law: consent and autonomy. Moreover, it poses threats of discrimination and under- mining of consumer privacy. It is argued that the recent legislative reaction by the EU Commission, in the form of the ‘New Deal for Consumers’, was a step in the right direction, but fell short due to its continued reliance on consent, autonomy and failure to adequately protect consumers from indirect discrimination. It is posited that a focus on creating a contracting landscape where the consumer may be properly informed in material respects is required, which in turn necessitates blending the approaches of competition, consumer protection and data protection laws.
A consistent muscle activation strategy underlies crawling and swimming in Caenorhabditis elegans
(2014)
Although undulatory swimming is observed in many organisms, the neuromuscular basis for undulatory movement patterns is not well understood. To better understand the basis for the generation of these movement patterns, we studied muscle activity in the nematode Caenorhabditis elegans. Caenorhabditis elegans exhibits a range of locomotion patterns: in low viscosity fluids the undulation has a wavelength longer than the body and propagates rapidly, while in high viscosity fluids or on agar media the undulatory waves are shorter and slower. Theoretical treatment of observed behaviour has suggested a large change in force–posture relationships at different viscosities, but analysis of bend propagation suggests that short-range proprioceptive feedback is used to control and generate body bends. How muscles could be activated in a way consistent with both these results is unclear. We therefore combined automated worm tracking with calcium imaging to determine muscle activation strategy in a variety of external substrates. Remarkably, we observed that across locomotion patterns spanning a threefold change in wavelength, peak muscle activation occurs approximately 45° (1/8th of a cycle) ahead of peak midline curvature. Although the location of peak force is predicted to vary widely, the activation pattern is consistent with required force in a model incorporating putative length- and velocity-dependence of muscle strength. Furthermore, a linear combination of local curvature and velocity can match the pattern of activation. This suggests that proprioception can enable the worm to swim effectively while working within the limitations of muscle biomechanics and neural control.
Introduction: Encouraged by the change in licensing regulations the practical professional skills in Germany received a higher priority and are taught in medical schools therefore increasingly. This created the need to standardize the process more and more. On the initiative of the German skills labs the German Medical Association Committee for practical skills was established and developed a competency-based catalogue of learning objectives, whose origin and structure is described here.
Goal of the catalogue is to define the practical skills in undergraduate medical education and to give the medical schools a rational planning basis for the necessary resources to teach them.
Methods: Building on already existing German catalogues of learning objectives a multi-iterative process of condensation was performed, which corresponds to the development of S1 guidelines, in order to get a broad professional and political support.
Results: 289 different practical learning goals were identified and assigned to twelve different organ systems with three overlapping areas to other fields of expertise and one area of across organ system skills. They were three depths and three different chronological dimensions assigned and the objectives were matched with the Swiss and the Austrian equivalent.
Discussion: This consensus statement may provide the German faculties with a basis for planning the teaching of practical skills and is an important step towards a national standard of medical learning objectives.
Looking ahead: The consensus statement may have a formative effect on the medical schools to teach practical skills and plan the resources accordingly.
Publicly available compound and bioactivity databases provide an essential basis for data-driven applications in life-science research and drug design. By analyzing several bioactivity repositories, we discovered differences in compound and target coverage advocating the combined use of data from multiple sources. Using data from ChEMBL, PubChem, IUPHAR/BPS, BindingDB, and Probes & Drugs, we assembled a consensus dataset focusing on small molecules with bioactivity on human macromolecular targets. This allowed an improved coverage of compound space and targets, and an automated comparison and curation of structural and bioactivity data to reveal potentially erroneous entries and increase confidence. The consensus dataset comprised of more than 1.1 million compounds with over 10.9 million bioactivity data points with annotations on assay type and bioactivity confidence, providing a useful ensemble for computational applications in drug design and chemogenomics.
Ubiquitin fold modifier 1 (UFM1) is a member of the ubiquitin-like protein family. UFM1 undergoes a cascade of enzymatic reactions including activation by UBA5 (E1), transfer to UFC1 (E2) and selective conjugation to a number of target proteins via UFL1 (E3) enzymes. Despite the importance of ufmylation in a variety of cellular processes and its role in the pathogenicity of many human diseases, the molecular mechanisms of the ufmylation cascade remains unclear. In this study we focused on the biophysical and biochemical characterization of the interaction between UBA5 and UFC1. We explored the hypothesis that the unstructured C-terminal region of UBA5 serves as a regulatory region, controlling cellular localization of the elements of the ufmylation cascade and effective interaction between them. We found that the last 20 residues in UBA5 are pivotal for binding to UFC1 and can accelerate the transfer of UFM1 to UFC1. We solved the structure of a complex of UFC1 and a peptide spanning the last 20 residues of UBA5 by NMR spectroscopy. This structure in combination with additional NMR titration and isothermal titration calorimetry experiments revealed the mechanism of interaction and confirmed the importance of the C-terminal unstructured region in UBA5 for the ufmylation cascade.
Background: The differentiation between Gaucher disease type 3 (GD3) and type 1 is challenging because pathognomonic neurologic symptoms may be subtle and develop at late stages. The ophthalmologist plays a crucial role in identifying the typical impairment of horizontal saccadic eye movements, followed by vertical ones. Little is known about further ocular involvement. The aim of this monocentric cohort study is to comprehensively describe the ophthalmological features of Gaucher disease type 3. We suggest recommendations for a set of useful ophthalmologic investigations for diagnosis and follow up and for saccadometry parameters enabling a correlation to disease severity.
Methods: Sixteen patients with biochemically and genetically diagnosed GD3 completed ophthalmologic examination including optical coherence tomography (OCT), clinical oculomotor assessment and saccadometry by infrared based video-oculography. Saccadic peak velocity, gain and latency were compared to 100 healthy controls, using parametric tests. Correlations between saccadic assessment and clinical parameters were calculated.
Results: Peripapillary subretinal drusen-like deposits with retinal atrophy (2/16), preretinal opacities of the vitreous (4/16) and increased retinal vessel tortuosity (3/16) were found. Oculomotor pathology with clinically slowed saccades was more frequent horizontally (15/16) than vertically (12/16). Saccadometry revealed slowed peak velocity compared to 100 controls (most evident horizontally and downwards). Saccades were delayed and hypometric. Best correlating with SARA (scale for the assessment and rating of ataxia), disease duration, mSST (modified Severity Scoring Tool) and reduced IQ was peak velocity (both up- and downwards). Motility restriction occurred in 8/16 patients affecting horizontal eye movements, while vertical motility restriction was seen less frequently. Impaired abduction presented with esophoria or esotropia, the latter in combination with reduced stereopsis.
Conclusions: Vitreoretinal lesions may occur in 25% of Gaucher type 3 patients, while we additionally observed subretinal lesions with retinal atrophy in advanced disease stages. Vertical saccadic peak velocity seems the most promising "biomarker" for neuropathic manifestation for future longitudinal studies, as it correlates best with other neurologic symptoms. Apart from the well documented abduction deficit in Gaucher type 3 we were able to demonstrate motility impairment in all directions of gaze.
Background: Alterations in the DNA methylation pattern are a hallmark of leukemias and lymphomas. However, most epigenetic studies in hematologic neoplasms (HNs) have focused either on the analysis of few candidate genes or many genes and few HN entities, and comprehensive studies are required. Methodology/Principal Findings: Here, we report for the first time a microarray-based DNA methylation study of 767 genes in 367 HNs diagnosed with 16 of the most representative B-cell (n = 203), T-cell (n = 30), and myeloid (n = 134) neoplasias, as well as 37 samples from different cell types of the hematopoietic system. Using appropriate controls of B-, T-, or myeloid cellular origin, we identified a total of 220 genes hypermethylated in at least one HN entity. In general, promoter hypermethylation was more frequent in lymphoid malignancies than in myeloid malignancies, being germinal center mature B-cell lymphomas as well as B and T precursor lymphoid neoplasias those entities with highest frequency of gene-associated DNA hypermethylation. We also observed a significant correlation between the number of hypermethylated and hypomethylated genes in several mature B-cell neoplasias, but not in precursor B- and T-cell leukemias. Most of the genes becoming hypermethylated contained promoters with high CpG content, and a significant fraction of them are targets of the polycomb repressor complex. Interestingly, T-cell prolymphocytic leukemias show low levels of DNA hypermethylation and a comparatively large number of hypomethylated genes, many of them showing an increased gene expression. Conclusions/Significance: We have characterized the DNA methylation profile of a wide range of different HNs entities. As well as identifying genes showing aberrant DNA methylation in certain HN subtypes, we also detected six genes—DBC1, DIO3, FZD9, HS3ST2, MOS, and MYOD1—that were significantly hypermethylated in B-cell, T-cell, and myeloid malignancies. These might therefore play an important role in the development of different HNs.
Immersion freezing is the most relevant heterogeneous ice nucleation mechanism through which ice crystals are formed in mixed-phase clouds. In recent years, an increasing number of laboratory experiments utilizing a variety of instruments have examined immersion freezing activity of atmospherically relevant ice nucleating particles (INPs). However, an inter-comparison of these laboratory results is a difficult task because investigators have used different ice nucleation (IN) measurement methods to produce these results. A remaining challenge is to explore the sensitivity and accuracy of these techniques and to understand how the IN results are potentially influenced or biased by experimental parameters associated with these techniques.
Within the framework of INUIT (Ice Nucleation research UnIT), we distributed an illite rich sample (illite NX) as a representative surrogate for atmospheric mineral dust particles to investigators to perform immersion freezing experiments using different IN measurement methods and to obtain IN data as a function of particle concentration, temperature (T), cooling rate and nucleation time. Seventeen measurement methods were involved in the data inter-comparison. Experiments with seven instruments started with the test sample pre-suspended in water before cooling, while ten other instruments employed water vapor condensation onto dry-dispersed particles followed by immersion freezing. The resulting comprehensive immersion freezing dataset was evaluated using the ice nucleation active surface-site density (ns) to develop a representative ns(T) spectrum that spans a wide temperature range (−37 °C < T < −11 °C) and covers nine orders of magnitude in ns.
Our inter-comparison results revealed a discrepancy between suspension and dry-dispersed particle measurements for this mineral dust. While the agreement was good below ~ −26 °C, the ice nucleation activity, expressed in ns, was smaller for the wet suspended samples and higher for the dry-dispersed aerosol samples between about −26 and −18 °C. Only instruments making measurement techniques with wet suspended samples were able to measure ice nucleation above −18 °C. A possible explanation for the deviation between −26 and −18 °C is discussed. In general, the seventeen immersion freezing measurement techniques deviate, within the range of about 7 °C in terms of temperature, by three orders of magnitude with respect to ns. In addition, we show evidence that the immersion freezing efficiency (i.e., ns) of illite NX particles is relatively independent on droplet size, particle mass in suspension, particle size and cooling rate during freezing. A strong temperature-dependence and weak time- and size-dependence of immersion freezing efficiency of illite-rich clay mineral particles enabled the ns parameterization solely as a function of temperature. We also characterized the ns (T) spectra, and identified a section with a steep slope between −20 and −27 °C, where a large fraction of active sites of our test dust may trigger immersion freezing. This slope was followed by a region with a gentler slope at temperatures below −27 °C. A multiple exponential distribution fit is expressed as ns(T) = exp(23.82 × exp(−exp(0.16 × (T + 17.49))) + 1.39) based on the specific surface area and ns(T) = exp(25.75 × exp(−exp(0.13 × (T + 17.17))) + 3.34) based on the geometric area (ns and T in m−2 and °C, respectively). These new fits, constrained by using an identical reference samples, will help to compare IN measurement methods that are not included in the present study and, thereby, IN data from future IN instruments.