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Einleitung: Ziel dieser Studie war es zu evaluieren, ob das Prüfungsformat einer OSPE (Objective Structured Practical Examination) durchgeführt im Fach Zahnerhaltungskunde (6. Fachsemester) den Studienerfolg im praktischen Teil des Staatsexamens (11. Fachsemester) im selben Fach prädiziert. Ferner sollte unter Berücksichtigung allgemeiner Angaben der StudienteilnehmerInnen (Abitursnote, Physikumsnote, Studiendauer, Kohorte und Geschlecht) analysiert werden, ob bezüglich der Gesamt- sowie Teilnoten der OSPE und der adäquaten Staatsexamensprüfung Zusammenhänge oder Unterschiede bestehen.
Methoden: Im Rahmen dieser longitudinalen, retrospektiven Studie wurden für einen Zeitraum von 11 Semestern prüfungsbezogene Daten von Studierenden (N=223) des Fachbereichs Zahnmedizin in Frankfurt am Main erhoben und untersucht. Für die statistische Auswertung der Daten wurden Spearman Rangkorrelationen, Partialkorrelationen, Korrelationskoeffizienten nach Pearson, und Multiple Regressionen (SPSS Statistics 21, IBM Corporation, New York) berechnet.
Ergebnisse: Die Ergebnisse zeigen, dass OSPE (Cronbachs α=.87) mit dem Erfolg im praktischen Teil des Staatsexamens im Fach Zahnerhaltungskunde korreliert (p=.01, r=.17). Als eine weitere signifikante Korrelation mit der Examensleistung erwies sich die Dauer des Studiums (p=.001, r=.23). Gemeinsam leisten diese beiden Variablen einen signifikanten Beitrag zur Vorhersage der Examensnote (p=.001, R2=.076). Das zeigte sich im größeren Umfang bei weiblichen Studierenden. Zudem wurde festgestellt, dass diese bessere Abiturnoten als männliche Studierende aufweisen (F=6.09, p=.01, η2=.027) und dass es lediglich bei männlichen Studierenden eine signifikante Korrelation zwischen der Physikumsnote (Zahnärztliche Vorprüfung) und der OSPE-Benotung gab (r=.17, p=.01).
Schlussfolgerung: In der vorliegenden Untersuchung konnte der prädiktive Effekt einer klinischen OSPE auf die Prüfungsleistung im Staatsexamen gezeigt werden. Unter Berücksichtigung der Limitation der Studie empfiehlt sich aus unserer Sicht die Durchführung eines solchen Prüfungsformats im Rahmen des klinischen Studienabschnitts im 6. Semester im Fach Zahnmedizin.
Introduction: The aim of this study was to ascertain whether the testing format of an OSPE (Objective Structured Practical Examination) in conservative dentistry (sixth semester) predicts the scores on the practical section of the state examination (11th semester) in the same subject. Taking general student profiles into consideration (score on the school-leaving exam [Abitur], score on the preliminary exam in dental medicine [Physikum], length of university study, cohorts, and sex), we also investigated if any correlations or differences exist in regard to the total and partial scores on the OSPE and the corresponding state examination.
Methods: Within the scope of this longitudinal retrospective study, exam-specific data spanning 11 semesters for dental students (N=223) in Frankfurt am Main were collected and analyzed. Statistical analysis was carried out by calculating Spearman rank correlations, partial correlations, Pearson’s correlation coefficients, and multiple regressions (SPSS Statistics 21, IBM Corporation, New York).
Results: The results show that the OSPE (Cronbach’s α=.87) correlates with level of success on the practical section of the state exam in conservative dentistry (p=.01, r=.17). Length of university study also emerged to correlate significantly with the state exam score (p=.001, r=.23). Together, these two variables contribute significantly to predicting the state exam score (p=.001, R2=.076). This was seen extensively among female students. It was also discovered that these female students had higher school-leaving exam scores than male students (F=6.09, p=.01, η2=.027), and that a significant correlation between scores on the Physikum (preliminary exam in dental medicine) and OSPE scores existed only for male students (r=.17, p=.01).
Conclusion: This study was able to demonstrate the predictive effect of a clinical OSPE regarding scores achieved on the state exam. Taking the limitations of this study into account, we are able to recommend using the OSPE testing format in the sixth semester during the clinical phase of dental study.
The red yeast Xanthophyllomyces dendrorhous is an established platform for the synthesis of carotenoids. It was used for the generation of novel multi oxygenated carotenoid structures. This was achieved by a combinatorial approach starting with the selection of a β-carotene accumulating mutant, stepwise pathway engineering by integration of three microbial genes into the genome and finally the chemical reduction of the resulting 4,4’-diketo-nostoxanthin (2,3,2’,3’-tetrahydroxy-4,4’-diketo-β-carotene) and 4-keto-nostoxanthin (2,3,2’,3’-tetrahydroxy-4-monoketo-β-carotene). Both keto carotenoids and the resulting 4,4’-dihydroxy-nostoxanthin (2,3,4,2’,3’,4’-hexahydroxy-β-carotene) and 4-hydroxy-nostoxanthin (2,3,4,2’3’-pentahydroxy-β-carotene) were separated by high-performance liquid chromatography (HPLC) and analyzed by mass spectrometry. Their molecular masses and fragmentation patterns allowed the unequivocal identification of all four carotenoids.
Background: Electrical stimulation (ES) has been successfully used to treat bone defects clinically. Recently, both cellular and molecular approaches have demonstrated that ES can change cell behavior such as migration, proliferation and differentiation.
Methods: In the present study we exposed rat bone marrow- (BM-) and adipose tissue- (AT-) derived mesenchymal stem cells (MSCs) to direct current electrical stimulation (DC ES) and assessed temporal changes in osteogenic differentiation. We applied 100 mV/mm of DC ES for 1 h per day for three, seven and 14 days to cells cultivated in osteogenic differentiation medium and assessed viability and calcium deposition at the different time points. In addition, expression of osteogenic genes, Runx2, Osteopontin, and Col1A2 was assessed in BM- and AT-derived MSCs at the different time points.
Results: Results showed that ES changed osteogenic gene expression patterns in both BM- and AT-MSCs, and these changes differed between the two groups. In BM-MSCs, ES caused a significant increase in mRNA levels of Runx2, Osteopontin and Col1A2 at day 7, while in AT-MSCs, the increase in Runx2 and Osteopontin expression were observed after 14 days of ES.
Discussion: This study shows that rat bone marrow- and adipose tissue-derived stem cells react differently to electrical stimuli, an observation that could be important for application of electrical stimulation in tissue engineering.
Background/objectives: Obesity is independently associated with left ventricular (LV) diastolic dysfunction and altered cardiac morphology. Morbidity and mortality in patients with diastolic dysfunction are similar to values observed in patients with systolic heart failure. We hypothesized that dysfunctional cardiac responses in people with obesity are reversible after weight loss. Thus, we studied the effect of dietary weight reduction on LV diastolic function as well as on cardiac structure using transthoracic echocardiography and tissue Doppler imaging (TDI).
Subjects/methods: Thirty-two subjects with obesity underwent a 12-week low-calorie fasting phase of a formula diet. Echocardiographic tissue Doppler indices of diastolic function and measurements of cardiac size were obtained prior to and after the fasting phase.
Results: A 12-week diet significantly reduced body mass index from 40.3 ± 6.6 kg/m 2 to 33.2 ± 6.1 kg/m 2 ( p < 0.01). Weight loss was associated with a significant reduction in blood pressure and heart rate. Echocardiography revealed diastolic dysfunction in subjects with obesity, which was improved by dieting. After weight loss, trans-mitral Doppler echocardiography showed a significant reduction in A-wave velocity, from 65.8 ± 19.2 cm/s to 57.0 ± 16.8 cm/s, and an increase in E/A ratio from 1.2 ± 0.4 to 1.4 ± 0.5 ( p < 0.01). TDI displayed a significantly lower a'-wave velocity (10.3 ± 2.3 cm/s and 8.9 ± 1.7 cm/s; p < 0.01). Left atrial and LV dimensions were normal and remained unchanged after weight loss.
Conclusion: Obesity is associated with diastolic dysfunction. A 12-week low-calorie diet with successful weight loss can reduce blood pressure and heart rate and partially normalize diastolic dysfunction.
We present an implementation of an interpreter LRPi for the call-by-need calculus LRP, based on a variant of Sestoft's abstract machine Mark 1, extended with an eager garbage collector. It is used as a tool for exact space usage analyses as a support for our investigations into space improvements of call-by-need calculi.
The lumbodorsal fascia (LF) has been proposed to represent a possible source of idiopathic low back pain. In fact, histological studies have demonstrated the presence of nociceptive free nerve endings within the LF, which, furthermore, appear to exhibit morphological changes in patients with chronic low back pain. However, it is unclear how these characteristics relate to the aetiology of the pain. In vivo elicitation of back pain via experimental stimulation of the LF suggests that dorsal horn neurons react by increasing their excitability. Such sensitization of fascia-related dorsal horn neurons, in turn, could be related to microinjuries and/or inflammation in the LF. Despite available data point towards a significant role of the LF in low back pain, further studies are needed to better understand the involved neurophysiological dynamics.
Broad AOX expression in a genetically tractable mouse model does not disturb normal physiology
(2017)
Plants and many lower organisms, but not mammals, express alternative oxidases (AOXs) that branch the mitochondrial respiratory chain, transferring electrons directly from ubiquinol to oxygen without proton pumping. Thus, they maintain electron flow under conditions when the classical respiratory chain is impaired, limiting excess production of oxygen radicals and supporting redox and metabolic homeostasis. AOX from Ciona intestinalis has been used to study and mitigate mitochondrial impairments in mammalian cell lines, Drosophila disease models and, most recently, in the mouse, where multiple lentivector-AOX transgenes conferred substantial expression in specific tissues. Here, we describe a genetically tractable mouse model in which Ciona AOX has been targeted to the Rosa26 locus for ubiquitous expression. The AOXRosa26 mouse exhibited only subtle phenotypic effects on respiratory complex formation, oxygen consumption or the global metabolome, and showed an essentially normal physiology. AOX conferred robust resistance to inhibitors of the respiratory chain in organello; moreover, animals exposed to a systemically applied LD50 dose of cyanide did not succumb. The AOXRosa26 mouse is a useful tool to investigate respiratory control mechanisms and to decipher mitochondrial disease aetiology in vivo.
This paper discusses the syntax of relative clauses in European Portuguese (EP) by focussing on the status of the relativizer que in restrictive and appositive relative clauses. We propose a unified account of que in terms of a D-element and discuss the syntactic implications of this assumption for an adequate analysis of relative clauses in EP. We assume that relative que has properties of demonstrative and interrogative determiners. In restrictive object and subject relative clauses, que occurs as a transitive determiner [DP que [NP e]], which selects for a nominal complement, whereas in prepositional and appositive relative clauses, [DP que] is an intransitive determiner parallel to an e-type pronoun. We discuss the position of restrictive relative clauses in the DP containing the modified noun, and propose that they are merged pre-nominally, in the same fashion as demonstratives.
The disruption of coupling between brain areas has been suggested as the mechanism underlying loss of consciousness in anesthesia. This hypothesis has been tested previously by measuring the information transfer between brain areas, and by taking reduced information transfer as a proxy for decoupling. Yet, information transfer is a function of the amount of information available in the information source—such that transfer decreases even for unchanged coupling when less source information is available. Therefore, we reconsidered past interpretations of reduced information transfer as a sign of decoupling, and asked whether impaired local information processing leads to a loss of information transfer. An important prediction of this alternative hypothesis is that changes in locally available information (signal entropy) should be at least as pronounced as changes in information transfer. We tested this prediction by recording local field potentials in two ferrets after administration of isoflurane in concentrations of 0.0%, 0.5%, and 1.0%. We found strong decreases in the source entropy under isoflurane in area V1 and the prefrontal cortex (PFC)—as predicted by our alternative hypothesis. The decrease in source entropy was stronger in PFC compared to V1. Information transfer between V1 and PFC was reduced bidirectionally, but with a stronger decrease from PFC to V1. This links the stronger decrease in information transfer to the stronger decrease in source entropy—suggesting reduced source entropy reduces information transfer. This conclusion fits the observation that the synaptic targets of isoflurane are located in local cortical circuits rather than on the synapses formed by interareal axonal projections. Thus, changes in information transfer under isoflurane seem to be a consequence of changes in local processing more than of decoupling between brain areas. We suggest that source entropy changes must be considered whenever interpreting changes in information transfer as decoupling.
Aesthetic perception and judgement are not merely cognitive processes, but also involve feelings. Therefore, the empirical study of these experiences requires conceptualization and measurement of aesthetic emotions. Despite the long-standing interest in such emotions, we still lack an assessment tool to capture the broad range of emotions that occur in response to the perceived aesthetic appeal of stimuli. Elicitors of aesthetic emotions are not limited to the arts in the strict sense, but extend to design, built environments, and nature. In this article, we describe the development of a questionnaire that is applicable across many of these domains: the Aesthetic Emotions Scale (Aesthemos). Drawing on theoretical accounts of aesthetic emotions and an extensive review of extant measures of aesthetic emotions within specific domains such as music, literature, film, painting, advertisements, design, and architecture, we propose a framework for studying aesthetic emotions. The Aesthemos, which is based on this framework, contains 21 subscales with two items each, that are designed to assess the emotional signature of responses to stimuli’s perceived aesthetic appeal in a highly differentiated manner. These scales cover prototypical aesthetic emotions (e.g., the feeling of beauty, being moved, fascination, and awe), epistemic emotions (e.g., interest and insight), and emotions indicative of amusement (humor and joy). In addition, the Aesthemos subscales capture both the activating (energy and vitality) and the calming (relaxation) effects of aesthetic experiences, as well as negative emotions that may contribute to aesthetic displeasure (e.g., the feeling of ugliness, boredom, and confusion).
Purpose: Prisoners are at a particularly high risk of suicide. In contrast to other psychosocial risk factors it remains unclear to what degree the risk of suicide differs between prisoners with local citizenship and foreigners. In order to provide more detailed information for suicide prevention in prisons, this study aims to compare suicide rates (SR) between these populations in German criminal custody.
Methods: Based on a German national database of completed suicide in custody, suicides by prisoners were analysed and compared with epidemiological data of the prison population and the general population, stratified for German and foreign citizenship. Data analysis was adjusted for differences in the age distribution of both populations by calculating standard mortality ratios (SMR) for suicide.
Results: SR were higher in prisoners with German citizenship than those with foreign citizenship (SR = 76.5 vs. SR = 42.8, P<0.01). This association was not specific to the prison population, as the higher SR in citizens compared to non-citizens (SR = 19.3 vs. SR = 9.0, P<0.01) were also found in the general population. The association between prison suicide and citizenship was comparable in juvenile and adult prisoners, indicating its relevance to both the juvenile and adult detention systems.
Conclusion: Imprisonment is associated with a substantially increased risk of suicide in both German and non-German citizens, a finding which needs to be taken into consideration by the justice system. The lower suicide risk in non-German citizens is independent of whether or not they are in custody.
To study the implications of highly space-demanding organic moieties on the properties of self-assembled monolayers (SAMs), triptycyl thiolates and selenolates with and without methylene spacers on Au(111) surfaces were comprehensively studied using ultra-high vacuum infrared reflection absorption spectroscopy, X-ray photoelectron spectroscopy, near-edge X-ray absorption fine structure spectroscopy and thermal desorption spectroscopy. Due to packing effects, the molecules in all monolayers are substantially tilted. In the presence of a methylene spacer the tilt is slightly less pronounced. The selenolate monolayers exhibit smaller defect densities and therefore are more densely packed than their thiolate analogues. The Se–Au binding energy in the investigated SAMs was found to be higher than the S–Au binding energy.
Box C/D snoRNAs are known to guide site-specific ribose methylation of ribosomal RNA. Here, we demonstrate a novel and unexpected role for box C/D snoRNAs in guiding 18S rRNA acetylation in yeast. Our results demonstrate, for the first time, that the acetylation of two cytosine residues in 18S rRNA catalyzed by Kre33 is guided by two orphan box C/D snoRNAs–snR4 and snR45 –not known to be involved in methylation in yeast. We identified Kre33 binding sites on these snoRNAs as well as on the 18S rRNA, and demonstrate that both snR4 and snR45 establish extended bipartite complementarity around the cytosines targeted for acetylation, similar to pseudouridylation pocket formation by the H/ACA snoRNPs. We show that base pairing between these snoRNAs and 18S rRNA requires the putative helicase activity of Kre33, which is also needed to aid early pre-rRNA processing. Compared to yeast, the number of orphan box C/D snoRNAs in higher eukaryotes is much larger and we hypothesize that several of these may be involved in base-modifications.
We study the sensitivities of the directed flow in Au+Au collisions on the equation of state (EoS), employing the transport theoretical model JAM. The EoS is modified by introducing a new collision term in order to control the pressure of a system by appropriately selecting an azimuthal angle in two-body collisions according to a given EoS. It is shown that this approach is an efficient method to modify the EoS in a transport model. The beam energy dependence of the directed flow of protons is examined with two different EoS, a first-order phase transition and crossover. It is found that our approach yields quite similar results as hydrodynamical predictions on the beam energy dependence of the directed flow; Transport theory predicts a minimum in the excitation function of the slope of proton directed flow and does indeed yield negative directed flow, if the EoS with a first-order phase transition is employed. Our result strongly suggests that the highest sensitivity for the critical point can be seen in the beam energy range of 4.7 ≤√sNN≤11.5GeV.
Local treatment of unresectable colorectal liver metastases : results of a randomized phase II trial
(2017)
Background: Tumor ablation is often employed for unresectable colorectal liver metastases. However, no survival benefit has ever been demonstrated in prospective randomized studies. Here, we investigate the long-term benefits of such an aggressive approach.
Methods: In this randomized phase II trial, 119 patients with unresectable colorectal liver metastases (n < 10 and no extrahepatic disease) received systemic treatment alone or systemic treatment plus aggressive local treatment by radiofrequency ablation ± resection. Previously, we reported that the primary end point (30-month overall survival [OS] > 38%) was met. We now report on long-term OS results. All statistical tests were two-sided. The analyses were according to intention to treat.
Results: At a median follow up of 9.7 years, 92 of 119 (77.3%) patients had died: 39 of 60 (65.0%) in the combined modality arm and 53 of 59 (89.8%) in the systemic treatment arm. Almost all patients died of progressive disease (35 patients in the combined modality arm, 49 patients in the systemic treatment arm). There was a statistically significant difference in OS in favor of the combined modality arm (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.38 to 0.88, P = .01). Three-, five-, and eight-year OS were 56.9% (95% CI = 43.3% to 68.5%), 43.1% (95% CI = 30.3% to 55.3%), 35.9% (95% CI = 23.8% to 48.2%), respectively, in the combined modality arm and 55.2% (95% CI = 41.6% to 66.9%), 30.3% (95% CI = 19.0% to 42.4%), 8.9% (95% CI = 3.3% to 18.1%), respectively, in the systemic treatment arm. Median OS was 45.6 months (95% CI = 30.3 to 67.8 months) in the combined modality arm vs 40.5 months (95% CI = 27.5 to 47.7 months) in the systemic treatment arm.
Conclusions: This phase II trial is the first randomized study demonstrating that aggressive local treatment can prolong OS in patients with unresectable colorectal liver metastases.
Genetic mutations underlying neurodegenerative disorders impair ribosomal DNA (rDNA) transcription suggesting that nucleolar dysfunction could be a novel pathomechanism in polyglutamine diseases and in certain forms of amyotrophic lateral sclerosis/frontotemporal dementia. Here, we investigated nucleolar activity in pre-symptomatic digenic models of Parkinson's disease (PD) that model the multifactorial aetiology of this disease. To this end, we analysed a novel mouse model mildly overexpressing mutant human α-synuclein (hA53T-SNCA) in a PTEN-induced kinase 1 (PINK1/PARK6) knockout background and mutant mice lacking both DJ-1 (also known as PARK7) and PINK1. We showed that overexpressed hA53T-SNCA localizes to the nucleolus. Moreover, these mutants show a progressive reduction of rDNA transcription linked to a reduced mouse lifespan. By contrast, rDNA transcription is preserved in DJ-1/PINK1 double knockout (DKO) mice. mRNA levels of the nucleolar transcription initiation factor 1A (TIF-IA, also known as RRN3) decrease in the substantia nigra of individuals with PD. Because loss of TIF-IA, as a tool to mimic nucleolar stress, increases oxidative stress and because DJ-1 and PINK1 mutations result in higher vulnerability to oxidative stress, we further explored the synergism between these PD-associated genes and impaired nucleolar function. By the conditional ablation of TIF-IA, we blocked ribosomal RNA (rRNA) synthesis in adult dopaminergic neurons in a DJ-1/PINK1 DKO background. However, the early phenotype of these triple knockout mice was similar to those mice exclusively lacking TIF-IA. These data sustain a model in which loss of DJ-1 and PINK1 does not impair nucleolar activity in a pre-symptomatic stage. This is the first study to analyse nucleolar function in digenic PD models. We can conclude that, at least in these models, the nucleolus is not as severely disrupted as previously shown in DA neurons from PD patients and neurotoxin-based PD mouse models. The results also show that the early increase in rDNA transcription and nucleolar integrity may represent specific homeostatic responses in these digenic pre-symptomatic PD models.
The effects of aging on response time were examined in a paper-based lexical-decision experiment with younger (age 18–36) and older (age 64–75) adults, applying Ratcliff’s diffusion model. Using digital pens allowed the paper-based assessment of response times for single items. Age differences previously reported by Ratcliff and colleagues in computer-based experiments were partly replicated: older adults responded more conservatively than younger adults and showed a slowing of their nondecision components of RT by 53 ms. The rates of evidence accumulation (drift rate) showed no age-related differences. Participants with a higher score in a vocabulary test also had higher drift rates. The experiment demonstrates the possibility to use formal processing models with paper-based tests.
In European Robins, Erithacus rubecula, the magnetic compass is lateralized in favor of the right eye/left hemisphere of the brain. This lateralization develops during the first winter and initially shows a great plasticity. During the first spring migration, it can be temporarily removed by covering the right eye. In the present paper, we used the migratory orientation of robins to analyze the circumstances under which the lateralization can be undone. Already a period of 1½ h being monocularly left-eyed before tests began proved sufficient to restore the ability to use the left eye for orientation, but this effect was rather short-lived, as lateralization recurred again within the next 1½ h. Interpretable magnetic information mediated by the left eye was necessary for removing the lateralization. In addition, monocularly, the left eye seeing robins could adjust to magnetic intensities outside the normal functional window, but this ability was not transferred to the “right-eye system”. Our results make it clear that asymmetry of magnetic compass perception is amenable to short-term changes, depending on lateralized stimulation. This could mean that the left hemispheric dominance for the analysis of magnetic compass information depends on lateralized interhemispheric interactions that in young birds can swiftly be altered by environmental effects.
The asymmetric unit of the title compound, C18H18I2N2O2, consists of one half-molecule, completed by the application of inversion symmetry. The molecule adopts the typical structure for this class of bis-benxozazines, characterized by an anti orientation of the two benzoxazine rings around the central C—C bond. The oxazinic ring adopts a half-chair conformation. In the crystal, molecules are linked by C—I⋯N short contacts [I⋯N = 3.378 (2) Å], generating layers lying parallel to the bc plane.
Denisovite is a rare mineral occurring as aggregates of fibres typically 200–500 nm diameter. It was confirmed as a new mineral in 1984, but important facts about its chemical formula, lattice parameters, symmetry and structure have remained incompletely known since then. Recently obtained results from studies using microprobe analysis, X-ray powder diffraction (XRPD), electron crystallography, modelling and Rietveld refinement will be reported. The electron crystallography methods include transmission electron microscopy (TEM), selected-area electron diffraction (SAED), high-angle annular dark-field imaging (HAADF), high-resolution transmission electron microscopy (HRTEM), precession electron diffraction (PED) and electron diffraction tomography (EDT). A structural model of denisovite was developed from HAADF images and later completed on the basis of quasi-kinematic EDT data by ab initio structure solution using direct methods and least-squares refinement. The model was confirmed by Rietveld refinement. The lattice parameters are a = 31.024 (1), b = 19.554 (1) and c = 7.1441 (5) Å, β = 95.99 (3)°, V = 4310.1 (5) Å3 and space group P12/a1. The structure consists of three topologically distinct dreier silicate chains, viz. two xonotlite-like dreier double chains, [Si6O17]10−, and a tubular loop-branched dreier triple chain, [Si12O30]12−. The silicate chains occur between three walls of edge-sharing (Ca,Na) octahedra. The chains of silicate tetrahedra and the octahedra walls extend parallel to the z axis and form a layer parallel to (100). Water molecules and K+ cations are located at the centre of the tubular silicate chain. The latter also occupy positions close to the centres of eight-membered rings in the silicate chains. The silicate chains are geometrically constrained by neighbouring octahedra walls and present an ambiguity with respect to their z position along these walls, with displacements between neighbouring layers being either Δz = c/4 or −c/4. Such behaviour is typical for polytypic sequences and leads to disorder along [100]. In fact, the diffraction pattern does not show any sharp reflections with l odd, but continuous diffuse streaks parallel to a* instead. Only reflections with l even are sharp. The diffuse scattering is caused by (100) nanolamellae separated by stacking faults and twin boundaries. The structure can be described according to the order–disorder (OD) theory as a stacking of layers parallel to (100).
I summarize recent developments in the hard-thermal-loop approach to QCD. I first discuss a finite-temperature and -density calculation of QCD thermodynamics at NNLO from the hard-thermal-loop perturbation theory. I then discuss a generalization of the hard-thermal-loop framework to the magnetic scale g2T, from which a novel non-Abelian massless mode is uncovered.
We study a random matrix model for QCD at finite density via complex Langevin dynamics. This model has a phase transition to a phase with nonzero baryon density. We study the convergence of the algorithm as a function of the quark mass and the chemical potential and focus on two main observables: the baryon density and the chiral condensate. For simulations close to the chiral limit, the algorithm has wrong convergence properties when the quark mass is in the spectral domain of the Dirac operator. A possible solution of this problem is discussed.
We report on the results on the dynamical modelling of cluster formation with the new combined PHSD+FRIGA model at Nuclotron and NICA energies. The FRIGA clusterization algorithm, which can be applied to the transport models, is based on the simulated annealing technique to obtain the most bound configuration of fragments and nucleons. The PHSD+FRIGA model is able to predict isotope yields as well as hypernucleus production. Based on present predictions of the combined model we study the possibility to detect such clusters and hypernuclei in the BM@N and MPD/NICA detectors.
The properties of matter at finite baryon densities play an important role for the astrophysics of compact stars as well as for heavy ion collisions or the description of nuclear matter. Because of the sign problem of the quark determinant, lattice QCD cannot be simulated by standard Monte Carlo at finite baryon densities. I review alternative attempts to treat dense QCD with an effective lattice theory derived by analytic strong coupling and hopping expansions, which close to the continuum is valid for heavy quarks only, but shows all qualitative features of nuclear physics emerging from QCD. In particular, the nuclear liquid gas transition and an equation of state for baryons can be calculated directly from QCD. A second effective theory based on strong coupling methods permits studies of the phase diagram in the chiral limit on coarse lattices.
Aims: The purpose of this study was to analyze the prevalence of depression, anxiety, adjustment disorders, and somatoform disorders in patients diagnosed with age-related macular degeneration (AMD) in Germany.
Methods: This study included 7,580 patients between the ages of 40 and 90 diagnosed with AMD between January 2011 and December 2014 in 1,072 primary care practices (index date). The last follow-up was in July 2016. We also included 7,580 controls without AMD, which were matched (1:1) to the AMD cases by age, sex, type of health insurance (private or statutory), physician, and Charlson comorbidity score as a generic marker of comorbidity. The outcome of the study was the prevalence of depression, anxiety, adjustment disorders, and somatoform disorders recorded in the database between the index date and the end of follow-up.
Results: The mean age among subjects was 75.7 years (SD=10.1 years), 34.0% were men, and 7.8% had private health insurance coverage. The Charlson comorbidity index was 2.0 (SD=1.8). Depression was the most frequent disease (33.7% in AMD patients versus 27.3% in controls), followed by somatoform disorders (19.6% and 16.7%), adjustment disorders (14.8% and 10.5%), and anxiety disorders (11.7% and 8.2%). Depression (OR=1.37, 95% CI: 1.27–1.47), anxiety (OR=1.50, 95% CI: 1.35–1.67), adjustment disorders (OR=1.50, 95% CI: 1.36–1.65), and somatoform disorders (OR=1.22, 95% CI: 1.12–1.32) were all positively associated with AMD.
Conclusion: Overall, a significant association was found between AMD and depression, anxiety, adjustment disorders, and somatoform disorders.
Green tea (GT) and green tea extracts (GTE) have been postulated to decrease cancer incidence. In vitro results indicate a possible effect; however, epidemiological data do not support cancer chemoprevention. We have performed a PubMED literature search for green tea consumption and the correlation to the common tumor types lung, colorectal, breast, prostate, esophageal and gastric cancer, with cohorts from both Western and Asian countries. We additionally included selected mechanistical studies for a possible mode of action. The comparability between studies was limited due to major differences in study outlines; a meta analysis was thus not possible and studies were evaluated individually. Only for breast cancer could a possible small protective effect be seen in Asian and Western cohorts, whereas for esophagus and stomach cancer, green tea increased the cancer incidence, possibly due to heat stress. No effect was found for colonic/colorectal and prostatic cancer in any country, for lung cancer Chinese studies found a protective effect, but not studies from outside China. Epidemiological studies thus do not support a cancer protective effect. GT as an indicator of as yet undefined parameters in lifestyle, environment and/or ethnicity may explain some of the observed differences between China and other countries.
Objective: The glucose stimulation of insulin secretion (GSIS) by pancreatic β-cells critically depends on increased production of metabolic coupling factors, including NADPH. Nicotinamide nucleotide transhydrogenase (NNT) typically produces NADPH at the expense of NADH and ΔpH in energized mitochondria. Its spontaneous inactivation in C57BL/6J mice was previously shown to alter ATP production, Ca2+ influx, and GSIS, thereby leading to glucose intolerance. Here, we tested the role of NNT in the glucose regulation of mitochondrial NADPH and glutathione redox state and reinvestigated its role in GSIS coupling events in mouse pancreatic islets.
Methods: Islets were isolated from female C57BL/6J mice (J-islets), which lack functional NNT, and genetically close C57BL/6N mice (N-islets). Wild-type mouse NNT was expressed in J-islets by adenoviral infection. Mitochondrial and cytosolic glutathione oxidation was measured with glutaredoxin 1-fused roGFP2 probes targeted or not to the mitochondrial matrix. NADPH and NADH redox state was measured biochemically. Insulin secretion and upstream coupling events were measured under dynamic or static conditions by standard procedures.
Results: NNT is largely responsible for the acute glucose-induced rise in islet NADPH/NADP+ ratio and decrease in mitochondrial glutathione oxidation, with a small impact on cytosolic glutathione. However, contrary to current views on NNT in β-cells, these effects resulted from a glucose-dependent reduction in NADPH consumption by NNT reverse mode of operation, rather than from a stimulation of its forward mode of operation. Accordingly, the lack of NNT in J-islets decreased their sensitivity to exogenous H2O2 at non-stimulating glucose. Surprisingly, the lack of NNT did not alter the glucose-stimulation of Ca2+ influx and upstream mitochondrial events, but it markedly reduced both phases of GSIS by altering Ca2+-induced exocytosis and its metabolic amplification.
Conclusion: These results drastically modify current views on NNT operation and mitochondrial function in pancreatic β-cells.
Photodynamic treatment of oral squamous cell carcinoma cells with low curcumin concentrations
(2017)
Objective: Curcumin is known for its anti-oxidative, anti-inflammatory and anti-tumorigenic qualities at concentrations ranging from 3.7µg/ml to 55µg/ml. Therefore it is pre-destined for tumour therapy. Due to high oral doses that have to be administered and the low bioavailability of curcumin new therapy concepts have to be developed. One of these therapy concepts is the combination of low curcumin concentrations and UVA or visible light. Aim of our study was to investigate the influence of this treatment regime on oral squamous cell carcinoma cells.
Materials and Methods: A human oral squamous cell carcinoma cell line (HN) was pre-incubated with low curcumin concentrations (0.01µg/ml to 1µg/ml). Thereafter cell cultures were either left un-irradiated or were irradiated either with 1J/cm2 UVA or for 5min with visible light. Quantitative analysis of proliferation, membrane integrity, oxidative potential and DNA fragmentation were done.
Results: It could be shown that low curcumin concentrations neither influenced proliferation, nor cell morphology, nor cell integrity nor apoptosis. When combining these curcumin concentrations with UVA or visible light irradiation cell proliferation as well as development of reactive oxygen species was reduced whereas DNA fragmentation was increased. Concentration as well as light entity specific effects could be observed.
Conclusions: The present findings substantiate the potential of the combination of low curcumin concentrations and light as a new therapeutic concept to increase the efficacy of curcumin in the treatment of cancer of the oral mucosa.
The production of 77,79,85,85mKr and 77Br via the reaction Se(a, x) was investigated between Ea = 11 and 15 MeV using the activation technique. The irradiation of natural selenium targets on aluminum backings was conducted at the Physikalisch-Technische Bundesanstalt (PTB) in Braunschweig, Germany. The spectroscopic analysis of the reaction products was performed using a high-purity germanium detector located at PTB and a low energy photon spectrometer detector at the Goethe University Frankfurt, Germany. Thicktarget yields were determined. The corresponding energy-dependent production cross sections of 77,79,85,85mKr and 77Br were calculated from the thicktarget yields. Good agreement between experimental data and theoretical predictions using the TALYS-1.6 code was found.
Editorial
(2017)
Bevacizumab for patients with recurrent gliomas presenting with a gliomatosis cerebri growth pattern
(2017)
Bevacizumab has been shown to improve progression-free survival and neurologic function, but failed to improve overall survival in newly diagnosed glioblastoma and at first recurrence. Nonetheless, bevacizumab is widely used in patients with recurrent glioma. However, its use in patients with gliomas showing a gliomatosis cerebri growth pattern is contentious. Due to the marked diffuse and infiltrative growth with less angiogenic tumor growth, it may appear questionable whether bevacizumab can have a therapeutic effect in those patients. However, the development of nodular, necrotic, and/or contrast-enhancing lesions in patients with a gliomatosis cerebri growth pattern is not uncommon and may indicate focal neo-angiogenesis. Therefore, control of growth of these lesions as well as control of edema and reduction of steroid use may be regarded as rationales for the use of bevacizumab in these patients. In this retrospective patient series, we report on 17 patients with primary brain tumors displaying a gliomatosis cerebri growth pattern (including seven glioblastomas, two anaplastic astrocytomas, one anaplastic oligodendroglioma, and seven diffuse astrocytomas). Patients have been treated with bevacizumab alone or in combination with lomustine or irinotecan. Seventeen matched patients treated with bevacizumab for gliomas with a classical growth pattern served as a control cohort. Response rate, progression-free survival, and overall survival were similar in both groups. Based on these results, anti-angiogenic therapy with bevacizumab should also be considered in patients suffering from gliomas with a mainly infiltrative phenotype.
Overrepresentation of bidirectional connections in local cortical networks has been repeatedly reported and is a focus of the ongoing discussion of nonrandom connectivity. Here we show in a brief mathematical analysis that in a network in which connection probabilities are symmetric in pairs, Pij = Pji, the occurrences of bidirectional connections and nonrandom structures are inherently linked; an overabundance of reciprocally connected pairs emerges necessarily when some pairs of neurons are more likely to be connected than others. Our numerical results imply that such overrepresentation can also be sustained when connection probabilities are only approximately symmetric.
The adaptor protein Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) plays a crucial role in T cell activation by linking antigen receptor (T cell receptor, TCR) signals to downstream pathways. At its N terminus, SLP-76 has three key tyrosines (Tyr-113, Tyr-128, and Tyr-145, “3Y”) as well as a sterile α motif (SAM) domain whose function is unclear. We showed previously that the SAM domain has two binding regions that mediate dimer and oligomer formation. In this study, we have identified SAM domain-carrying non-receptor tyrosine kinase, activated Cdc42-associated tyrosine kinase 1 (ACK1; also known as Tnk2, tyrosine kinase non-receptor 2) as a novel binding partner of SLP-76. Co-precipitation, laser-scanning confocal microscopy, and in situ proximity analysis confirmed the binding of ACK1 to SLP-76. Further, the interaction was induced in response to the anti-TCR ligation and abrogated by the deletion of SLP-76 SAM domain (ΔSAM) or mutation of Tyr-113, Tyr-128, and Tyr-145 to phenylalanine (3Y3F). ACK1 induced phosphorylation of the SLP-76 N-terminal tyrosines (3Y) dependent on the SAM domain. Further, ACK1 promoted calcium flux and NFAT-AP1 promoter activity and decreased the motility of murine CD4+ primary T cells on ICAM-1-coated plates, an event reversed by a small molecule inhibitor of ACK1 (AIM-100). These findings identify ACK1 as a novel SLP-76-associated protein-tyrosine kinase that modulates early activation events in T cells.
The growing interest of the Arabs in Arabic translations from Greek since the 8th century has been interpreted as a sign of humanism in Islam. This is comparable to humanists in Europe who, since the 14th century, considered the Greek and Latin literature the foundation of spiritual and moral education. We will have to address the question of whether a similar ideal of education has been developed in harmony with religion in the Islamic cultural sphere. The perceived tension between the humanists of antiquity and Christianity has a parallel in the tensions between Islamic religiosity and a rational Islamic worldview. However, there are past and present approaches to developing an educational ideal, which is comparable to the European concept of a moral shaping of the individual. The Qur’ān and Islamic tradition do not impede the free development of personality and creative responsibility if their historicity is taken into account and if they are not elevated to an unreflected norm.
Keywords: Humanism, Islamic and European, education, individuality, solidarity, free will and subordination, Ibn al-Muqaffa’, Fārābī, Yaḥyā Ibn’Adī, Miskawayh, Rāghib al-Isfahānī, Ghazzālī, Ibn Khaldūn, Renaissance of Islam - Italian Renaissance, Pico della Mirandola, Nahda, Tāhā Husayn, Sadik J. Al-Azm, Edward W. Said, Naquib Al-Attas
Stroke patients with proximal occlusions of the main stems of cerebral arteries are no optimal candidates for i. v. thrombolysis. For many years interventional stroke treatment could not be established as alternative. This changed with the introduction of stent retrievers and flexible large lumen aspiration catheters. Randomized trials now proved a significant benefit from intervention for a wide spectrum of severely compromised stroke patients in time windows of up to 8 hrs. However, the randomized trials leave open questions concerning proper patient selection. The benefit for patients with larger infarcts with an ASPECTS between 3 and 5 or patients in time windows above 8 hrs is still uncertain. Especially for critical candidates imaging for reliable detection of the ischemic core and surrounding salvageable brain tissue plays an important role. Technically equivalence between new aspiration techniques as alternative to the use of stent-retrievers is not finally proven. Recanalization of tandem occlusions with the necessity of acute stenting demands better materials for plaque coverage and thrombus withhold. Management of cases with occlusions due to intracranial atherosclerosis is also debatable. The positive trial results provide especially new challenges to establish countrywide neurointerventional services. Even in developed countries recruitment and training of interventional radiologists as well as priority transportation of stroke patients is challenging to organize.
This is an abstract presented in the 33rd Iranian congress of radiology (ICR) and the 15th congress of Iranian radiographic science association (IRSA).
Disabling practices
(2017)
Following Foucault’s theory of discourse this article aims at reformulating the established concept of disability. To this end, the author reconstructs ways in which disabling practices of subjectivation occur in and through public media discourses. The article focuses on the discoursive production of infantile identities in people with cognitive disabilities. The examples demonstrate that this discoursive production occurs in self-representational media formats and in outside media representations. Hence, the author develops a concept of disability as a discoursively produced ordering category, from which follows a reformulation of the disability concept. This reformulated concept, which grasps disability as discourse disability, allows in turn for a perspective on disability as practice and thus as independent from the subject. To conclude, the article discusses implications of such a perspective of disability for pedagogy and the social sciences, ultimately arguing for a broader definition of disability and for making respective benefits a matter of social pedagogy.
Criticality meets learning : criticality signatures in a self-organizing recurrent neural network
(2017)
Many experiments have suggested that the brain operates close to a critical state, based on signatures of criticality such as power-law distributed neuronal avalanches. In neural network models, criticality is a dynamical state that maximizes information processing capacities, e.g. sensitivity to input, dynamical range and storage capacity, which makes it a favorable candidate state for brain function. Although models that self-organize towards a critical state have been proposed, the relation between criticality signatures and learning is still unclear. Here, we investigate signatures of criticality in a self-organizing recurrent neural network (SORN). Investigating criticality in the SORN is of particular interest because it has not been developed to show criticality. Instead, the SORN has been shown to exhibit spatio-temporal pattern learning through a combination of neural plasticity mechanisms and it reproduces a number of biological findings on neural variability and the statistics and fluctuations of synaptic efficacies. We show that, after a transient, the SORN spontaneously self-organizes into a dynamical state that shows criticality signatures comparable to those found in experiments. The plasticity mechanisms are necessary to attain that dynamical state, but not to maintain it. Furthermore, onset of external input transiently changes the slope of the avalanche distributions – matching recent experimental findings. Interestingly, the membrane noise level necessary for the occurrence of the criticality signatures reduces the model’s performance in simple learning tasks. Overall, our work shows that the biologically inspired plasticity and homeostasis mechanisms responsible for the SORN’s spatio-temporal learning abilities can give rise to criticality signatures in its activity when driven by random input, but these break down under the structured input of short repeating sequences.
Background: Currently, there is inadequate evidence on which to base clinical management of neurotoxic snakebite envenoming, especially in the choice of initial antivenom dosage. This randomised controlled trial compared the effectiveness and safety of high versus low initial antivenom dosage in victims of neurotoxic envenoming.
Methodology/ Principal findings: This was a balanced, randomised, double-blind trial that was conducted in three health care centers located in the Terai plains of Nepal. Participants received either low (two vials) or high (10 vials) initial dosage of Indian polyvalent antivenom. The primary composite outcome consisted of death, the need for assisted ventilation and worsening/recurrence of neurotoxicity. Hourly evaluations followed antivenom treatment. Between April 2011 and October 2012, 157 snakebite victims were enrolled, of which 154 were analysed (76 in the low and 78 in the high initial dose group). Sixty-seven (43·5%) participants met the primary outcome definition. The proportions were similar in the low (37 or 48.7%) vs. high (30 or 38.5%) initial dose group (difference = 10·2%, 95%CI [-6·7 to 27·1], p = 0·264). The mean number of vials used was similar between treatment groups. Overall, patients bitten by kraits did worse than those bitten by cobras. The occurrence of treatment-related adverse events did not differ among treatment groups. A total of 19 serious adverse events occurred, including seven attributed to antivenom.
Conclusions: This first robust trial investigating antivenom dosage for neurotoxic snakebite envenoming shows that the antivenom currently used in Nepal performs poorly. Although the high initial dose regimen is not more effective than the low initial dose, it offers the practical advantage of being a single dose, while not incurring higher consumption or enhanced risk of adverse reaction. The development of new and more effective antivenoms that better target the species responsible for bites in the region will help improve future patients’ outcomes.
Trial registration: The study was registered on clinicaltrials.gov (NCT01284855) (GJ 5/1)
Hematopoietic differentiation is controlled by key transcription factors, which regulate stem cell functions and differentiation. TAL1 is a central transcription factor for hematopoietic stem cell development in the embryo and for gene regulation during erythroid/megakaryocytic differentiation. Knowledge of the target genes controlled by a given transcription factor is important to understand its contribution to normal development and disease. To uncover direct target genes of TAL1 we used high affinity streptavidin/biotin-based chromatin precipitation (Strep-CP) followed by Strep-CP on ChIP analysis using ChIP promoter arrays. We identified 451 TAL1 target genes in K562 cells. Furthermore, we analysed the regulation of one of these genes, the catalytic subunit beta of protein kinase A (PRKACB), during megakaryopoiesis of K562 and primary human CD34+ stem cell/progenitor cells. We found that TAL1 together with hematopoietic transcription factors RUNX1 and GATA1 binds to the promoter of the isoform 3 of PRKACB (Cβ3). During megakaryocytic differentiation a coactivator complex on the Cβ3 promoter, which includes WDR5 and p300, is replaced with a corepressor complex. In this manner, activating chromatin modifications are removed and expression of the PRKACB-Cβ3 isoform during megakaryocytic differentiation is reduced. Our data uncover a role of the TAL1 complex in controlling differential isoform expression of PRKACB. These results reveal a novel function of TAL1, RUNX1 and GATA1 in the transcriptional control of protein kinase A activity, with implications for cellular signalling control during differentiation and disease.
A recent report showed PINK1 transcript levels to be up- or down-regulated by the gain or loss of Ataxin-2 function, respectively, in human blood, in a human neural cell line and in mouse tissues. These observations may have profound implications for the regulation of cell growth and may be medically exploited for the treatment of cancer and neural atrophy...
Body image dissatisfaction is a serious, global problem that negatively affects life satisfaction. Several claims have been made about the possible psychological benefits of naturist activities, but very little empirical research has investigated these benefits or any plausible explanations for them. In three studies—one large-scale, cross-sectional study (n = 849), and 2 prospective studies (n = 24, n = 100) this research developed and applied knowledge about the possible benefits of naturist activities. It was found that more participation in naturist activities predicted greater life satisfaction—a relationship that was mediated by more positive body image, and higher self-esteem (Study 1). Applying these findings, it was found that participation in actual naturist activities led to an increase in life satisfaction, an effect that was also mediated by improvements in body image and self-esteem (Studies 2 and 3). The potential benefits of naturism are discussed, as well as possible future research, and implications for the use of naturist activities.
The important role of fire in regulating vegetation community composition and contributions to emissions of greenhouse gases and aerosols make it a critical component of dynamic global vegetation models and Earth system models. Over 2 decades of development, a wide variety of model structures and mechanisms have been designed and incorporated into global fire models, which have been linked to different vegetation models. However, there has not yet been a systematic examination of how these different strategies contribute to model performance. Here we describe the structure of the first phase of the Fire Model Intercomparison Project (FireMIP), which for the first time seeks to systematically compare a number of models. By combining a standardized set of input data and model experiments with a rigorous comparison of model outputs to each other and to observations, we will improve the understanding of what drives vegetation fire, how it can best be simulated, and what new or improved observational data could allow better constraints on model behavior. In this paper, we introduce the fire models used in the first phase of FireMIP, the simulation protocols applied, and the benchmarking system used to evaluate the models. We have also created supplementary tables that describe, in thorough mathematical detail, the structure of each model.
In this study, we construct a new monthly zonal mean carbon dioxide (CO2) distribution from the upper troposphere to the stratosphere over the 2000–2010 time period. This reconstructed CO2 product is based on a Lagrangian backward trajectory model driven by ERA-Interim reanalysis meteorology and tropospheric CO2 measurements. Comparisons of our CO2 product to extratropical in situ measurements from aircraft transects and balloon profiles show remarkably good agreement. The main features of the CO2 distribution include (1) relatively large mixing ratios in the tropical stratosphere; (2) seasonal variability in the extratropics, with relatively high mixing ratios in the summer and autumn hemisphere in the 15–20 km altitude layer; and (3) decreasing mixing ratios with increasing altitude from the upper troposphere to the middle stratosphere ( ∼ 35 km). These features are consistent with expected variability due to the transport of long-lived trace gases by the stratospheric Brewer–Dobson circulation. The method used here to construct this CO2 product is unique from other modelling efforts and should be useful for model and satellite validation in the upper troposphere and stratosphere as a prior for inversion modelling and to analyse features of stratosphere–troposphere exchange as well as the stratospheric circulation and its variability.
The fractional release factor (FRF) gives information on the amount of a halocarbon that is released at some point into the stratosphere from its source form to the inorganic form, which can harm the ozone layer through catalytic reactions. The quantity is of major importance because it directly affects the calculation of the ozone depletion potential (ODP). In this context time-independent values are needed which, in particular, should be independent of the trends in the tropospheric mixing ratios (tropospheric trends) of the respective halogenated trace gases. For a given atmospheric situation, such FRF values would represent a molecular property.
We analysed the temporal evolution of FRF from ECHAM/MESSy Atmospheric Chemistry (EMAC) model simulations for several halocarbons and nitrous oxide between 1965 and 2011 on different mean age levels and found that the widely used formulation of FRF yields highly time-dependent values. We show that this is caused by the way that the tropospheric trend is handled in the widely used calculation method of FRF.
Taking into account chemical loss in the calculation of stratospheric mixing ratios reduces the time dependence in FRFs. Therefore we implemented a loss term in the formulation of the FRF and applied the parameterization of a mean arrival time to our data set.
We find that the time dependence in the FRF can almost be compensated for by applying a new trend correction in the calculation of the FRF. We suggest that this new method should be used to calculate time-independent FRFs, which can then be used e.g. for the calculation of ODP.
Background: Women’s participation in medicine and the need for gender equality in healthcare are increasingly recognised, yet little attention is paid to leadership and management positions in large publicly funded academic health centres. This study illustrates such a need, taking the case of four large European centres: Charité – Universitätsmedizin Berlin (Germany), Karolinska Institutet (Sweden), Medizinische Universität Wien (Austria), and Oxford Academic Health Science Centre (United Kingdom).
Case:The percentage of female medical students and doctors in all four countries is now well within the 40–60% gender balance zone. Women are less well represented among specialists and remain significantly under-represented among senior doctors and full professors. All four centres have made progress in closing the gender leadership gap on boards and other top-level decision-making bodies, but a gender leadership gap remains relevant. The level of achieved gender balance varies significantly between the centres and largely mirrors country-specific welfare state models, with more equal gender relations in Sweden than in the other countries. Notably, there are also similar trends across countries and centres: gender inequality is stronger within academic enterprises than within hospital enterprises and stronger in middle management than at the top level. These novel findings reveal fissures in the ‘glass ceiling’ effects at top-level management, while the barriers for women shift to middle-level management and remain strong in academic positions. The uneven shifts in the leadership gap are highly relevant and have policy implications.
Conclusion: Setting gender balance objectives exclusively for top-level decision-making bodies may not effectively promote a wider goal of gender equality. Academic health centres should pay greater attention to gender equality as an issue of organisational performance and good leadership at all levels of management, with particular attention to academic enterprises and newly created management structures. Developing comprehensive gender-sensitive health workforce monitoring systems and comparing progress across academic health centres in Europe could help to identify the gender leadership gap and utilise health human resources more effectively.
The hallmark of classical Hodgkin lymphoma (cHL) is the presence of giant, mostly multinucleated Hodgkin-Reed-Sternberg (HRS) cells. Whereas it has recently been shown that giant HRS cells evolve from small Hodgkin cells by incomplete cytokinesis and re-fusion of tethered sister cells, it remains unsolved why this phenomenon particularly takes place in this lymphoma and what the differences between these cell types of variable sizes are. The aim of the present study was to characterize microdissected small and giant HRS cells by gene expression profiling and to assess differences of clonal growth behavior as well as susceptibility toward cytotoxic intervention between these different cell types to provide more insight into their distinct cellular potential. Applying stringent filter criteria, only two differentially expressed genes between small and giant HRS cells, SHFM1 and LDHB, were identified. With looser filter criteria, 13 genes were identified to be differentially overexpressed in small compared to giant HRS cells. These were mainly related to energy metabolism and protein synthesis, further suggesting that small Hodgkin cells resemble the proliferative compartment of cHL. SHFM1, which is known to be involved in the generation of giant cells, was downregulated in giant RS cells at the RNA level. However, reduced mRNA levels of SHFM1, LDHB and HSPA8 did not translate into decreased protein levels in giant HRS cells. In cell culture experiments it was observed that the fraction of small and big HRS cells was adjusted to the basic level several days after enrichment of these populations via cell sorting, indicating that small and big HRS cells can reconstitute the full spectrum of cells usually observed in the culture. However, assessment of clonal growth of HRS cells indicated a significantly reduced potential of big HRS cells to form single cell colonies. Taken together, our findings pinpoint to strong similarities but also some differences between small and big HRS cells.
Der Erzählforscher Johannes Merkel hat unlängst (2015) einen bemerkenswerten Überblick zur Gesamttradition des mündlichen Erzählens vorgelegt. Die folgenden Überlegungen, von einer Teilbesprechung dieser Neuerscheinung ausgehend, zielen grundsätzlich auf eine kritische Überprüfung von verschiedenen in der bisherigen Forschung für selbstverständlich gehaltenen Basisfaktoren (insbesondere den theoretischen Ansätzen von Nilsson und Parry). Dabei geht es zunächst einmal um jene allgemein vorausgesetzte vorgriechische Phase von oral poetry, auf die sich auch Merkel im 3. Kapitel unter dem Titel ‚Das singende Gedächtnis: Epenvortrag in Mittelasien und auf dem Balkan‘ bezog (105-148). Die neuere Forschung tendiert bekanntlich dazu, es habe eine längere oral poetry in den sog. "dunklen Jahrhunderten" zwischen 1200 und 850 v. Chr. noch vor Ausbildung der frühgriechischen Kultur gegeben; so z.B. der englische Althistoriker Robin Lane Fox (2008/11): "Ilias und Odyssee sind im Wesentlichen Werke der Mündlichkeit, die letzten in einem langen 'Zeitalter der Mündlichkeit'…". Eng damit verbunden waren Martin P. Nilssons Hypothese "The Mycenaen Origin of Greek Mythology" (1932) und der von Milman Parry seit 1928 konstituierte, von seinem Schüler Arthur B. Lord weiter entwickelte Ansatz, dass für frühgriechische Epen eine Vergleichbarkeit mit neueren Phasen mündlicher Epik z.B. auf dem Balkan gegeben sei. Merkels jüngste Ausführungen verstärken meine früheren Bedenken gegen dieses Gesamtkonzept.
In den Jahren 1886 und 1887 fanden sich in Avenches (Schweiz, Kanton Waadt), der ehemaligen römischen Colonia Pia Flavia Constans Emerita Helvetiorum Foederata, mehrere Fragmente einer Grabinschrift aus Marmor, die schon häufiger das Interesse der Forschung geweckt haben, da auf der Grabplatte anscheinend eine kaiserliche Gouvernante, eine educatrix Augusti nostri, genannt wird...
The paper assesses current rising reparations claims for the Maafa/ Maangamizi (‘African holocaust,’ comprising transatlantic slavery, colonialism and neo-colonialism) from two angles. First, it explores the connectivity of reparations and global justice, peace and security. Second, it discusses how the claim is justified in international law. The concept of reparations in international law is also explored, revealing that reparations cannot be limited to financial compensation due to the nature of the damage and international law prescriptions. Comprehensive reparations based in international law require the removal of structures built on centuries of illegal acts and aggression, in the forms of transatlantic slavery, colonialism and neo-colonialism. Reparations must also lead to the restitution of sovereignty to African and indigenous peoples globally. They are indispensable to halt the destruction of the earth as human habitat, caused by the violent European cultural, political, socio-economic system known as apitalism that is rooted in transatlantic slavery.
From reparations for slavery to international racial justice: a critical republican perspective
(2017)
This paper focuses on demands for reparations for colonial slavery and their public reception in France. It argues that this bottom-up, context-sensitive approach to theorising reparations enables us to formulate a critical republican theory of international racial justice. It contrasts the critical republican perspective on reparations with a nation-state centred approach in which reparations activists are accused of threatening the French republic’s sense of homogeneity and unity, thus undermining the national narrative on the French identity. It also rejects the liberal egalitarian perspective, which itself rejects reparations in favour of focusing on present disadvantages. In so doing, this paper illustrates how the notion of non-domination offers a superior way of conceptualising global racial injustices compared to more traditional distributive outlooks.
If Third World women form ‘the bedrock of a certain kind of global exploitation of labour,’ as Chandra Mohanty argues, how can our theoretical definitions of exploitation account for this? This paper argues that liberal theories of exploitation are insufficiently structural and that Marxian accounts are structural but are insufficiently intersectional. What we need is a structural and intersectional definition of exploitation in order to correctly identify global structural exploitation. Drawing on feminist, critical race/post-colonial and post-Fordist critiques of the Marxist definition and the intersectional accounts of Maria Mies and Iris Marion Young, this paper offers the following definition of structural exploitation: structural exploitation refers to the forced transfer of the productive powers of groups positioned as socially inferior to the advantage of groups positioned as socially superior. Global structural exploitation is a form of global injustice because it is a form of oppression.
Many theories of global distributive justice are based on the assumption that all humans hold common ownership of the earth. As the earth is finite and our actions interconnect, we need a system of justice that regulates the potential appropriation of the common earth to ensure fairness. According to these theories, imposing limits and distributive obligations on private and public property arrangements may be the best mechanism for governing common ownership. We present a critique of the assumption that this issue can be solved within the private–public property regime, arguing that the boundaries of this regime should not be taken for granted and that the growing literature on the democratic commons movement suggests how this can be accomplished. We consider that, if the earth is defined as a common, the private– public property paradigm must be open to questioning, and democratic commoners’ activities should be considered.
All cosmopolitan approaches to global distributive justice are premised on the idea that humans are the primary units of moral concern. In this paper, I argue that neither relational nor non-relational cosmopolitans can unquestioningly assume the moral primacy of humans. Furthermore, I argue that, by their own lights, cosmopolitans must extend the scope of justice to most, if not all, nonhuman animals. To demonstrate that cosmopolitans cannot simply ‘add nonhuman animals and stir,’ I examine the cosmopolitan position developed by Martha Nussbaum in Frontiers of Justice. I argue that while Nussbaum explicitly includes nonhuman animals within the scope of justice, her account is marked by an unjustifiable anthropocentric bias. I ultimately conclude that we must radically reconceptualise the primary unit of cosmopolitan moral concern to encompass most, if not all, sentient animals.
Excessive neutrophil activation accompanied by delayed apoptotic cell death in inflammatory conditions causes progressive damage of cells and tissues, leading to life-threatening multiple organ dysfunction syndrome. Previous work suggested that circulating serum factors during inflammation are critically involved in the suppression of neutrophil cell death although the identity of these antiapoptotic mediators remained elusive. In this study, we identified the acute phase protein α-1 Antitrypsin (AAT) as a potent suppressor of staurosporine (STS)-induced apoptosis in human neutrophils through a mechanism implicating caspases-independent pathways. We show here that serum levels of AAT, potentially in part released by stimulated neutrophils, are markedly elevated in major trauma patients suffering from systemic inflammatory response syndrome (SIRS). Notably, AAT depletion from serum increased sensitivity of human neutrophils for STS-induced cell death. In fact, AAT was demonstrated to confer intrinsic apoptosis resistance by preventing PKC/Akt inactivation and subsequent proteasomal degradation of antiapoptotic Mcl-1 protein in response to STS treatment. Neither MAP kinase ERK1/2 nor caspases were found to be involved in AAT-triggered antiapoptotic pathways in neutrophils. In summary, these results establish a novel pivotal role of circulating AAT in mediating survival by antagonizing the proapoptotic action of the PKC inhibitor STS and should be considered for AAT augmentation therapies in future.
Natural killer (NK) cells are a promising tool for the use in adoptive immunotherapy, since they efficiently recognize and kill tumor cells. In this context, ex vivo cultivation is an attractive option to increase NK cells in numbers and to improve their antitumor potential prior to clinical applications. Consequently, various strategies to generate NK cells for adoptive immunotherapy have been developed. Here, we give an overview of different NK cell cultivation approaches and their impact on shaping the NK cell antitumor activity. So far, the cytokines interleukin (IL)-2, IL-12, IL-15, IL-18, and IL-21 are used to culture and expand NK cells. The selection of the respective cytokine combination is an important factor that directly affects NK cell maturation, proliferation, survival, distribution of NK cell subpopulations, activation, and function in terms of cytokine production and cytotoxic potential. Importantly, cytokines can upregulate the expression of certain activating receptors on NK cells, thereby increasing their responsiveness against tumor cells that express the corresponding ligands. Apart from using cytokines, cocultivation with autologous accessory non-NK cells or addition of growth-inactivated feeder cells are approaches for NK cell cultivation with pronounced effects on NK cell activation and expansion. Furthermore, ex vivo cultivation was reported to prime NK cells for the killing of tumor cells that were previously resistant to NK cell attack. In general, NK cells become frequently dysfunctional in cancer patients, for instance, by downregulation of NK cell activating receptors, disabling them in their antitumor response. In such scenario, ex vivo cultivation can be helpful to arm NK cells with enhanced antitumor properties to overcome immunosuppression. In this review, we summarize the current knowledge on NK cell modulation by different ex vivo cultivation strategies focused on increasing NK cytotoxicity for clinical application in malignant diseases. Moreover, we critically discuss the technical and regulatory aspects and challenges underlying NK cell based therapeutic approaches in the clinics.
Background and Purpose: This review aims to provide a comprehensive overview of the literature and elucidate open questions for future clinical trials concerning diagnostics and treatment modalities for cervical cancer of unknown primary (CUP).
Methods: A literature search for head and neck CUP was performed with focus on diagnostics and therapies as well as molecular markers.
Results: High level evidence on CUP is limited. However, it seems that a consensus exists regarding the optimal diagnostic procedures. The correct implementation of biomarkers for patient stratification and treatment remains unclear. An even greater dispute dominates about the ideal treatment with publications ranging from sole surgery to surgery with postoperative bilateral radiotherapy with inclusion of the mucosa and concomitant chemotherapy.
Conclusions: Cervical CUP represents a very heterogeneous malignant disease. On this account many aspects concerning treatment optimization remain unclear, despite a considerable number of publications in the past. Future research in form of prospective randomized trials is needed in order to better define patient stratification criteria and enable tailored treatment.
We explored the characteristics and motivations of people who, having obtained their genetic or genomic data from Direct-To-Consumer genetic testing (DTC-GT) companies, voluntarily decide to share them on the publicly accessible web platform openSNP. The study is the first attempt to describe open data sharing activities undertaken by individuals without institutional oversight. In the paper we provide a detailed overview of the distribution of the demographic characteristics and motivations of people engaged in genetic or genomic open data sharing. The geographical distribution of the respondents showed the USA as dominant. There was no significant gender divide, the age distribution was broad, educational background varied and respondents with and without children were equally represented. Health, even though prominent, was not the respondents’ primary or only motivation to be tested. As to their motivations to openly share their data, 86.05% indicated wanting to learn about themselves as relevant, followed by contributing to the advancement of medical research (80.30%), improving the predictability of genetic testing (76.02%) and considering it fun to explore genotype and phenotype data (75.51%). Whereas most respondents were well aware of the privacy risks of their involvement in open genetic data sharing and considered the possibility of direct, personal repercussions troubling, they estimated the risk of this happening to be negligible. Our findings highlight the diversity of DTC-GT consumers who decide to openly share their data. Instead of focusing exclusively on health-related aspects of genetic testing and data sharing, our study emphasizes the importance of taking into account benefits and risks that stretch beyond the health spectrum. Our results thus lend further support to the call for a broader and multi-faceted conceptualization of genomic utility.
In evidence-based weight-loss programs weight regain is common after an initial weight reduction. Eating slowly significantly lowers meal energy intake and hunger ratings. Despite this knowledge, obese individuals do not implement this behaviour. We, thus tested the hypothesis of changing eating behaviour with an intra-oral medical device leading to constant weight reduction in overweight and obesity.
Six obese patients (6 men, age 56 ± 14, BMI 29 ± 2 kg / m2) with increased CVRF profile were included in this prospective study. All patients had been treated for obesity during the last 10 years in a single centre and had at least 3 frustrate evidence-based diets. Patients received a novel non-invasive intra-oral medical device to slow eating time. Further advice included not to count calories, to avoid any other form of diet, to take their time with their meals, and to eat whatever they liked.
This device was used only during meals for the first 4 to 8 weeks for a total of 88 [20–160] hours. Follow-up period was 23 [15–38] months. During this period, patients lost 11% [5–20%] (p<0.001) of their initial weight. At 12 months, all patients had lost >5%, and 67% (4/6) achieved a >10% bodyweight loss. In the course of the study, altered eating patterns were observed. There were no complications with the medical device. Of note, all patients continued to lose weight after the initial intervention period (p<0.001) and none of them had weight regain.
With this medical device, overweight and obese patients with a history of previously frustrating attempts to lose weight achieved a significant and sustained weight loss over two years. These results warrant the ongoing prospective randomised controlled trial to prove concept and mechanism of action.
Decreased STARD10 expression is associated with defective insulin secretion in humans and mice
(2017)
Genetic variants near ARAP1 (CENTD2) and STARD10 influence type 2 diabetes (T2D) risk. The risk alleles impair glucose-induced insulin secretion and, paradoxically but characteristically, are associated with decreased proinsulin:insulin ratios, indicating improved proinsulin conversion. Neither the identity of the causal variants nor the gene(s) through which risk is conferred have been firmly established. Whereas ARAP1 encodes a GTPase activating protein, STARD10 is a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer protein family. By integrating genetic fine-mapping and epigenomic annotation data and performing promoter-reporter and chromatin conformational capture (3C) studies in β cell lines, we localize the causal variant(s) at this locus to a 5 kb region that overlaps a stretch-enhancer active in islets. This region contains several highly correlated T2D-risk variants, including the rs140130268 indel. Expression QTL analysis of islet transcriptomes from three independent subject groups demonstrated that T2D-risk allele carriers displayed reduced levels of STARD10 mRNA, with no concomitant change in ARAP1 mRNA levels. Correspondingly, β-cell-selective deletion of StarD10 in mice led to impaired glucose-stimulated Ca2+ dynamics and insulin secretion and recapitulated the pattern of improved proinsulin processing observed at the human GWAS signal. Conversely, overexpression of StarD10 in the adult β cell improved glucose tolerance in high fat-fed animals. In contrast, manipulation of Arap1 in β cells had no impact on insulin secretion or proinsulin conversion in mice. This convergence of human and murine data provides compelling evidence that the T2D risk associated with variation at this locus is mediated through reduction in STARD10 expression in the β cell.
Rationale: The AMP-activated protein kinase (AMPK) is stimulated by hypoxia, and although the AMPKα1 catalytic subunit has been implicated in angiogenesis, little is known about the role played by the AMPKα2 subunit in vascular repair.
Objective: To determine the role of the AMPKα2 subunit in vascular repair.
Methods and Results: Recovery of blood flow after femoral artery ligation was impaired (>80%) in AMPKα2-/- versus wild-type mice, a phenotype reproduced in mice lacking AMPKα2 in myeloid cells (AMPKα2ΔMC). Three days after ligation, neutrophil infiltration into ischemic limbs of AMPKα2ΔMC mice was lower than that in wild-type mice despite being higher after 24 hours. Neutrophil survival in ischemic tissue is required to attract monocytes that contribute to the angiogenic response. Indeed, apoptosis was increased in hypoxic neutrophils from AMPKα2ΔMC mice, fewer monocytes were recruited, and gene array analysis revealed attenuated expression of proangiogenic proteins in ischemic AMPKα2ΔMC hindlimbs. Many angiogenic growth factors are regulated by hypoxia-inducible factor, and hypoxia-inducible factor-1α induction was attenuated in AMPKα2-deficient cells and accompanied by its enhanced hydroxylation. Also, fewer proteins were regulated by hypoxia in neutrophils from AMPKα2ΔMC mice. Mechanistically, isocitrate dehydrogenase expression and the production of α-ketoglutarate, which negatively regulate hypoxia-inducible factor-1α stability, were attenuated in neutrophils from wild-type mice but remained elevated in cells from AMPKα2ΔMC mice.
Conclusions: AMPKα2 regulates α-ketoglutarate generation, hypoxia-inducible factor-1α stability, and neutrophil survival, which in turn determine further myeloid cell recruitment and repair potential. The activation of AMPKα2 in neutrophils is a decisive event in the initiation of vascular repair after ischemia.
MRI-detection rate and incidence of lumbar bleeding sources in 190 patients with non-aneurysmal SAH
(2017)
Background: Up to 15% of all spontaneous subarachnoid hemorrhages (SAH) have a non-aneurysmal SAH (NASAH). The evaluation of SAH patients with negative digital subtraction angiography (DSA) is sometimes a diagnostic challenge. Our goal in this study was to reassess the yield of standard MR-imaging of the complete spinal axis to rule out spinal bleeding sources in patients with NASAH.
Methods: We retrospectively analyzed the spinal MRI findings in 190 patients with spontaneous NASAH, containing perimesencephalic (PM) and non-perimesencephalic (NPM) SAH, diagnosed by computer tomography (CT) and/or lumbar puncture (LP), and negative 2nd DSA.
Results: 190 NASAH patients were included in the study, divided into PM-SAH (n = 87; 46%) and NPM-SAH (n = 103; 54%). Overall, 23 (22%) patients had a CT negative SAH, diagnosed by positive LP. MR-imaging of the spinal axis detected two patients with lumbar ependymoma (n = 2; 1,05%). Both patients complained of radicular sciatic pain. The detection rate raised up to 25%, if only patients with radicular sciatic pain received an MRI.
Conclusion: Routine radiological investigation of the complete spinal axis in NASAH patients is expensive and can not be recommended for standard procedure. However, patients with clinical signs of low-back/sciatic pain should be worked up for a spinal pathology.
Human beings are assumed to possess an approximate number system (ANS) dedicated to extracting and representing approximate numerical magnitude information. The ANS is assumed to be fundamental to arithmetic learning and has been shown to be associated with arithmetic performance. It is, however, still a matter of debate whether better arithmetic skills are reflected in the ANS. To address this issue, Chinese and German adults were compared regarding their performance in simple arithmetic tasks and in a non-symbolic numerical magnitude comparison task. Chinese participants showed a better performance in solving simple arithmetic tasks and faster reaction times in the non-symbolic numerical magnitude comparison task without making more errors than their German peers. These differences in performance could not be ascribed to differences in general cognitive abilities. Better arithmetic skills were thus found to be accompanied by a higher speed of retrieving non-symbolic numerical magnitude knowledge but not by a higher precision of non-symbolic numerical magnitude representations. The group difference in the speed of retrieving non-symbolic numerical magnitude knowledge was fully mediated by the performance in arithmetic tasks, suggesting that arithmetic skills shape non-symbolic numerical magnitude processing skills.
The acidification of the oceans could potentially alter marine plankton communities with consequences for ecosystem functioning. While several studies have investigated effects of ocean acidification on communities using traditional methods, few have used genetic analyses. Here, we use community barcoding to assess the impact of ocean acidification on the composition of a coastal plankton community in a large scale, in situ, long-term mesocosm experiment. High-throughput sequencing resulted in the identification of a wide range of planktonic taxa (Alveolata, Cryptophyta, Haptophyceae, Fungi, Metazoa, Hydrozoa, Rhizaria, Straminipila, Chlorophyta). Analyses based on predicted operational taxonomical units as well as taxonomical compositions revealed no differences between communities in high CO2 mesocosms (~ 760 μatm) and those exposed to present-day CO2 conditions. Observed shifts in the planktonic community composition were mainly related to seasonal changes in temperature and nutrients. Furthermore, based on our investigations, the elevated CO2 did not affect the intraspecific diversity of the most common mesozooplankter, the calanoid copepod Pseudocalanus acuspes. Nevertheless, accompanying studies found temporary effects attributed to a raise in CO2. Differences in taxa composition between the CO2 treatments could, however, only be observed in a specific period of the experiment. Based on our genetic investigations, no compositional long-term shifts of the plankton communities exposed to elevated CO2 conditions were observed. Thus, we conclude that the compositions of planktonic communities, especially those in coastal areas, remain rather unaffected by increased CO2.
Background: Legionella pneumophila (L. pneumophila) is a causative agent of severe pneumonia. It is highly adapted to intracellular replication and manipulates host cell functions like vesicle trafficking and mRNA translation to its own advantage. However, it is still unknown to what extent microRNAs (miRNAs) are involved in the Legionella-host cell interaction.
Methods: WT and MyD88-/- murine bone marrow-derived macrophages (BMM) were infected with L. pneumophila, the transcriptome was analyzed by high throughput qPCR array (microRNAs) and conventional qPCR (mRNAs), and mRNA-miRNA interaction was validated by luciferase assays with 3´-UTR mutations and western blot.
Results: L. pneumophila infection caused a pro-inflammatory reaction and significant miRNA changes in murine macrophages. In MyD88-/- cells, induction of inflammatory markers, such as Ccxl1/Kc, Il6 and miR-146a-5p was reduced. Induction of miR-125a-3p was completely abrogated in MyD88-/- cells. Target prediction analyses revealed N-terminal asparagine amidase 1 (NTAN1), a factor from the n-end rule pathway, to be a putative target of miR-125a-3p. This interaction could be confirmed by luciferase assay and western blot.
Conclusion: Taken together, we characterized the miRNA regulation in L. pneumophila infection with regard to MyD88 signaling and identified NTAN1 as a target of miR-125a-3p. This finding unravels a yet unknown feature of Legionella-host cell interaction, potentially relevant for new treatment options.
Introduction: Preclinical CT-guided radiotherapy platforms are increasingly used but the CT images are characterized by poor soft tissue contrast. The aim of this study was to develop a robust and accurate method of MRI-guided radiotherapy (MR-IGRT) delivery to abdominal targets in the mouse.
Methods: A multimodality cradle was developed for providing subject immobilisation and its performance was evaluated. Whilst CT was still used for dose calculations, target identification was based on MRI. Each step of the radiotherapy planning procedure was validated initially in vitro using BANG gel dosimeters. Subsequently, MR-IGRT of normal adrenal glands with a size-matched collimated beam was performed. Additionally, the SK-N-SH neuroblastoma xenograft model and the transgenic KPC model of pancreatic ductal adenocarcinoma were used to demonstrate the applicability of our methods for the accurate delivery of radiation to CT-invisible abdominal tumours.
Results: The BANG gel phantoms demonstrated a targeting efficiency error of 0.56 ± 0.18 mm. The in vivo stability tests of body motion during MR-IGRT and the associated cradle transfer showed that the residual body movements are within this MR-IGRT targeting error. Accurate MR-IGRT of the normal adrenal glands with a size-matched collimated beam was confirmed by γH2AX staining. Regression in tumour volume was observed almost immediately post MR-IGRT in the neuroblastoma model, further demonstrating accuracy of x-ray delivery. Finally, MR-IGRT in the KPC model facilitated precise contouring and comparison of different treatment plans and radiotherapy dose distributions not only to the intra-abdominal tumour but also to the organs at risk.
Conclusion: This is, to our knowledge, the first study to demonstrate preclinical MR-IGRT in intra-abdominal organs. The proposed MR-IGRT method presents a state-of-the-art solution to enabling robust, accurate and efficient targeting of extracranial organs in the mouse and can operate with a sufficiently high throughput to allow fractionated treatments to be given.
Glial cell line-derived neurotrophic factor (GDNF) is a ligand that activates, through co-receptor GDNF family receptor alpha-1 (GFRα1) and receptor tyrosine kinase “RET”, several signaling pathways crucial in the development and sustainment of multiple neuronal populations. We decided to study whether non-mammalian orthologs of these three proteins have conserved their function: can they activate the human counterparts? Using the baculovirus expression system, we expressed and purified Danio rerio RET, and its binding partners GFRα1 and GDNF, and Drosophila melanogaster RET and two isoforms of co-receptor GDNF receptor-like. Our results report high-level insect cell expression of post-translationally modified and dimerized zebrafish RET and its binding partners. We also found that zebrafish GFRα1 and GDNF are comparably active as mammalian cell-produced ones. We also report the first measurements of the affinity of the complex to RET in solution: at least for zebrafish, the Kd for GFRα1-GDNF binding RET is 5.9 μM. Surprisingly, we also found that zebrafish GDNF as well as zebrafish GFRα1 robustly activated human RET signaling and promoted the survival of cultured mouse dopaminergic neurons with comparable efficiency to mammalian GDNF, unlike E. coli-produced human proteins. These results contradict previous studies suggesting that mammalian GFRα1 and GDNF cannot bind and activate non-mammalian RET and vice versa.
For a chaotic system pairs of initially close-by trajectories become eventually fully uncorrelated on the attracting set. This process of decorrelation can split into an initial exponential decrease and a subsequent diffusive process on the chaotic attractor causing the final loss of predictability. Both processes can be either of the same or of very different time scales. In the latter case the two trajectories linger within a finite but small distance (with respect to the overall extent of the attractor) for exceedingly long times and remain partially predictable. Standard tests for chaos widely use inter-orbital correlations as an indicator. However, testing partially predictable chaos yields mostly ambiguous results, as this type of chaos is characterized by attractors of fractally broadened braids. For a resolution we introduce a novel 0-1 indicator for chaos based on the cross-distance scaling of pairs of initially close trajectories. This test robustly discriminates chaos, including partially predictable chaos, from laminar flow. Additionally using the finite time cross-correlation of pairs of initially close trajectories, we are able to identify laminar flow as well as strong and partially predictable chaos in a 0-1 manner solely from the properties of pairs of trajectories.
Background: The Objective Structured Clinical Examination (OSCE) is increasingly used at medical schools to assess practical competencies. To compare the outcomes of students at different medical schools, we introduced standardized OSCE stations with identical checklists.
Methods: We investigated examiner bias at standardized OSCE stations for knee- and shoulder-joint examinations, which were implemented into the surgical OSCE at five different medical schools. The checklists for the assessment consisted of part A for knowledge and performance of the skill and part B for communication and interaction with the patient. At each medical faculty, one reference examiner also scored independently to the local examiner. The scores from both examiners were compared and analysed for inter-rater reliability and correlation with the level of clinical experience. Possible gender bias was also evaluated.
Results: In part A of the checklist, local examiners graded students higher compared to the reference examiner; in part B of the checklist, there was no trend to the findings. The inter-rater reliability was weak, and the scoring correlated only weakly with the examiner’s level of experience. Female examiners rated generally higher, but male examiners scored significantly higher if the examinee was female.
Conclusions: These findings of examiner effects, even in standardized situations, may influence outcome even when students perform equally well. Examiners need to be made aware of these biases prior to examining.
Parkinson's disease (PD) is a frequent neurodegenerative process in old age. Accumulation and aggregation of the lipid-binding SNARE complex component α-synuclein (SNCA) underlies this vulnerability and defines stages of disease progression. Determinants of SNCA levels and mechanisms of SNCA neurotoxicity have been intensely investigated. In view of the physiological roles of SNCA in blood to modulate vesicle release, we studied blood samples from a new large pedigree with SNCA gene duplication (PARK4 mutation) to identify effects of SNCA gain of function as potential disease biomarkers. Downregulation of complexin 1 (CPLX1) mRNA was correlated with genotype, but the expression of other Parkinson's disease genes was not. In global RNA-seq profiling of blood from presymptomatic PARK4 indviduals, bioinformatics detected significant upregulations for platelet activation, hemostasis, lipoproteins, endocytosis, lysosome, cytokine, Toll-like receptor signaling and extracellular pathways. In PARK4 platelets, stimulus-triggered degranulation was impaired. Strong SPP1, GZMH and PLTP mRNA upregulations were validated in PARK4. When analysing individuals with rapid eye movement sleep behavior disorder, the most specific known prodromal stage of general PD, only blood CPLX1 levels were altered. Validation experiments confirmed an inverse mutual regulation of SNCA and CPLX1 mRNA levels. In the 3′-UTR of the CPLX1 gene we identified a single nucleotide polymorphism that is significantly associated with PD risk. In summary, our data define CPLX1 as a PD risk factor and provide functional insights into the role and regulation of blood SNCA levels. The new blood biomarkers of PARK4 in this Turkish family might become useful for PD prediction.
Patient-reported outcomes (PROs) such as quality of life and work productivity are important for measuring patient's experience. We assessed PROs during and after treatment of hepatitis C virus (HCV) patients.Data were obtained from a phase 3 open label study of sofosbuvir and ribavirin (SOF + RBV) with and without interferon (IFN). Patients completed 4 PRO assessment instruments (SF-36, Functional Assessment of Chronic Illness Therapy-Fatigue, Chronic Liver Disease Questionnaire- HCV, Work Productivity and Activity-Specific Health Problem) before, during, and after treatment.A total of 533 patients with chronic HCV were enrolled; 28.9% treatment-naïve, 23.1% cirrhotic, 219 received IFN + SOF + RBV and 314 received IFN-free SOF + RBV. At baseline, there were no differences in PROs between the IFN-free and IFN-containing treatment arms (all P > 0.05). During treatment, patients receiving IFN + SOF + RBV had a substantial impairment in their PROs (up to -24.4% by treatment week 12, up to -8.3% at week 4 post-treatment). The PRO decrements seen in the SOF + RBV arm were smaller in magnitude (up to -7.1% by treatment week 12), and all returned to baseline or improved by post-treatment week 4. By 12 weeks after treatment cessation, patients who achieved sustained viral response-12 showed some improvement of PRO scores regardless of the regimen (up to +7.1%, P < 0.0001) or previous treatment experience. In multivariate analysis, the use of IFN was independently associated with lower PROs.IFN-based regimens have a profoundly negative impact to PROs. By contrast, the impact of RBV on these PROs is relatively modest. Achieving HCV cure is associated with improvement of most of the PRO scores.
Ocular gene therapy approaches have been developed for a variety of different diseases. In particular, clinical gene therapy trials for RPE65 mutations, X-linked retinoschisis, and choroideremia have been conducted at different centers in recent years, showing that adeno-associated virus (AAV)-mediated gene therapy is safe, but limitations exist as to the therapeutic benefit and long-term duration of the treatment. The technique of vector delivery to retinal cells relies on subretinal injection of the vector solution, causing a transient retinal detachment. Although retinal detachments are known to cause remodeling of retinal neuronal structures as well as significant cell loss, the possible effects of this short-term therapeutic retinal detachment on retinal structure and circuitry have not yet been studied in detail. In this study, retinal morphology and apoptotic status were examined in healthy rat retinas following AAV-mediated gene transfer via subretinal injection with AAV2/5.CMV.d2GFP or sham injection with fluorescein. Outer plexiform layer (OPL) morphology was assessed by immunohistochemical labeling, laser scanning confocal microscopy, and electron microscopy. The number of synaptic contacts in the OPL was quantified after labeling with structural markers. To assess the apoptotic status, inflammatory and pro-apoptotic markers were tested and TUNEL assay for the detection of apoptotic nuclei was performed. Pre- and postsynaptic structures in the OPL, such as synaptic ribbons or horizontal and bipolar cell processes, did not differ in size or shape in injected versus non-injected areas and control retinas. Absolute numbers of synaptic ribbons were not altered. No signs of relevant gliosis were detected. TUNEL labeling of retinal cells did not vary between injected and non-injected areas, and apoptosis-inducing factor was not delocalized to the nucleus in transduced areas. The neuronal circuits in the OPL of healthy rat retinas undergoing AAV-mediated gene transfer were not altered by the temporary retinal detachment caused by subretinal injection, the presence of viral particles, or the expression of green fluorescent protein as a transgene. This observation likely requires further investigations in the dog model for RPE65 deficiency in order to determine the impact of RPE65 transgene expression on diseased retinas in animals and men.
Hyponatremia is the most common and by far underestimated electrolyte disorder in clinical practice. Especially in elderly patients, treatment of symptomatic hyponatremia is challenging. Herein we describe the case of an octogenarian with recurrent symptomatic hyponatremia due to idiopathic syndrome of inappropriate antidiuretic hormone release (SIADH). Fluid restriction was insufficient to prevent repeated episodes of hyponatremia complicated by falls and coma. After introduction of a low-dose therapy with tolvaptan, serum sodium levels as well as the clinical condition were stable under vaptan therapy, without any relapse for more than six years now. This case demonstrates that long-term tolvaptan treatment for hyponatremia caused by SIADH is safe and well tolerated, even in the elderly.
Systemic lupus erythematosus (SLE) is a chronic disease characterized by progressive tissue damage. In recent decades, novel treatments have greatly extended the life span of SLE patients. This creates a high demand for identifying the overarching symptoms associated with SLE and developing therapies that improve their life quality under chronic care. We hypothesized that SLE patients would present dysphonic symptoms. Given that voice disorders can reduce life quality, identifying a potential SLE-related dysphonia could be relevant for the appraisal and management of this disease. We measured objective vocal parameters and perceived vocal quality with the GRBAS (Grade, Roughness, Breathiness, Asthenia, Strain) scale in SLE patients and compared them to matched healthy controls. SLE patients also filled a questionnaire reporting perceived vocal deficits. SLE patients had significantly lower vocal intensity and harmonics to noise ratio, as well as increased jitter and shimmer. All subjective parameters of the GRBAS scale were significantly abnormal in SLE patients. Additionally, the vast majority of SLE patients (29/36) reported at least one perceived vocal deficit, with the most prevalent deficits being vocal fatigue (19/36) and hoarseness (17/36). Self-reported voice deficits were highly correlated with altered GRBAS scores. Additionally, tissue damage scores in different organ systems correlated with dysphonic symptoms, suggesting that some features of SLE-related dysphonia are due to tissue damage. Our results show that a large fraction of SLE patients suffers from perceivable dysphonia and may benefit from voice therapy in order to improve quality of life.
Bears are iconic mammals with a complex evolutionary history. Natural bear hybrids and studies of few nuclear genes indicate that gene flow among bears may be more common than expected and not limited to polar and brown bears. Here we present a genome analysis of the bear family with representatives of all living species. Phylogenomic analyses of 869 mega base pairs divided into 18,621 genome fragments yielded a well-resolved coalescent species tree despite signals for extensive gene flow across species. However, genome analyses using different statistical methods show that gene flow is not limited to closely related species pairs. Strong ancestral gene flow between the Asiatic black bear and the ancestor to polar, brown and American black bear explains uncertainties in reconstructing the bear phylogeny. Gene flow across the bear clade may be mediated by intermediate species such as the geographically wide-spread brown bears leading to large amounts of phylogenetic conflict. Genome-scale analyses lead to a more complete understanding of complex evolutionary processes. Evidence for extensive inter-specific gene flow, found also in other animal species, necessitates shifting the attention from speciation processes achieving genome-wide reproductive isolation to the selective processes that maintain species divergence in the face of gene flow.
The role of endogenous melatonin for the control of the circadian system under entrained conditions and for the determination of the chronotype is still poorly understood. Mice with deletions in the melatoninergic system (melatonin deficiency or the lack of melatonin receptors, respectively) do not display any obvious defects in either their spontaneous (circadian) or entrained (diurnal) rhythmic behavior. However, there are effects that can be detected by analyzing the periodicity of the locomotor behaviors in some detail. We found that melatonin-deficient mice (C57Bl), as well as melatonin-proficient C3H mice that lack the melatonin receptors (MT) 1 and 2 (C3H MT1,2 KO), reproduce their diurnal locomotor rhythms with significantly less accuracy than mice with an intact melatoninergic system. However, their respective chronotypes remained unaltered. These results show that one function of the endogenous melatoninergic system might be to stabilize internal rhythms under conditions of a steady entrainment, while it has no effects on the chronotype.
In its soluble form, the extracellular matrix proteoglycan biglycan triggers the synthesis of the macrophage chemoattractants, chemokine (C-C motif) ligand CCL2 and CCL5 through selective utilization of Toll-like receptors (TLRs) and their adaptor molecules. However, the respective downstream signaling events resulting in biglycan-induced CCL2 and CCL5 production have not yet been defined. Here, we show that biglycan stimulates the production and activation of sphingosine kinase 1 (SphK1) in a TLR4- and Toll/interleukin (IL)-1R domain-containing adaptor inducing interferon (IFN)-β (TRIF)-dependent manner in murine primary macrophages. We provide genetic and pharmacological proof that SphK1 is a crucial downstream mediator of biglycan-triggered CCL2 and CCL5 mRNA and protein expression. This is selectively driven by biglycan/SphK1-dependent phosphorylation of the nuclear factor NF-κB p65 subunit, extracellular signal-regulated kinase (Erk)1/2 and p38 mitogen-activated protein kinases. Importantly, in vivo overexpression of soluble biglycan causes Sphk1-dependent enhancement of renal CCL2 and CCL5 and macrophage recruitment into the kidney. Our findings describe the crosstalk between biglycan- and SphK1-driven extracellular matrix- and lipid-signaling. Thus, SphK1 may represent a new target for therapeutic intervention in biglycan-evoked inflammatory conditions.
Background: In oldest-old patients (>80), few trials showed efficacy of treating hypertension and they included mostly the healthiest elderly. The resulting lack of knowledge has led to inconsistent guidelines, mainly based on systolic blood pressure (SBP), cardiovascular disease (CVD) but not on frailty despite the high prevalence in oldest-old. This may lead to variation how General Practitioners (GPs) treat hypertension. Our aim was to investigate treatment variation of GPs in oldest-olds across countries and to identify the role of frailty in that decision.
Methods: Using a survey, we compared treatment decisions in cases of oldest-old varying in SBP, CVD, and frailty. GPs were asked if they would start antihypertensive treatment in each case. In 2016, we invited GPs in Europe, Brazil, Israel, and New Zealand. We compared the percentage of cases that would be treated per countries. A logistic mixed-effects model was used to derive odds ratio (OR) for frailty with 95% confidence intervals (CI), adjusted for SBP, CVD, and GP characteristics (sex, location and prevalence of oldest-old per GP office, and years of experience). The mixed-effects model was used to account for the multiple assessments per GP.
Results: The 29 countries yielded 2543 participating GPs: 52% were female, 51% located in a city, 71% reported a high prevalence of oldest-old in their offices, 38% and had >20 years of experience. Across countries, considerable variation was found in the decision to start antihypertensive treatment in the oldest-old ranging from 34 to 88%. In 24/29 (83%) countries, frailty was associated with GPs’ decision not to start treatment even after adjustment for SBP, CVD, and GP characteristics (OR 0.53, 95%CI 0.48–0.59; ORs per country 0.11–1.78).
Conclusions: Across countries, we found considerable variation in starting antihypertensive medication in oldest-old. The frail oldest-old had an odds ratio of 0.53 of receiving antihypertensive treatment. Future hypertension trials should also include frail patients to acquire evidence on the efficacy of antihypertensive treatment in oldest-old patients with frailty, with the aim to get evidence-based data for clinical decision-making.
Drug induced liver injury (DILI) is a potentially serious adverse reaction in a few susceptible individuals under therapy by various drugs. Health care professionals facing DILI are confronted with a wealth of drug-unrelated liver diseases with high incidence and prevalence rates, which can confound the DILI diagnosis. Searching for alternative causes is a key element of RUCAM (Roussel Uclaf Causality Assessment Method) to assess rigorously causality in suspected DILI cases. Diagnostic biomarkers as blood tests would be a great help to clinicians, regulators, and pharmaceutical industry would be more comfortable if, in addition to RUCAM, causality of DILI can be confirmed. High specificity and sensitivity are required for any diagnostic biomarker. Although some risk factors are available to evaluate liver safety of drugs in patients, no valid diagnostic or prognostic biomarker exists currently for idiosyncratic DILI when a liver injury occurred. Identifying a biomarker in idiosyncratic DILI requires detailed knowledge of cellular and biochemical disturbances leading to apoptosis or cell necrosis and causing leakage of specific products in blood. As idiosyncratic DILI is typically a human disease and hardly reproducible in animals, pathogenetic events and resulting possible biomarkers remain largely undisclosed. Potential new diagnostic biomarkers should be evaluated in patients with DILI and RUCAM-based established causality. In conclusion, causality assessment in cases of suspected idiosyncratic DILI is still best achieved using RUCAM since specific biomarkers as diagnostic blood tests that could enhance RUCAM results are not yet available.
Gallbladder cancer (GBC) is a lethal cancer with poor prognosis associated with high invasiveness and poor response to chemotherapy and radiotherapy. New therapeutic approaches are urgently needed in order to improve survival and response rates of GBC patients. We screened 130 small molecule inhibitors on a panel of seven GBC cell lines and identified the HSP90 inhibitor 17-AAG as one of the most potent inhibitory drugs across the different lines. We tested the antitumor efficacy of 17-AAG and geldanamycin (GA) in vitro and in a subcutaneous preclinical tumor model NOD-SCID mice. We also evaluated the expression of HSP90 by immunohistochemistry in human GBC tumors.
In vitro assays showed that 17-AAG and GA significantly reduced the expression of HSP90 target proteins, including EGFR, AKT, phospho-AKT, Cyclin B1, phospho-ERK and Cyclin D1. These molecular changes were consistent with reduced cell viability and cell migration and promotion of G2/M cell cycle arrest and apoptosis observed in our in vitro studies.
In vivo, 17-AAG showed efficacy in reducing subcutaneous tumors size, exhibiting a 69.6% reduction in tumor size in the treatment group compared to control mice (p < 0.05).
The HSP90 immunohistochemical staining was seen in 182/209 cases of GBC (87%) and it was strongly expressed in 70 cases (33%), moderately in 58 cases (28%), and weakly in 54 cases (26%).
Our pre-clinical observations strongly suggest that the inhibition of HSP90 function by HSP90 inhibitors is a promising therapeutic strategy for gallbladder cancer that may benefit from new HSP90 inhibitors currently in development.
The detailed biophysical mechanisms through which transcranial magnetic stimulation (TMS) activates cortical circuits are still not fully understood. Here we present a multi-scale computational model to describe and explain the activation of different pyramidal cell types in motor cortex due to TMS. Our model determines precise electric fields based on an individual head model derived from magnetic resonance imaging and calculates how these electric fields activate morphologically detailed models of different neuron types. We predict neural activation patterns for different coil orientations consistent with experimental findings. Beyond this, our model allows us to calculate activation thresholds for individual neurons and precise initiation sites of individual action potentials on the neurons’ complex morphologies. Specifically, our model predicts that cortical layer 3 pyramidal neurons are generally easier to stimulate than layer 5 pyramidal neurons, thereby explaining the lower stimulation thresholds observed for I-waves compared to D-waves. It also shows differences in the regions of activated cortical layer 5 and layer 3 pyramidal cells depending on coil orientation. Finally, it predicts that under standard stimulation conditions, action potentials are mostly generated at the axon initial segment of cortical pyramidal cells, with a much less important activation site being the part of a layer 5 pyramidal cell axon where it crosses the boundary between grey matter and white matter. In conclusion, our computational model offers a detailed account of the mechanisms through which TMS activates different cortical pyramidal cell types, paving the way for more targeted application of TMS based on individual brain morphology in clinical and basic research settings.
Massive global spread of multidrug-resistant (MDR) Salmonella spp. expressing extended-spectrum beta-lactamase (ESBL) and additional resistance to fluoroquinolones has often been attributed to high international mobility as well as excessive use of oral antibiotics in livestock farming. However, MDR Salmonella spp. have not been mentioned as a widespread pathogen in clinical settings so far. We demonstrate the case of a 25-year-old male with primary sclerosing cholangitis who tested positive for MDR Salmonella enterica serotype Choleraesuis expressing ESBL and fluoroquinolone resistance. The pathogen was supposedly acquired during a trip to Thailand, causing severe fever, cholangitis and pancreatitis. To our knowledge, this is the first report of Salmonella enterica serotype Choleraesuis in Europe expressing such a multidrug resistance pattern. ESBL resistance of Salmonella enterica spp. should be considered in patients with obstructive biliary tract pathology and travel history in endemic countries.
The release of RNA-containing extracellular vesicles (EV) into the extracellular milieu has been demonstrated in a multitude of different in vitro cell systems and in a variety of body fluids. RNA-containing EV are in the limelight for their capacity to communicate genetically encoded messages to other cells, their suitability as candidate biomarkers for diseases, and their use as therapeutic agents. Although EV-RNA has attracted enormous interest from basic researchers, clinicians, and industry, we currently have limited knowledge on which mechanisms drive and regulate RNA incorporation into EV and on how RNA-encoded messages affect signalling processes in EV-targeted cells. Moreover, EV-RNA research faces various technical challenges, such as standardisation of EV isolation methods, optimisation of methodologies to isolate and characterise minute quantities of RNA found in EV, and development of approaches to demonstrate functional transfer of EV-RNA in vivo. These topics were discussed at the 2015 EV-RNA workshop of the International Society for Extracellular Vesicles. This position paper was written by the participants of the workshop not only to give an overview of the current state of knowledge in the field, but also to clarify that our incomplete knowledge – of the nature of EV(-RNA)s and of how to effectively and reliably study them – currently prohibits the implementation of gold standards in EV-RNA research. In addition, this paper creates awareness of possibilities and limitations of currently used strategies to investigate EV-RNA and calls for caution in interpretation of the obtained data.
Rhabdomyosarcoma (RMS), the most common cancer of connective tissues in pediatrics, is often resistant to conventional therapies. One underlying mechanism of this resistance is the overexpression of Inhibitor of Apoptosis (IAP) proteins, leading to a dysfunctional cell death program within tumor cells. Smac mimetics (SM) are small molecules that can reactivate the cell death program by antagonizing IAP proteins and thereby compensating their overexpression. Here, we report that SM sensitize two RMS cell lines (RD and RH30) toward natural killer (NK) cell-mediated killing on the one hand, and increase the cytotoxic potential of NK cells on the other. The SM-induced sensitization of RH30 cells toward NK cell-mediated killing is significantly reduced through blocking tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on NK cells prior to coculture. In addition, the presence of zVAD.fmk, a pancaspase inhibitor, rescues tumor cells from the increase in killing, indicating an apoptosis-dependent cell death. On the NK cell side, the presence of SM in addition to IL-2 during the ex vivo expansion leads to an increase in their cytotoxic activity against RH30 cells. This effect is mainly TNFα-dependent and partially mediated by NK cell activation, which is associated with transcriptional upregulation of NF-κB target genes such as IκBα and RelB. Taken together, our findings implicate that SM represent a novel double-hit strategy, sensitizing tumor and activating NK cells with one single drug.
Current anti-epileptic drugs (AEDs) act on a limited set of neuronal targets, are ineffective in a third of patients with epilepsy, and do not show disease-modifying properties. MicroRNAs are small noncoding RNAs that regulate levels of proteins by post-transcriptional control of mRNA stability and translation. MicroRNA-134 is involved in controlling neuronal microstructure and brain excitability and previous studies showed that intracerebroventricular injections of locked nucleic acid (LNA), cholesterol-tagged antagomirs targeting microRNA-134 (Ant-134) reduced evoked and spontaneous seizures in mouse models of status epilepticus. Translation of these findings would benefit from evidence of efficacy in non-status epilepticus models and validation in another species. Here, we report that electrographic seizures and convulsive behavior are strongly reduced in adult mice pre-treated with Ant-134 in the pentylenetetrazol model. Pre-treatment with Ant-134 did not affect the severity of status epilepticus induced by perforant pathway stimulation in adult rats, a toxin-free model of acquired epilepsy. Nevertheless, Ant-134 post-treatment reduced the number of rats developing spontaneous seizures by 86% in the perforant pathway stimulation model and Ant-134 delayed epileptiform activity in a rat ex vivo hippocampal slice model. The potent anticonvulsant effects of Ant-134 in multiple models may encourage pre-clinical development of this approach to epilepsy therapy.
Borrelia (B.) miyamotoi, an emerging tick-borne relapsing fever spirochete, resists complement-mediated killing. To decipher the molecular principles of immune evasion, we sought to identify determinants contributing to complement resistance. Employing bioinformatics, we identified a gene encoding for a putative Factor H-binding protein, termed CbiA (complement binding and inhibitory protein A). Functional analyses revealed that CbiA interacted with complement regulator Factor H (FH), C3, C3b, C4b, C5, and C9. Upon binding to CbiA, FH retained its cofactor activity for Factor I-mediated inactivation of C3b. The Factor H-binding site within CbiA was mapped to domain 20 whereby the C-terminus of CbiA was involved in FH binding. Additionally, CbiA directly inhibited the activation of the classical pathway and the assembly of the terminal complement complex. Of importance, CbiA displayed inhibitory activity when ectopically produced in serum-sensitive B. garinii G1, rendering this surrogate strain resistant to human serum. In addition, long-term in vitro cultivation lead to an incremental loss of the cbiA gene accompanied by an increase in serum susceptibility. In conclusion, our data revealed a dual strategy of B. miyamotoi to efficiently evade complement via CbiA, which possesses complement binding and inhibitory activities.
In healthy older adults, resveratrol supplementation has been shown to improve long-term glucose control, resting-state functional connectivity (RSFC) of the hippocampus, and memory function. Here, we aimed to investigate if these beneficial effects extend to individuals at high-risk for dementia, i.e., patients with mild cognitive impairment (MCI). In a randomized, double-blind interventional study, 40 well-characterized patients with MCI (21 females; 50–80 years) completed 26 weeks of resveratrol (200 mg/d; n = 18) or placebo (1,015 mg/d olive oil; n = 22) intake. Serum levels of glucose, glycated hemoglobin A1c and insulin were determined before and after intervention. Moreover, cerebral magnetic resonance imaging (MRI) (3T) (n = 14 vs. 16) was conducted to analyze hippocampus volume, microstructure and RSFC, and neuropsychological testing was conducted to assess learning and memory (primary endpoint) at both time points. In comparison to the control group, resveratrol supplementation resulted in lower glycated hemoglobin A1c concentration with a moderate effect size (ANOVARM p = 0.059, Cohen's d = 0.66), higher RSFC between right anterior hippocampus and right angular cortex (p < 0.001), and led to a moderate preservation of left anterior hippocampus volume (ANOVARM p = 0.061, Cohen's d = 0.68). No significant differences in memory performance emerged between groups. This proof-of-concept study indicates for the first-time that resveratrol intake may reduce glycated hemoglobin A1c, preserves hippocampus volume, and improves hippocampus RSFC in at-risk patients for dementia. Larger trials with longer intervention time should now determine if these benefits can be validated and extended to cognitive function.
Retinal OFF bipolar cells show distinct connectivity patterns with photoreceptors in the wild-type mouse retina. Some types are cone-specific while others penetrate further through the outer plexiform layer (OPL) to contact rods in addition to cones. To explore dendritic stratification of OFF bipolar cells in the absence of rods, we made use of the ‘cone-full’ Nrl-/- mouse retina in which all photoreceptor precursor cells commit to a cone fate including those which would have become rods in wild-type retinas. The dendritic distribution of OFF bipolar cell types was investigated by confocal and electron microscopic imaging of immunolabeled tissue sections. The cells’ dendrites formed basal contacts with cone terminals and expressed the corresponding glutamate receptor subunits at those sites, indicating putative synapses. All of the four analyzed cell populations showed distinctive patterns of vertical dendritic invasion through the OPL. This disparate behavior of dendritic extension in an environment containing only cone terminals demonstrates type-dependent specificity for dendritic outgrowth in OFF bipolar cells: rod terminals are not required for inducing dendritic extension into distal areas of the OPL.
Processes shaping the African Guineo-Congolian rain forest, especially in the West African part, are not well understood. Recent molecular studies, based mainly on forest tree species, confirmed the previously proposed division of the western African Guineo-Congolian rain forest into Upper Guinea (UG) and Lower Guinea (LG) separated by the Dahomey Gap (DG). Here we studied nine populations in the area of the DG and the borders of LG and UG of the widespread liana species, Chasmanthera dependens (Menispermaceae) by amplified fragment length polymorphism (AFLP), a chloroplast DNA sequence marker, and modelled the distribution based on current as well as paleoclimatic data (Holocene Climate Optimum, ca. 6 kyr BP and Last Glacial Maximum, ca. 22 kyr BP). Current population genetic structure and geographical pattern of cpDNA was related to present as well as historical modelled distributions. Results from this study show that past historical factors played an important role in shaping the distribution of C. dependens across West Africa. The Cameroon Volcanic Line seems to represent a barrier for gene flow in the present as well as in the past. Distribution modelling proposed refugia in the Dahomey Gap, supported also by higher genetic diversity. This is in contrast with the phylogeographic patterns observed in several rainforest tree species and could be explained by either diverging or more relaxed ecological requirements of this liana species.
The effect-response framework states that plant functional traits link the abiotic environment to ecosystem functioning. One ecosystem property is the body size of the animals living in the system, which is assumed to depend on temperature or resource availability, among others. For primary consumers, resource availability may directly be related to plant traits, while for secondary consumers the relationship is indirect. We used plant traits to describe resource availability along an elevational gradient on Mount Kilimanjaro, Tanzania. Using structural equation models, we determined the response of plant traits to changes in precipitation, temperature and disturbance with and assessed whether abiotic conditions or community-weighted means of plant traits are stronger predictors of the mean size of bees, moths, frugivorous birds, and insectivorous birds. Traits indicating tissue density and nutrient content strongly responded to variations in precipitation, temperature and disturbance. They had direct effects on pollination and fruit traits. However, the average body sizes of the animal groups considered could only be explained by temperature and habitat structure, not by plant traits. Our results demonstrate a strong link between traits and the abiotic environment, but suggest that temperature is the most relevant predictor of mean animal body size. Community-weighted means of plant traits and body sizes appear unsuitable to capture the complexity of plant-animal interactions.
Clustering of cardiovascular risk factors and carotid intima-media thickness : the USE-IMT study
(2017)
Background: The relation of a single risk factor with atherosclerosis is established. Clinically we know of risk factor clustering within individuals. Yet, studies into the magnitude of the relation of risk factor clusters with atherosclerosis are limited. Here, we assessed that relation.
Methods: Individual participant data from 14 cohorts, involving 59,025 individuals were used in this cross-sectional analysis. We made 15 clusters of four risk factors (current smoking, overweight, elevated blood pressure, elevated total cholesterol). Multilevel age and sex adjusted linear regression models were applied to estimate mean differences in common carotid intima-media thickness (CIMT) between clusters using those without any of the four risk factors as reference group.
Results: Compared to the reference, those with 1, 2, 3 or 4 risk factors had a significantly higher common CIMT: mean difference of 0.026 mm, 0.052 mm, 0.074 mm and 0.114 mm, respectively. These findings were the same in men and in women, and across ethnic groups. Within each risk factor cluster (1, 2, 3 risk factors), groups with elevated blood pressure had the largest CIMT and those with elevated cholesterol the lowest CIMT, a pattern similar for men and women.
Conclusion: Clusters of risk factors relate to increased common CIMT in a graded manner, similar in men, women and across race-ethnic groups. Some clusters seemed more atherogenic than others. Our findings support the notion that cardiovascular prevention should focus on sets of risk factors rather than individual levels alone, but may prioritize within clusters.
The widespread application of fertilizers has greatly influenced many processes and properties of agroecosystems, and agricultural fertilization is expected to increase even further in the future. To date, most research on fertilizer impacts has used short-term studies, which may be unrepresentative of long-term responses, thus hindering our capacity to predict long-term impacts. Here, we examined the effects of long-term fertilizer addition on key ecosystem properties in a long-term grassland experiment (Palace Leas Hay Meadow) in which farmyard manure (FYM) and inorganic fertilizer treatments have been applied consistently for 120 years in order to characterize the experimental site more fully and compare ecosystem responses with those observed at other long-term and short-term experiments. FYM inputs increased soil organic carbon (SOC) stocks, hay yield, nutrient availability and acted as a buffer against soil acidification (>pH 5). In contrast, N-containing inorganic fertilizers strongly acidified the soil (<pH 4.5) and increased surface SOC stocks by increasing the C stored in the coarse (2.8 mm-200 μm) and fine (200–50 μm) fractions. Application of N fertilizers also reduced plant species richness and the abundance of forbs and legumes. Overall, our results were broadly consistent with those observed in other very long-term studies (the Park Grass and Steinach Grassland experiments) in that fertilization effects on plant and soil properties appeared to be driven by differences in both nutrient input and changes to soil pH. We also established that the direction of long-term fertilization effects tended to be comparable with short-term experiments, but that their magnitude differed considerably, particularly where ammonium sulphate-induced acidification had occurred. We therefore conclude that short-term studies are unlikely to possess the required timeframe to accurately predict long-term responses, thus necessitating the use of long-term study sites. Such experiments should be strategically established in regions where future fertilizer use is expected to increase rapidly.
Background: Histone lysine demethylases (KDMs) are of interest as drug targets due to their regulatory roles in chromatin organization and their tight associations with diseases including cancer and mental disorders. The first KDM inhibitors for KDM1 have entered clinical trials, and efforts are ongoing to develop potent, selective and cell-active ‘probe’ molecules for this target class. Robust cellular assays to assess the specific engagement of KDM inhibitors in cells as well as their cellular selectivity are a prerequisite for the development of high-quality inhibitors. Here we describe the use of a high-content cellular immunofluorescence assay as a method for demonstrating target engagement in cells.
Results: A panel of assays for the Jumonji C subfamily of KDMs was developed to encompass all major branches of the JmjC phylogenetic tree. These assays compare compound activity against wild-type KDM proteins to a catalytically inactive version of the KDM, in which residues involved in the active-site iron coordination are mutated to inactivate the enzyme activity. These mutants are critical for assessing the specific effect of KDM inhibitors and for revealing indirect effects on histone methylation status. The reported assays make use of ectopically expressed demethylases, and we demonstrate their use to profile several recently identified classes of KDM inhibitors and their structurally matched inactive controls. The generated data correlate well with assay results assessing endogenous KDM inhibition and confirm the selectivity observed in biochemical assays with isolated enzymes. We find that both cellular permeability and competition with 2-oxoglutarate affect the translation of biochemical activity to cellular inhibition.
Conclusions: High-content-based immunofluorescence assays have been established for eight KDM members of the 2-oxoglutarate-dependent oxygenases covering all major branches of the JmjC-KDM phylogenetic tree. The usage of both full-length, wild-type and catalytically inactive mutant ectopically expressed protein, as well as structure-matched inactive control compounds, allowed for detection of nonspecific effects causing changes in histone methylation as a result of compound toxicity. The developed assays offer a histone lysine demethylase family-wide tool for assessing KDM inhibitors for cell activity and on-target efficacy. In addition, the presented data may inform further studies to assess the cell-based activity of histone lysine methylation inhibitors.
The amyloid precursor protein (APP) was discovered in the 1980s as the precursor protein of the amyloid A4 peptide. The amyloid A4 peptide, also known as A-beta (Aβ), is the main constituent of senile plaques implicated in Alzheimer’s disease (AD). In association with the amyloid deposits, increasing impairments in learning and memory as well as the degeneration of neurons especially in the hippocampus formation are hallmarks of the pathogenesis of AD. Within the last decades much effort has been expended into understanding the pathogenesis of AD. However, little is known about the physiological role of APP within the central nervous system (CNS). Allocating APP to the proteome of the highly dynamic presynaptic active zone (PAZ) identified APP as a novel player within this neuronal communication and signaling network. The analysis of the hippocampal PAZ proteome derived from APP-mutant mice demonstrates that APP is tightly embedded in the underlying protein network. Strikingly, APP deletion accounts for major dysregulation within the PAZ proteome network. Ca2+-homeostasis, neurotransmitter release and mitochondrial function are affected and resemble the outcome during the pathogenesis of AD. The observed changes in protein abundance that occur in the absence of APP as well as in AD suggest that APP is a structural and functional regulator within the hippocampal PAZ proteome. Within this review article, we intend to introduce APP as an important player within the hippocampal PAZ proteome and to outline the impact of APP deletion on individual PAZ proteome subcommunities.
Fit to play : posture and seating position analysis with professional musicians - a study protocol
(2017)
Background: Musical performance-associated musculoskeletal disorders (MSD) are a common health problem among professional musicians. Considering the manifold consequences arising for the musicians, they can be seen as a threat for their professional activity. String players are the most affected group of musicians in this matter. Faults in upper body posture while playing the instrument, causing un-ergonomic static strain on the back and unergonomic limp-movements, are a main reason for musculoskeletal disorders and pain syndromes.
Methods: A total of 66 professional musicians, divided into three groups, are measured.
The division is performed by average duration of performance, intensity of daily exercise and professional experience. Video raster stereography, a three-dimensional analysis of the body posture, is used to analyse the instrument-specific posture. Furthermore the pressure distribution during seating is analysed. Measurements are performed because the musician is sitting on varying music chairs differing in structure and/or construction of the seating surface. The measurements take place in habitual seating position as well as during playing the instrument.
Results: To analyse the influence of different chairs, ANOVA for repeated measurements or Friedman-test is used, depending on normality assumptions. Comparison of posture between amateur musicians, students, and professional orchestral musicians is carried out the non-parametric Jonckheere-Terpstra-test.
Conclusions: Our method attempts to give the musicians indications for the right music chair choice by analyzing the chair concepts, so that thereby preemptively MSD can be reduced or prevented.
Three basic elements should be part of researching in contexts where power asymmetries and colonial connotations are relevant (which applies to many, if not the majority of research contexts in conflict studies): a thorough reflexivity of the researcher’s own role and social conditioning, the construction of research as a political act as it intervenes in scientific and political discourse, and the fact that (especially empirical) research is a product of many (Kaltmeier 2012, Abu Lughod 1991)...
In my paper I claim that methodology inspired by postcolonial theory not only unearths how Western international institutions perpetuate hegemonic truth claims, but that at the same time engaging in a “learning to learn from below” might sense irritations within these truth claims which can open up spaces to think beyond truth in a sense of a justice to come. (Derrida 2002) Since the (mis)understanding of knowledge production as truth finding is constitutive of both, the scientific and the legal discourse, the engagement in such research accordingly has the potential to unfold a twofold deconstructive force...