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Pittner, Stefan ; Merold, Veronika ; Anders, Sven ; Lohner, Larissa ; Amendt, Jens ; Klinger, Miriam ; Hausmann, Roland ; Kißling, Steffen ; Monticelli, Fabio Carlo ; Geissenberger, Janine ; Zissler, Angela ; Steinbacher, Peter
The analysis of postmortem protein degradation has become of large interest for the estimation of the postmortem interval (PMI). Although several techniques have been published in recent years, protein degradation-based techniques still largely did not exceed basic research stages. Reasons include impractical and complex sampling procedures, as well as highly variable protocols in the literature, making it difficult to compare results. Following a three-step procedure, this study aimed to establish an easily replicable standardized procedure for sampling and processing, and further investigated the reliability and limitations for routine application. Initially, sampling and processing were optimized using a rat animal model. In a second step, the possible influences of sample handling and storage on postmortem protein degradation dynamics were assessed on a specifically developed human extracorporeal degradation model. Finally, the practical application was simulated by the collection of tissue in three European forensic institutes and an international transfer to our forensic laboratory, where the samples were processed and analyzed according to the established protocol.
Lucaciu, Alexandra ; Kuhn, Hannah ; Trautmann, Sandra ; Ferreirós Bouzas, Nerea ; Steinmetz, Helmuth ; Pfeilschifter, Josef ; Brunkhorst, Robert ; Pfeilschifter, Waltraud ; Subburayalu, Julien ; Vutukuri, Rajkumar
Emerging evidence suggests a complex relationship between sphingosine 1-phosphate (S1P) signaling and stroke. Here, we show the kinetics of S1P in the acute phase of ischemic stroke and highlight accompanying changes in immune cells and S1P receptors (S1PR). Using a C57BL/6 mouse model of middle cerebral artery occlusion (MCAO), we assessed S1P concentrations in the brain, plasma, and spleen. We found a steep S1P gradient from the spleen towards the brain. Results obtained by qPCR suggested that cells expressing the S1PR type 1 (S1P1+) were the predominant population deserting the spleen. Here, we report the cerebral recruitment of T helper (TH) and regulatory T (TREG) cells to the ipsilateral hemisphere, which was associated with differential regulation of cerebral S1PR expression patterns in the brain after MCAO. This study provides insight that the S1P-S1PR axis facilitates splenic T cell egress and is linked to the cerebral recruitment of S1PR+ TH and TREG cells. Further insights by which means the S1P-S1PR-axis orchestrates neuronal positioning may offer new therapeutic perspectives after ischemic stroke.
After a short introduction into traditional image transform coding, multirate systems and multiscale signal coding the paper focuses on the subject of image encoding by a neural network. Taking also noise into account a network model is proposed which not only learns the optimal localized basis functions for the transform but also learns to implement a whitening filter by multi-resolution encoding. A simulation showing the multi-resolution capabilitys concludes the contribution.
Helling, Bianca ; König, Martin ; Dälken, Benjamin ; Engling, Andre ; Krömer, Wolfgang ; Heim, Katharina ; Wallmeier, Holger ; Haas, Jürgen ; Wildemann, Brigitte ; Fritz, Brigitte ; Jonuleit, Helmut ; Kubach, Jan ; Dingermann, Theodor ; Radeke, Heinfried H. ; Osterroth, Frank ; Uherek, Christoph ; Czeloth, Niklas ; Schüttrumpf, Jörg
CD4+CD25+ regulatory T cells (Tregs) represent a specialized subpopulation of T cells, which are essential for maintaining peripheral tolerance and preventing autoimmunity. The immunomodulatory effects of Tregs depend on their activation status. Here we show that, in contrast to conventional anti-CD4 monoclonal antibodies (mAbs), the humanized CD4-specific monoclonal antibody tregalizumab (BT-061) is able to selectively activate the suppressive properties of Tregs in vitro. BT-061 activates Tregs by binding to CD4 and activation of signaling downstream pathways. The specific functionality of BT-061 may be explained by the recognition of a unique, conformational epitope on domain 2 of the CD4 molecule that is not recognized by other anti-CD4 mAbs. We found that, due to this special epitope binding, BT-061 induces a unique phosphorylation of T-cell receptor complex-associated signaling molecules. This is sufficient to activate the function of Tregs without activating effector T cells. Furthermore, BT-061 does not induce the release of pro-inflammatory cytokines. These results demonstrate that BT-061 stimulation via the CD4 receptor is able to induce T-cell receptor-independent activation of Tregs. Selective activation of Tregs via CD4 is a promising approach for the treatment of autoimmune diseases where insufficient Treg activity has been described. Clinical investigation of this new approach is currently ongoing.
Kaluza, Antonia J. ; Aydin, Anna Lisa ; Cordes, Berrit L. ; Ebers, Gianna ; Fuchs, Albert ; Konietzny, Christiane ; Dick, Rolf van ; Baumann, Ulrich
Taking blood via venipuncture is part of the necessary surveillance before and after liver transplantation. The spectrum of response from children and their parents is variable, ranging from a short and limited aversion to paralyzing phobia. The aim of this retrospective, cross-sectional study was to determine the level of anxiety amongst children during venipuncture, to compare the anxiety reported by children and parents, and to identify the factors affecting the children’s and parents’ anxiety in order to develop therapeutic strategies. In total, 147 children (aged 0–17 years, 78 female) and their parents completed questionnaires. Statistical analysis was performed using qualitative and quantitative methods. Results showed that the majority of children reported anxiety and pain during venipuncture. Younger children had more anxiety (self-reported or assessed by parents). Children and parental reports of anxiety were highly correlated. However, the child’s anxiety was often reported as higher by parents than by the children themselves. The child’s general anxiety as well as the parents’ perceived stress from surgical interventions (but not the number of surgical interventions) prompted parental report of child anxiety. For children, the main stressors that correlated with anxiety and pain were factors during the blood collection itself (e.g., feeling the puncture, seeing the syringe). Parental anxiety was mainly related to circumstances before the blood collection (e.g., approaching the clinic, sitting in the waiting room). The main stressors mentioned by parents were the child’s discomfort and their inability to calm the child. Results indicate that the children’s fear of factors during the blood collection, along with the parents’ perceived stress and helplessness as well as their anticipatory anxiety are important starting points for facilitating the drawing of blood from children before and after liver transplantation, thereby supporting a better disease course in the future.
Small RNAs have been implicated in numerous cellular processes, including effects on chromatin structure and the repression of transposons. We describe the generation of a small RNA response at DNA ends in Drosophila that is analogous to the recently reported double-strand break (DSB)-induced RNAs or Dicer- and Drosha-dependent small RNAs in Arabidopsis and vertebrates. Active transcription in the vicinity of the break amplifies this small RNA response, demonstrating that the normal messenger RNA contributes to the endogenous small interfering RNAs precursor. The double-stranded RNA precursor forms with an antisense transcript that initiates at the DNA break. Breaks are thus sites of transcription initiation, a novel aspect of the cellular DSB response. This response is specific to a double-strand break since nicked DNA structures do not trigger small RNA production. The small RNAs are generated independently of the exact end structure (blunt, 3′- or 5′-overhang), can repress homologous sequences in trans and may therefore—in addition to putative roles in repair—exert a quality control function by clearing potentially truncated messages from genes in the vicinity of the break.
Riva, Antonella ; Morazzoni, Paolo ; Artaria, Christian ; Allegrini, Pietro ; Meins, Jürgen ; Savio, Daniele ; Appendino, Giovanni ; Schubert-Zsilavecz, Manfred ; Abdel Tawab, Mona
Background: The oral administration of the gum resin extracts of Indian frankincense (Boswellia serrata Roxb. ex Colebr) results in very low plasma concentrations of boswellic acids (BAs), being far below the pharmacologically active concentrations required in vitro for anti-inflammatory activity. For that reason the use of Indian frankincense in clinical practice and pharmaceutical development has substantially lagged behind. Recently the application of new formulation technologies resulted in a formulation of frankincense extract with lecithin, which revealed improved absorption and tissue penetration of BAs in a rodent study, leading for the first time to plasma concentrations of BAs in the range of their anti-inflammatory activity.
Purpose: In order to verify these encouraging results in humans, the absorption of a standardized Boswellia serrata extract (BE) and its lecithin formulation (CSP) was comparatively investigated in healthy volunteers.
Study design: According to a randomized cross-over design with two treatments, two sequences and two periods, 12 volunteers alternatively received the lecithin-formulated Boswellia extract (CSP) or the non-formulated Boswellia extract (BE) at a dosage of 2 × 250 mg capsules.
Methods: The plasma concentrations of the six major BAs (KBA, AKBA, βBA, αBA, AβBA, AαBA) were determined using LC/MS.
Results: With the exception of KBA, a significantly higher (both in terms of weight-to-weight and molar comparison) and quicker absorption of BAs from the lecithin formulation was observed, leading to Cmax in the range required for the interaction with their molecular targets.
Conclusion: These findings pave the way to further studies evaluating the clinical potential of BAs, and verify the beneficial effect of lecithin formulation to improve the absorption of poorly soluble phytochemicals.
Karimova, Madina ; Baker, Oliver ; Camgoz, Aylin ; Naumann, Ronald ; Buchholz, Frank ; Anastassiadis, Konstantinos
Site-specific recombinases (SSR) are utilized as important genome engineering tools to precisely modify the genome of mice and other model organisms. Reporter mice that mark cells that at any given time had expressed the enzyme are frequently used for lineage tracing and to characterize newly generated mice expressing a recombinase from a chosen promoter. With increasing sophistication of genome alteration strategies, the demand for novel SSR systems that efficiently and specifically recombine their targets is rising and several SSR-systems are now used in combination to address complex biological questions in vivo. Generation of reporter mice for each one of these recombinases is cumbersome and increases the number of mouse lines that need to be maintained in animal facilities. Here we present a multi-reporter mouse line for loci-of-recombination (X) (MuX) that streamlines the characterization of mice expressing prominent recombinases. MuX mice constitutively express nuclear green fluorescent protein after recombination by either Cre, Flp, Dre or Vika recombinase, rationalizing the number of animal lines that need to be maintained. We also pioneer the use of the Vika/vox system in mice, illustrating its high efficacy and specificity, thereby facilitating future designs of sophisticated recombinase-based in vivo genome engineering strategies.
Sharma, Sunny ; David Hartmann, Johannes ; Watzinger, Peter ; Klepper, Arvid ; Peifer, Christian ; Kötter, Peter ; Lafontaine, Denis L. J. ; Entian, Karl-Dieter
The entire chemical modification repertoire of yeast ribosomal RNAs and the enzymes responsible for it have recently been identified. Nonetheless, in most cases the precise roles played by these chemical modifications in ribosome structure, function and regulation remain totally unclear. Previously, we demonstrated that yeast Rrp8 methylates m1A645 of 25S rRNA in yeast. Here, using mung bean nuclease protection assays in combination with quantitative RP-HPLC and primer extension, we report that 25S/28S rRNA of S. pombe, C. albicans and humans also contain a single m1A methylation in the helix 25.1. We characterized nucleomethylin (NML) as a human homolog of yeast Rrp8 and demonstrate that NML catalyzes the m1A1322 methylation of 28S rRNA in humans. Our in vivo structural probing of 25S rRNA, using both DMS and SHAPE, revealed that the loss of the Rrp8-catalyzed m1A modification alters the conformation of domain I of yeast 25S rRNA causing translation initiation defects detectable as halfmers formation, likely because of incompetent loading of 60S on the 43S-preinitiation complex. Quantitative proteomic analysis of the yeast Δrrp8 mutant strain using 2D-DIGE, revealed that loss of m1A645 impacts production of specific set of proteins involved in carbohydrate metabolism, translation and ribosome synthesis. In mouse, NML has been characterized as a metabolic disease-associated gene linked to obesity. Our findings in yeast also point to a role of Rrp8 in primary metabolism. In conclusion, the m1A modification is crucial for maintaining an optimal 60S conformation, which in turn is important for regulating the production of key metabolic enzymes.
Hutten, Nadia R. P. W. ; Kuypers, Kim P. C. ; Wel, Janelle van ; Theunissen, Eef L. ; Tönnes, Stefan W. ; Verkes, Robbert Jan ; Ramaekers, Johannes G.
Background: Prospective memory is the ability to recall intended actions or events at the right time or in the right context. While cannabis is known to impair prospective memory, the acute effect of cocaine is unknown. In addition, it is not clear whether changes in prospective memory represent specific alterations in memory processing or result from more general effects on cognition that spread across multiple domains such as arousal and attention.
Aims: The main objective of the study was, therefore, to determine whether drug-induced changes in prospective memory are memory specific or associated with more general drug-induced changes in attention and arousal.
Methods: A placebo-controlled, three-way, cross-over study including 15 regular poly-drug users was set up to test the influence of oral cocaine (300 mg) and vaporised cannabis (300+150 ‘booster’ µg/kg bodyweight) on an event-based prospective memory task. Attentional performance was assessed using a divided attention task and subjective arousal was assessed with the Profile of Mood States questionnaire.
Results: Results showed that cocaine enhanced prospective memory, attention and arousal. Mean performance of prospective memory and attention, as well as levels of arousal were lowest during treatment with cannabis as compared with placebo and cocaine as evinced by a significantly increased trend across treatment conditions. Prospective memory performance was only weakly positively associated to measures of attention and arousal.
Conclusion: Together, these results indicate that cocaine enhancement of prospective memory performance cannot be fully explained by parallel changes in arousal and attention levels, and is likely to represent a direct change in the neural network underlying prospective memory.
Riessen, Reimer ; Behmenburg, Melanie ; Blumenstock, Gunnar ; Guenon, Doris ; Enkel, Sigrid ; Schäfer, Richard ; Haap, Michael
Introduction: Aim of this study was to reduce blood loss caused by diagnostic blood sampling and to minimize the development of anemia in a high-risk group of mechanically ventilated medical intensive care patients. We therefore implemented a “blood-saving bundle” (BSB) combining a closed-loop arterial blood sampling system, smaller sampling tubes, reduced frequency of blood drawings, and reduced sample numbers.
Methods: The study included all patients from our medical ICU who were ventilated for more than 72 hours. Exclusion criteria were: acute or chronic anemia on admission, bleeding episode(s) during the ICU stay, or end-of-life therapy. The BSB was introduced in 2009 with training and educational support. Patients treated in 2008, before the introduction of the BSB, served as a control group (n = 41, 617 observation days), and were compared with patients treated in 2010 after the introduction of the BSB (BSB group, n = 50, 559 observation days). Primary endpoints were blood loss per day, and development of anemia. Secondary endpoints were numbers of blood transfusions, number of days on mechanical ventilation, and length of the ICU stay.
Results: Mean blood loss per ICU day was decreased from 43.3 ml (95% CI: 41.2 to 45.3 ml) in the controls to 15.0 ml (14.3 to 15.7 ml) in the BSB group (P < 0.001). The introduction of a closed-loop arterial blood sampling system was the major contributor to this effect. Mean hemoglobin concentrations showed no significant differences in both groups during the ICU stay. Hemoglobin values <9 g/dl, however, were recorded in 21.2% of observation days in the controls versus 15.4% in the BSB group (P = 0.01). Units of transfused red blood cells per 100 observation days decreased from 7 to 2.3 (P < 0.001). The mean number of ventilation days was 7.1 days (6.1 to 8.3 days) in the controls and 7.5 days (6.6 to 8.5 days) in the BSB group (P = NS). In total, patients in the BSB group stayed in ICU for a mean of 9.9 days (8.6 to 11.3 days), compared to a mean ICU stay of 13.0 days (10.9 to 15.4 days) in the control group (P = 0.014). Due to the longitudinal study design, however, we cannot exclude uncontrolled confounders affecting the transfusion frequency and mean ICU stay.
Conclusion: Our BSB could be easily implemented and was able to reduce diagnostic blood loss.
Specifying accurate informative prior distributions is a question of carefully selecting studies that comprise the body of comparable background knowledge. Psychological research, however, consists of studies that are being conducted under different circumstances, with different samples and varying instruments. Thus, results of previous studies are heterogeneous, and not all available results can and should contribute equally to an informative prior distribution. This implies a necessary weighting of background information based on the similarity of the previous studies to the focal study at hand. Current approaches to account for heterogeneity by weighting informative prior distributions, such as the power prior and the meta-analytic predictive prior are either not easily accessible or incomplete. To complicate matters further, in the context of Bayesian multiple regression models there are no methods available for quantifying the similarity of a given body of background knowledge to the focal study at hand. Consequently, the purpose of this study is threefold. We first present a novel method to combine the aforementioned sources of heterogeneity in the similarity measure ω. This method is based on a combination of a propensity-score approach to assess the similarity of samples with random- and mixed-effects meta-analytic models to quantify the heterogeneity in outcomes and study characteristics. Second, we show how to use the similarity measure ω as a weight for informative prior distributions for the substantial parameters (regression coefficients) in Bayesian multiple regression models. Third, we investigate the performance and the behavior of the similarity-weighted informative prior distribution in a comprehensive simulation study, where it is compared to the normalized power prior and the meta-analytic predictive prior. The similarity measure ω and the similarity-weighted informative prior distribution as the primary results of this study provide applied researchers with means to specify accurate informative prior distributions.
We present an immersed boundary method for the solution of elliptic interface problems with discontinuous coefficients which provides a second-order approximation of the solution. The proposed method can be categorised as an extended or enriched finite element method. In contrast to other extended FEM approaches, the new shape functions get projected in order to satisfy the Kronecker-delta property with respect to the interface. The resulting combination of projection and restriction was already derived in Höllbacher and Wittum (TBA, 2019a) for application to particulate flows. The crucial benefits are the preservation of the symmetry and positive definiteness of the continuous bilinear operator. Besides, no additional stabilisation terms are necessary. Furthermore, since our enrichment can be interpreted as adaptive mesh refinement, the standard integration schemes can be applied on the cut elements. Finally, small cut elements do not impair the condition of the scheme and we propose a simple procedure to ensure good conditioning independent of the location of the interface. The stability and convergence of the solution will be proven and the numerical tests demonstrate optimal order of convergence.
Forrester, Alison ; De Leonibus, Chiara ; Grumati, Paolo ; Fasana, Elisa ; Piemontese, Marilina ; Staiano, Leopoldo ; Fregno, Ilaria ; Raimondi, Andrea ; Marazza, Alessandro ; Bruno, Gemma ; Iavazzo, Maria ; Intartaglia, Daniela ; Seczynska, Marta ; Anken, Eelco van ; Conte, Ivan ; De Matteis, Maria Antonietta ; Đikić, Ivan ; Molinari, Maurizio ; Settembre, Carmine
Autophagy is a cytosolic quality control process that recognizes substrates through receptor‐mediated mechanisms. Procollagens, the most abundant gene products in Metazoa, are synthesized in the endoplasmic reticulum (ER), and a fraction that fails to attain the native structure is cleared by autophagy. However, how autophagy selectively recognizes misfolded procollagens in the ER lumen is still unknown. We performed siRNA interference, CRISPR‐Cas9 or knockout‐mediated gene deletion of candidate autophagy and ER proteins in collagen producing cells. We found that the ER‐resident lectin chaperone Calnexin (CANX) and the ER‐phagy receptor FAM134B are required for autophagy‐mediated quality control of endogenous procollagens. Mechanistically, CANX acts as co‐receptor that recognizes ER luminal misfolded procollagens and interacts with the ER‐phagy receptor FAM134B. In turn, FAM134B binds the autophagosome membrane‐associated protein LC3 and delivers a portion of ER containing both CANX and procollagen to the lysosome for degradation. Thus, a crosstalk between the ER quality control machinery and the autophagy pathway selectively disposes of proteasome‐resistant misfolded clients from the ER.
We explore the parameter space of the two-flavor thermal quark–meson model and its Polyakov loop-extended version under the influence of a constant external magnetic field B. We investigate the behavior of the pseudo critical temperature for chiral symmetry breaking taking into account the likely dependence of two parameters on the magnetic field: the Yukawa quark–meson coupling and the parameter T0 of the Polyakov loop potential. Under the constraints that magnetic catalysis is realized at zero temperature and the chiral transition at B=0 is a crossover, we find that the quark–meson model leads to thermal magnetic catalysis for the whole allowed parameter space, in contrast to the present picture stemming from lattice QCD.
Bramsen, Jesper B. ; Pakula, Malgorzata M. ; Hansen, Thomas B. ; Bus, Claus ; Langkjær, Niels ; Odadžić, Dalibor ; Smicius, Romualdas ; Wengel, Suzy L. ; Chattopadhyaya, Jyoti ; Engels, Joachim W. ; Herdewijn, Piet ; Wengel, Jesper ; Kjems, Jørgen
Small interfering RNAs (siRNAs) are now established as the preferred tool to inhibit gene function in mammalian cells yet trigger unintended gene silencing due to their inherent miRNA-like behavior. Such off-target effects are primarily mediated by the sequence-specific interaction between the siRNA seed regions (position 2–8 of either siRNA strand counting from the 5'-end) and complementary sequences in the 3'UTR of (off-) targets. It was previously shown that chemical modification of siRNAs can reduce off-targeting but only very few modifications have been tested leaving more to be identified. Here we developed a luciferase reporter-based assay suitable to monitor siRNA off-targeting in a high throughput manner using stable cell lines. We investigated the impact of chemically modifying single nucleotide positions within the siRNA seed on siRNA function and off-targeting using 10 different types of chemical modifications, three different target sequences and three siRNA concentrations. We found several differently modified siRNAs to exercise reduced off-targeting yet incorporation of the strongly destabilizing unlocked nucleic acid (UNA) modification into position 7 of the siRNA most potently reduced off-targeting for all tested sequences. Notably, such position-specific destabilization of siRNA–target interactions did not significantly reduce siRNA potency and is therefore well suited for future siRNA designs especially for applications in vivo where siRNA concentrations, expectedly, will be low.
This study presents a method for adjusting long-term climate data records (CDRs) for the integrated use with near-real-time data using the example of surface incoming solar irradiance (SIS). Recently, a 23-year long (1983–2005) continuous SIS CDR has been generated based on the visible channel (0.45–1 μm) of the MVIRI radiometers onboard the geostationary Meteosat First Generation Platform. The CDR is available from the EUMETSAT Satellite Application Facility on Climate Monitoring (CM SAF). Here, it is assessed whether a homogeneous extension of the SIS CDR to the present is possible with operationally generated surface radiation data provided by CM SAF using the SEVIRI and GERB instruments onboard the Meteosat Second Generation satellites. Three extended CM SAF SIS CDR versions consisting of MVIRI-derived SIS (1983–2005) and three different SIS products derived from the SEVIRI and GERB instruments onboard the MSG satellites (2006 onwards) were tested. A procedure to detect shift inhomogeneities in the extended data record (1983–present) was applied that combines the Standard Normal Homogeneity Test (SNHT) and a penalized maximal T-test with visual inspection. Shift detection was done by comparing the SIS time series with the ground stations mean, in accordance with statistical significance. Several stations of the Baseline Surface Radiation Network (BSRN) and about 50 stations of the Global Energy Balance Archive (GEBA) over Europe were used as the ground-based reference. The analysis indicates several breaks in the data record between 1987 and 1994 probably due to artefacts in the raw data and instrument failures. After 2005 the MVIRI radiometer was replaced by the narrow-band SEVIRI and the broadband GERB radiometers and a new retrieval algorithm was applied. This induces significant challenges for the homogenisation across the satellite generations. Homogenisation is performed by applying a mean-shift correction depending on the shift size of any segment between two break points to the last segment (2006–present). Corrections are applied to the most significant breaks that can be related to satellite changes. This study focuses on the European region, but the methods can be generalized to other regions. To account for seasonal dependence of the mean-shifts the correction was performed independently for each calendar month. In comparison to the ground-based reference the homogenised data record shows an improvement over the original data record in terms of anomaly correlation and bias. In general the method can also be applied for the adjustment of satellite datasets addressing other variables to bridge the gap between CDRs and near-real-time data.
Holzgreve, Fabian Christian ; Fräulin, Laura ; Betz, Werner ; Erbe, Christina ; Wanke, Eileen M. ; Brüggmann, Dörthe ; Nienhaus, Albert ; Groneberg, Jan David Alexander ; Maurer-Grubinger, Christian ; Ohlendorf, Daniela Maren
Background: In general, the prevalence of work-related musculoskeletal disorders (WMSD) in dentistry is high, and dental assistants (DA) are even more affected than dentists (D). Furthermore, differentiations between the fields of dental specialization (e.g., general dentistry, endodontology, oral and maxillofacial surgery, or orthodontics) are rare. Therefore, this study aims to investigate the ergonomic risk of the aforementioned four fields of dental specialization for D and DA on the one hand, and to compare the ergonomic risk of D and DA within each individual field of dental specialization. Methods: In total, 60 dentists (33 male/27 female) and 60 dental assistants (11 male/49 female) volunteered in this study. The sample was composed of 15 dentists and 15 dental assistants from each of the dental field, in order to represent the fields of dental specialization. In a laboratory setting, all tasks were recorded using an inertial motion capture system. The kinematic data were applied to an automated version of the Rapid Upper Limb Assessment (RULA). Results: The results revealed significantly reduced ergonomic risks in endodontology and orthodontics compared to oral and maxillofacial surgery and general dentistry in DAs, while orthodontics showed a significantly reduced ergonomic risk compared to general dentistry in Ds. Further differences between the fields of dental specialization were found in the right wrist, right lower arm, and left lower arm in DAs and in the neck, right wrist, right lower arm, and left wrist in Ds. The differences between Ds and DAs within a specialist discipline were rather small. Discussion: Independent of whether one works as a D or DA, the percentage of time spent working in higher risk scores is reduced in endodontologists, and especially in orthodontics, compared to general dentists or oral and maxillofacial surgeons. In order to counteract the development of WMSD, early intervention should be made. Consequently, ergonomic training or strength training is recommended.
A role of the Qв binding protein in the mechanism of cyanobacterial adaptation to light intensity?
(1986)
Growth of the unicellular blue-green alga Anacystis nidulans in media containing sublethal concentrations of DCMU-type inhibitors of photosynthetic electron transport in strong white light gave rise to shade type appearance in this organism, as characterized by an increased ratio of phycocyanin to chlorophyll and reduced ratios, both, of carotenoids to chlorophyll and of total chlorophyll to P700. Shade type in Anacystis was caused neither by phenolic inhibitors tested nor by those known to bind to the cytochrome b6/f-complex. Surprisingly enough, the molar ratio of phycocyanin to chlorophyll in artificially shade adapted Anacystis1 grown in strong white light in the presence of 10-6 м atrazine, was found to increase with temperature for a given light intensity and with light intensity for a given temperature.
Mutants of Anaeystis with a reduced binding capacity for DCMU-type herbicides due to an amino acid exchange in the 32 kDa Qв-binding polypeptide, also called D-1 protein, were ob- served to show shade type appearance in strong light, to respond very little to changes in light intensity and to show a reduced capability to further change their appearance to shade type by binding of competitors of Ob to the 32 kDa polypeptide.
In Anaeystis a concentration of atrazine (10-7 м), ten times lower than the one causing the highest rate of shade adaptation (10-6 м), was shown to induce an optimum in cell density, which in turn resulted in an optimum in light-dependent O2 evolution. Both factors together might be responsible for the so-called greening effect observed in higher plants treated with sublethal concentrations of DCMU-type inhibitors of photosynthetic electron transport.
Swart, Laura E. ; Koekman, Cornelis Arnold ; Seinen, Cor W. ; Issa, Hasan ; Rasouli, Milad ; Schiffelers, Raymond Michel ; Heidenreich, Olaf Torben
Targeted delivery of nucleic acids is gaining momentum due to improved efficacy, selectivity, increased circulation time and enhanced tissue retention in target cells. Using nucleic acid-based therapies previously undruggable targets have proven now to be amenable for treatment. Currently, several methods for preparing targeted or labelled delivery vehicles for nucleic acids are based on liposomal formulations. Lipid nanoparticles (LNPs) are structurally different from liposomes and these methods should therefore be evaluated before being translated to siRNA LNPs preparation protocols. Here, we describe a robust and facile method for the preparation of targeted or fluorescently labelled siRNA LNPs. Using a copper free strain-promoted azide-alkyne cycloaddition (SPAAC) we demonstrate that post-insertion of ligand-lipid conjugates into preformed LNPs is superior to direct-surface modification because it preserves the physicochemical parameters of the LNPs. We found that the time point of solvent removal by dialysis is critical and affects the hydrodynamic diameter of the LNPs; post-insertion after dialysis shows the smallest increase in hydrodynamic diameter and polydispersity index (PDI). The post-insertion of ligand-lipid conjugates also proceeded with rapid kinetics and high efficacy over a wide temperature range. Using this optimised protocol, we generated siRNA LNPs containing both targeting and fluorescent tracking ligands allowing us to monitor siRNA LNP uptake kinetics in dependence of the targeting ligand. In aggregate, we describe a robust approach for the generation of targeted and labelled siRNA LNPs that allows their controlled and facile decoration with ligand combinations.
A risk based assessment approach for chemical mixtures from wastewater treatment plant effluents
(2022)
Finckh, Saskia ; Beckers, Liza-Marie ; Busch, Wibke ; Carmona, Eric ; Dulio, Valeria ; Kramer, Lena ; Krauss, Martin ; Posthuma, Leo ; Schulze, Tobias ; Slootweg, Jaap ; Ohe, Peter Carsten von der ; Brack, Werner
In this study, 56 effluent samples from 52 European wastewater treatment plants (WWTPs) were investigated for the occurrence of 499 emerging chemicals (ECs) and their associated potential risks to the environment. The two main objectives were (i) to extend our knowledge on chemicals occurring in treated wastewater, and (ii) to identify and prioritize compounds of concern based on three different risk assessment approaches for the identification of consensus mixture risk drivers of concern. Approaches include (i) PNEC and EQS-based regulatory risk quotients (RQs), (ii) species sensitivity distribution (SSD)-based hazard units (HUs) and (iii) toxic units (TUs) for three biological quality elements (BQEs) algae, crustacean, and fish.
For this purpose, solid-phase extracts were analysed with wide-scope chemical target screening via liquid chromatography high-resolution mass spectrometry (LC-HRMS), resulting in 366 detected compounds, with concentrations ranging from < 1 ng/L to > 100 µg/L. The detected chemicals were categorized with respect to critical information relevant for risk assessment and management prioritization including: (1) frequency of occurrence, (2) measured concentrations, (3) use groups, (4) persistence & bioaccumulation, and (5) modes of action. A comprehensive assessment using RQ, HU and TU indicated exceedance of risk thresholds for the majority of effluents with RQ being the most sensitive metric. In total, 299 out of the 366 compounds were identified as mixture risk contributors in one of the approaches, while 32 chemicals were established as consensus mixture risk contributors of high concern, including a high percentage (66%) of pesticides and biocides. For samples which have passed an advanced treatment using ozonation or activated carbon (AC), consistently much lower risks were estimated.
Molecular phylogenetic studies of Moraea Mill. and the inclusion of Barnardiella Goldblatt, Galaxia Thunb., Gynandriris Parl., Hexaglottis Vent., Homeria Vent. and Roggeveldia Goldblatt in the genus have rendered the existing infrageneric classification, dating from 1976, in need of substantial revision. In particular, subg. Moraea and subg. Vieusseuxia have been shown to be paraphyletic. We propose a new infrageneric classification, based, as far as current data permit, on phylogenetic principles. Monophyletic subgenera and sections are circumscribed based on molecular phylogenies alone or in combination with morphological considerations. We recognize 11 subgenera, 15 sections and three series, arranged as follows in phylogenetic sequence: Plumarieae; Visciramosae (with sect. Multifoliae and sect. Visciramosae); Moraea (with sect. Moraea and sect. Polyphyllae); Galaxia (with ser. Unguiculatae, ser. Eurystigma and ser. Galaxia); Monocephalae; Acaules; Polyanthes (with sect. Serpentinae, sect. Deserticola, sect. Hexaglottis, sect. Gynandriris, sect. Polyanthes and sect. Pseudospicatae); Grandifl orae; Vieusseuxia (with sect. Integres, sect. Vieusseuxia and sect. Villosae); and Homeria (with sect. Stipanthera, sect. Flexuosae, sect. Homeria and sect. Conantherae). Most are moderately to well circumscribed at the morphological level either by floral or vegetative characters, except subg. Moraea, which includes a small number of unspecialized species apparently not linked by any apomorphic features. With over 27 new species described in the past 25 years and another 60 transferred to the genus, Moraea now includes 214 species. We provide a full taxonomic synopsis of the genus.
Orientation: Publishing methodologically sound, empirically based studies in reputable accredited scientific journals are essential in order to advance knowledge and evidence-based practice in the field of industrial and organisational psychology.
Research purpose: The purpose of the research was to conduct a broad content analysis of the articles published in the South African Journal of Industrial Psychology (SAJIP) between 2004 and 2013. The study aimed to provide a descriptive overview of the most frequent content themes,published authors and institutions, research approaches, strategies, designs and analysis techniques, software packages and sample sizes in industrial and organisational (I-O) psychology utilised in the publications.
Motivation for study: The periodic analyses of published content in scholarly journals provide an index of the extent to which the publications reflect the scope of practice in a given discipline and broaden insight into the direction and relevance of research published in a journal.
Research design, approach and method: A broad systematic content analysis was conducted of 342 documented articles published in the SAJIP between 2004 and 2013. Descriptive data(frequencies and percentages) were used to report the findings.
Main findings: The publishing pattern of the SAJIP appeared to correspond with its focus and scope. Manuscripts utilising mostly cross-sectional quantitative correlational research designs with large samples (n > 201) were published in the SAJIP. The University of Johannesburg and Professor Sebastiaan (Ian) Rothmann were the largest contributors to publications between 2004 and 2013. Organisational psychology and psychometrics were the most prominent domains in I-O psychology research. Data were predominantly processed utilising SPSS.
Practical implications: The insights derived from the findings can be employed to plan future research initiatives in the field of I-O psychology.
Contribution/value-add: The findings provide valuable insight into the current status of the foci of I-O psychology research as published in the SAJIP between 2004 and 2013 and the contribution made by the SAJIP to advancing knowledge and evidence-based practice in I-O psychology.
The relativistic method of moments is one of the most successful approaches to extract second order viscous hydrodynamics from a kinetic underlying background. The equations can be systematically improved to higher order, and they have already shown a fast convergence to the kinetic results. In order to generalize the method we introduced long range effects in the form of effective (medium dependent) masses and gauge (coherent) fields. The most straightforward generalization of the hydrodynamic expansion is problematic at higher order. Instead of introducing an additional set of approximations, we propose to rewrite the series in terms of moments resumming the contributions of infinite non-hydrodynamics modes. The resulting equations are are consistent with hydrodynamics and well defined at all order. We tested the new approximation against the exact solutions of the Maxwell-Boltzmann-Vlasov equations in (0 + 1)-dimensions, finding a fast and stable convergence to the exact results.
Bohus, Martin ; Schmahl, Christian ; Fydrich, Thomas ; Steil, Regina ; Müller-Engelmann, Meike ; Herzog, Julia ; Ludäscher, Petra ; Kleindienst, Nikolaus ; Priebe, Kathlen
Background: Posttraumatic stress disorder (PTSD) after childhood abuse (CA) is often related to severe co-occurring psychopathology, such as symptoms of borderline personality disorder (BPD). The ICD-11 has included Complex PTSD as a new diagnosis, which is defined by PTSD symptoms plus disturbances in emotion regulation, self-concept, and interpersonal relationships. Unfortunately, the empirical database on psychosocial treatments for survivors of CA is quite limited. Furthermore, the few existing studies often have either excluded subjects with self-harm behaviour and suicidal ideation — which is common behaviour in subjects suffering from Complex PTSD. Thus, researchers are still trying to identify efficacious treatment programmes for this group of patients.
We have designed DBT-PTSD to meet the specific needs of patients with Complex PTSD. The treatment programme is based on the rules and principles of dialectical behavioural therapy (DBT), and adds interventions derived from cognitive behavioural therapy, acceptance and commitment therapy and compassion-focused therapy. DBT-PTSD can be provided as a comprehensive residential programme or as an outpatient programme. The effects of the residential programme were evaluated in a randomised controlled trial. Data revealed significant reduction of posttraumatic symptoms, with large between-group effect sizes when compared to a treatment-as-usual wait list condition (Cohen’s d = 1.5).
The first aim of this project on hand is to evaluate the efficacy of the outpatient DBT-PTSD programme. The second aim is to identify the major therapeutic variables mediating treatment efficacy. The third aim is to study neural mechanisms and treatment sensitivity of two frequent sequelae of PTSD after CA: intrusions and dissociation.
Methods: To address these questions, we include female patients who experienced CA and who fulfil DSM-5 criteria for PTSD plus borderline features, including criteria for severe emotion dysregulation. The study is funded by the German Federal Ministry of Education and Research, and started in 2014. Participants are randomised to outpatient psychotherapy with either DBT-PTSD or Cognitive Processing Therapy. Formal power analysis revealed a minimum of 180 patients to be recruited. The primary outcome is the change on the Clinician-Administered PTSD Scale for DSM-5.
Discussion: The expected results will be a major step forward in establishing empirically supported psychological treatments for survivors of CA suffering from Complex PTSD.
Trial registration: German Clinical Trials Register: registration number DRKS00005578, date of registration 19 December 2013.
Fundamental rights protection, once a side show, has become important for the EU, as proved by the newfound treaty recognition of the EU fundamental rights charter (CFREU), and the upcoming accession to the European Convention on Human Rights (ECHR). At the same time the fundamental rights situation in a considerable number of Member States is an increasing cause for concern. This has mostly been illustrated with reference to minorities and asylum seekers. However, recent reports of organizations like the Council of Europe, the OSCE and various NGOs have also highlighted serious problems with regard to media freedom, such as overt political influence, media concentration, disproportionate sanctions on journalists, misuse of counter-terrorism legislation against the press, deficient protection of journalistic sources and failure to investigate violence against reporters. ...
A reply to my critics
(2021)
It is a real pleasure to reply to so many thoughtful and probing responses to my book. In what follows, I will focus on six key themes that emerge across the various pieces. Some of them call into question core commitments of my theory, and in those cases I will try to show what might be said in its defence. Quite a number of the critics, however, present what we might call expansionist arguments: though they endorse some of the arguments I make, that is – or pick up some of its key concepts – they seek to push them in new and interesting directions. I will suggest that many of those arguments look likely to be successful, though I will also express caution about one or two of them. I doubt, however, that I will be the final judge of their success. Early on in the book I express the hope that it might provide a set of conceptual tools capable of advancing discussions about resource justice more broadly, even for scholars who reject my own idiosyncratic approach. Having made that gambit, I cannot now claim to have a monopoly on the use of the tools in question. Witnessing the use that others have already made of them has been a refreshing and rewarding experience.
A remark on the bank cases
(2021)
Since their formulation by Keith DeRose (1992), the so-called bank cases have played a major role in the discussion about whether knowledge depends on practical factors. According to the proponents of pragmatic encroachment, the proper conclusion to be drawn from the bank cases and similar examples is that knowledge of a proposition p does not supervene on one’s evidence for or against p. In my view, this conclusion is ill-founded. The reason is that the bank cases and similar examples suffer from an ambiguity concerning the known proposition — an ambiguity that has so far been overlooked. When this ambiguity is made explicit, it becomes clear that the conclusion does not follow.
We show how nonlocal boundary conditions of Robin type can be encoded in the pointwise expression of the fractional operator. Notably, the fractional Laplacian of functions satisfying homogeneous nonlocal Neumann conditions can be expressed as a regional operator with a kernel having logarithmic behaviour at the boundary.
Com o advento da modernidade a filosofia passou a exigir que a religião prestasse contas à razão. A filosofia da religião de Kant é um exemplo desse tipo de iniciativa. Kant propôs julgar a religião no tribunal da razão. Mais de 200 anos depois, Habermas buscou renovar o projeto kantiano. Nosso trabalho visa esclarecer o modo como cada autor realiza o julgamento da religião no tribunal da razão. Além disso, discutiremos a relevância desse tipo de abordagem proposta por ambos os filósofos.
Sob a ótica do conceito adorniano de autonomia estética, analisamos aqui de qual forma se dá a relação entre sociedade e arte, passando por discussões quanto à separação entre teoria e práxis, quanto à lógica interna da obra de arte, quanto ao poder de integração da indústria cultural, em relação às obras de arte, e quanto à impossibilidade de controlar os seus efeitos sociais, seja ela autônoma, seja engajada. Trata-se, ainda, de demonstrar o caráter ilusório da proposição segundo a qual a arte seria eficaz instrumento politizador, quando utilizada de forma a engajar e adaptar seu conteúdo a objetivos políticos pré-determinados, o que será feito por meio da análise interpretativa das obras de Theodor W. Adorno e de seus comentadores, na área de estética.
O trabalho pretende discutir o duplo caráter das obras de arte a partir da obra de Theodor W. Adorno. Pretende-se examinar os argumentos sustentados pelo autor sobre o caráter social das obras, principalmente, no caso da música, em que se pode percebercomo o desenvolvimento do próprio material musical expressa as aporias encontradas na sociedade. Por meio de uma crítica dialética, modo pelo qual as obras de arte respondem às contradições da sociedade, colocando-se, assim, como força de resistência à reificação, quanto a influência negativa que sofrem, porexemplo, no contexto da indústria cultural. Além disso, o artigo pretende se dedicar à reflexão sobre a autonomia das obras de arte, qualidade que as mantém fechadas, desenvolvendo-se apenas segundo leis formais internas, sem que atendam a uma função social. É nesse sentido quese coloca a exigência de uma determinada forma de recepção dasobras, orientada não pela fruição, mas pela possibilidade de interpretar seu teor de verdade. Assim, a dialética presente no modo como as obras se relacionam com a sociedade torna possível concebê-las como possibilidade de crítica à realidade e de resistência à reificação.
Neurons collect their inputs from other neurons by sending out arborized dendritic structures. However, the relationship between the shape of dendrites and the precise organization of synaptic inputs in the neural tissue remains unclear. Inputs could be distributed in tight clusters, entirely randomly or else in a regular grid-like manner. Here, we analyze dendritic branching structures using a regularity index R, based on average nearest neighbor distances between branch and termination points, characterizing their spatial distribution. We find that the distributions of these points depend strongly on cell types, indicating possible fundamental differences in synaptic input organization. Moreover, R is independent of cell size and we find that it is only weakly correlated with other branching statistics, suggesting that it might reflect features of dendritic morphology that are not captured by commonly studied branching statistics. We then use morphological models based on optimal wiring principles to study the relation between input distributions and dendritic branching structures. Using our models, we find that branch point distributions correlate more closely with the input distributions while termination points in dendrites are generally spread out more randomly with a close to uniform distribution. We validate these model predictions with connectome data. Finally, we find that in spatial input distributions with increasing regularity, characteristic scaling relationships between branching features are altered significantly. In summary, we conclude that local statistics of input distributions and dendrite morphology depend on each other leading to potentially cell type specific branching features.
The frequency of extreme events has changed, having a direct impact on human lives. Regional climate models help us to predict these regional climate changes. This work presents an atmosphere–ocean coupled regional climate system model (RCSM; with the atmospheric component COSMO-CLM and the ocean component NEMO) over the European domain, including three marginal seas: the Mediterranean, North, and Baltic Sea. To test the model, we evaluate a simulation of more than 100 years (1900–2009) with a spatial grid resolution of about 25 km. The simulation was nested into a coupled global simulation with the model MPI-ESM in a low-resolution configuration, whose ocean temperature and salinity were nudged to the ocean–ice component of the MPI-ESM forced with the NOAA 20th Century Reanalysis (20CR). The evaluation shows the robustness of the RCSM and discusses the added value by the coupled marginal seas over an atmosphere-only simulation. The coupled system is stable for the complete 20th century and provides a better representation of extreme temperatures compared to the atmosphere-only model. The produced long-term dataset will help us to better understand the processes leading to meteorological and climate extremes.
Engel, Andreas ; Bönisch, Harald ; Ostermöller, Jennifer ; Chipperfield, Martyn P. ; Dhomse, Sandip ; Jöckel, Patrick
Chlorine and bromine atoms lead to catalytic depletion of ozone in the stratosphere. Therefore the use and production of ozone-depleting substances (ODSs) containing chlorine and bromine is regulated by the Montreal Protocol to protect the ozone layer. Equivalent effective stratospheric chlorine (EESC) has been adopted as an appropriate metric to describe the combined effects of chlorine and bromine released from halocarbons on stratospheric ozone. Here we revisit the concept of calculating EESC. We derive a refined formulation of EESC based on an advanced concept of ODS propagation into the stratosphere and reactive halogen release. A new transit time distribution is introduced in which the age spectrum for an inert tracer is weighted with the release function for inorganic halogen from the source gases. This distribution is termed the release time distribution. We show that a much better agreement with inorganic halogen loading from the chemistry transport model TOMCAT is achieved compared with using the current formulation. The refined formulation shows EESC levels in the year 1980 for the mid-latitude lower stratosphere, which are significantly lower than previously calculated. The year 1980 is commonly used as a benchmark to which EESC must return in order to reach significant progress towards halogen and ozone recovery. Assuming that – under otherwise unchanged conditions – the EESC value must return to the same level in order for ozone to fully recover, we show that it will take more than 10 years longer than estimated in this region of the stratosphere with the current method for calculation of EESC. We also present a range of sensitivity studies to investigate the effect of changes and uncertainties in the fractional release factors and in the assumptions on the shape of the release time distributions. We further discuss the value of EESC as a proxy for future evolution of inorganic halogen loading under changing atmospheric dynamics using simulations from the EMAC model. We show that while the expected changes in stratospheric transport lead to significant differences between EESC and modelled inorganic halogen loading at constant mean age, EESC is a reasonable proxy for modelled inorganic halogen on a constant pressure level.
Mishra, Bagdevi ; Gupta, Deepak Kumar ; Pfenninger, Markus ; Hickler, Thomas ; Langer, Ewald ; Nam, Bora ; Paule, Juraj ; Sharma, Rahul ; Ulaszewski, Bartosz ; Warmbier, Joanna ; Burczyk, Jarosław ; Thines, Marco
Background: The European beech is arguably the most important climax broad-leaved tree species in Central Europe, widely planted for its valuable wood. Here, we report the 542 Mb draft genome sequence of an up to 300-year-old individual (Bhaga) from an undisturbed stand in the Kellerwald-Edersee National Park in central Germany.
Findings: Using a hybrid assembly approach, Illumina reads with short- and long-insert libraries, coupled with long Pacific Biosciences reads, we obtained an assembled genome size of 542 Mb, in line with flow cytometric genome size estimation. The largest scaffold was of 1.15 Mb, the N50 length was 145 kb, and the L50 count was 983. The assembly contained 0.12% of Ns. A Benchmarking with Universal Single-Copy Orthologs (BUSCO) analysis retrieved 94% complete BUSCO genes, well in the range of other high-quality draft genomes of trees. A total of 62,012 protein-coding genes were predicted, assisted by transcriptome sequencing. In addition, we are reporting an efficient method for extracting high-molecular-weight DNA from dormant buds, by which contamination by environmental bacteria and fungi was kept at a minimum.
Conclusions: The assembled genome will be a valuable resource and reference for future population genomics studies on the evolution and past climate change adaptation of beech and will be helpful for identifying genes, e.g., involved in drought tolerance, in order to select and breed individuals to adapt forestry to climate change in Europe. A continuously updated genome browser and download page can be accessed from beechgenome.net, which will include future genome versions of the reference individual Bhaga, as new sequencing approaches develop.
Kaese, Thomas ; Trageser, Timo ; Budy, Hendrik ; Bolte, Michael ; Lerner, Hans-Wolfram ; Wagner, Matthias
Organoboranes are among the most versatile and widely used reagents in synthetic chemistry. A significant further expansion of their application spectrum would be achievable if boron-containing reactive intermediates capable of inserting into C–H bonds or performing nucleophilic substitution reactions were readily available. However, current progress in the field is still hampered by a lack of universal design concepts and mechanistic understanding. Herein we report that the doubly arylene-bridged diborane(6) 1H2 and its B[double bond, length as m-dash]B-bonded formal deprotonation product Li2[1] can activate the particularly inert C(sp3)–H bonds of added H3CLi and H3CCl, respectively. The first case involves the attack of [H3C]− on a Lewis-acidic boron center, whereas the second case follows a polarity-inverted pathway with nucleophilic attack of the B[double bond, length as m-dash]B double bond on H3CCl. Mechanistic details were elucidated by means of deuterium-labeled reagents, a radical clock, α,ω-dihaloalkane substrates, the experimental identification of key intermediates, and quantum-chemical calculations. It turned out that both systems, H3CLi/1H2 and H3CCl/Li2[1], ultimately funnel into the same reaction pathway, which likely proceeds past a borylene-type intermediate and requires the cooperative interaction of both boron atoms.
O artigo trata da análise crítica de Jürgen Habermas da redefinição do papel político da Europa, mais voltada para a justiça social e a solidariedade, para um viés predominantemente econômico, de versão mais econômico-liberal, mais próxima da produtividade e da concorrência. A mudança política da integração europeia busca reforçar o pilar econômico da união monetária pela implementação de programas de ajustamento econômico do FMI. A consequência da opção da União Europeia por uma Europa-mercado de formato neoliberal é o desmonte do Estado social (mais voltado para justiça social) e a corrosão do elemento democrático das democracias nacionais (o esvaziamento da democracia). A consequência política dessa opção pelo neoliberalismo é a centralização supranacional de competências reguladoras para agências e organismos transnacionais europeus (Banco Central Europeu, Comissão Europeia, Tribunal Europeu, Parlamento Europeu), que lidam com acordos, contratos e tratados internacionais que deveriam funcionar como equivalentes de uma regulação política. O problema é a aprovação, a portas fechadas, de medidas que visam o controle da política econômica em detrimento da coordenação política. Isso implica a imposição de resoluções em áreas centrais de responsabilidade dos parlamentos dos Estados membros, potencializando nos Estados nacionais os problemas de legitimação necessária para implementar as políticas recomendadas de cima, explicitando a falha na construção da união monetária pela ausência dos instrumentos de uma política econômica comum.
O presente objeto de pesquisa busca proceder ao estudo e identificação dos traços essenciais envolvidos na abordagem teórica das relações sociais e políticas trazidas na obra O Direito da Liberdade do filósofo alemão Axel Honneth. Faz-se uma análise da influência hegeliana sobre o conceito de liberdade, assim como dos fatores relacionados com o suprimento das carências subjetivas, mediadas pelas diferentes “esferas” sociais. Honneth, assim, procura trazer à tona a compreensão de um novo modelo de liberdade advindo da Filosofia do Direito de Hegel, o qual se distingue substancialmente dos modelos tradicionais. O autor busca evidenciar a limitação das teorias da justiça de tradição liberal, invocando a necessidade de uma visão integrada das relações sociais experimentadas nas esferas referidas por Hegel, concebendo-se uma experiência concreta de liberdade social. Nesse sentido, evidencia-se o caráter interdisciplinar e emancipatório do método de reconstrução normativa como base teórica para a justificação pública nas sociedades modernas.
THE FINANCIAL SERVICES INDUSTRY IS OPERATING IN HIGHLY VOLATILE MARKETS.
TO CONSIDER THE IMPACT OF UNCERTAIN MARKET ENVIRONMENTS ON INAND OUTSOURCING DECISIONS, WE INTRODUCE A REAL OPTIONS BASED DECISION SUPPORT MODEL. WE APPLY THE MODEL TO AN IT INFRASTRUCTURE OUTSOURCING DECISION AND DETERMINE - BASED ON COST SAVINGS RESULTING FROM OUTSOURCING AND OPTION VALUES ACCOUNTING FOR UNCERTAINTY - DIFFERENT “TRIGGER” OUTPUT VOLUMES WHICH INDICATE IF IN- OR OUTSOURCING IS PREFERABLE. FINALLY WE SHOW THAT THE MODEL CAN ALSO BE TRANSFERRED TO SOURCING DECISIONS OF TRANSACTION BASED BUSINESS PROCESSES LIKE CLEARING AND SETTLEMENT OF SECURITIES.
A rare cause of recurrent melena was identified by capsule endoscopy: arteriovenous malformation
(2013)
Small bowel endoscopy is indicated for patients with an unidentified bleeding site in esophagogastroduodenoscopy and ileocolonoscopy and symptoms of intestinal blood loss or unexplained anemia. In approximately two-thirds of these cases, capsule endoscopy (CE) detects a lesion within the small bowel that explains the patient's symptoms.
The case of an 80-year-old female patient with recurrent melena and anemia is presented here by the authors. Endoscopy of the upper gastrointestinal tract as well as ileocolonoscopy did not show any pathological findings. CE revealed an area with abnormal mucosa in the middle third of the small bowel, which was strongly suspected of having malignant origin. Surgical exploration led to resection of a small jejunal segment with a palpable mass and increased blood flow. Surprisingly, the final diagnosis determined by the pathologist was arteriovenous malformation (AVM). This article is part of an expert video encyclopedia.
A range-wide synthesis and timeline for phylogeographic events in the red fox (Vulpes vulpes)
(2013)
Kutschera, Verena Esther ; Lecomte, Nicolas ; Janke, Axel ; Selva, Nuria ; Sokolov, Alexander A. ; Haun, Timm ; Steyer, Katharina Gloria ; Nowak, Carsten ; Hailer, Frank
Background: Many boreo-temperate mammals have a Pleistocene fossil record throughout Eurasia and North America, but only few have a contemporary distribution that spans this large area. Examples of Holarctic-distributed carnivores are the brown bear, grey wolf, and red fox, all three ecological generalists with large dispersal capacity and a high adaptive flexibility. While the two former have been examined extensively across their ranges, no phylogeographic study of the red fox has been conducted across its entire Holarctic range. Moreover, no study included samples from central Asia, leaving a large sampling gap in the middle of the Eurasian landmass.
Results: Here we provide the first mitochondrial DNA sequence data of red foxes from central Asia (Siberia), and new sequences from several European populations. In a range-wide synthesis of 729 red fox mitochondrial control region sequences, including 677 previously published and 52 newly obtained sequences, this manuscript describes the pattern and timing of major phylogeographic events in red foxes, using a Bayesian coalescence approach with multiple fossil tip and root calibration points. In a 335 bp alignment we found in total 175 unique haplotypes. All newly sequenced individuals belonged to the previously described Holarctic lineage. Our analyses confirmed the presence of three Nearctic- and two Japan-restricted lineages that were formed since the Mid/Late Pleistocene.
Conclusions: The phylogeographic history of red foxes is highly similar to that previously described for grey wolves and brown bears, indicating that climatic fluctuations and habitat changes since the Pleistocene had similar effects on these highly mobile generalist species. All three species originally diversified in Eurasia and later colonized North America and Japan. North American lineages persisted through the last glacial maximum south of the ice sheets, meeting more recent colonizers from Beringia during postglacial expansion into the northern Nearctic. Both brown bears and red foxes colonized Japan’s northern island Hokkaido at least three times, all lineages being most closely related to different mainland lineages. Red foxes, grey wolves, and brown bears thus represent an interesting case where species that occupy similar ecological niches also exhibit similar phylogeographic histories.
Aygören-Pürsün, Emel ; Soteres, Daniel F. ; Nieto‐Martinez, Sandra A. ; Christensen, Jim ; Jacobson, Kraig W. ; Moldovan, Dumitru ; Leerberghe, Arthur van ; Tang, Yongqiang ; Lu, Peng ; Vardi, Moshe ; Schranz, Jennifer ; Martinez Saguer, Inmaculada
BACKGROUND: Patients with hereditary angioedema with C1 inhibitor deficiency or dysfunction have burdensome recurrent angioedema attacks. The safety, efficacy, and health-related quality of life (HRQoL) outcomes of C1 inhibitor (C1-INH) prophylaxis (intravenously administered) in patients aged 6-11 years were investigated.
METHODS: Eligible patients were enrolled in a randomized, single-blind, crossover, phase 3 trial. After a 12-week baseline observation period (BOP), patients received 500 or 1000 U C1-INH, twice weekly, for 12 weeks before crossing over to the alternate dose for 12 weeks. The primary efficacy end-point was the monthly normalized number of angioedema attacks (NNA). HRQoL was assessed using the EuroQoL 5-dimensional descriptive system youth version and visual analog scale (EQ-VAS).
RESULTS: Twelve randomized patients had a median (range) age of 10.0 (7-11) years. Mean (SD) percentage reduction in monthly NNA from BOP was 71.1% (27.1%) with 500 U and 84.5% (20.0%) with 1000 U C1-INH. Mean (SD) within-patient difference (-0.4 [0.58]) for monthly NNA with both doses was significant (P = 0.035 [90% CI, -0.706 to -0.102]). Cumulative attack severity, cumulative daily severity, and number of acute attacks treated were reduced. No serious adverse events or discontinuations occurred. Mean EQ-VAS change from BOP to week 9 of treatment (500 U C1-INH, 10.4; 1000 U C1-INH, 21.6) was greater than the minimal important difference, indicating a meaningful HRQoL change.
CONCLUSIONS: C1-INH prophylaxis was effective, safe, and well tolerated in children aged 6-11 years experiencing recurrent angioedema attacks. A post hoc analysis indicated a meaningful improvement in HRQoL with C1-INH.
TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02052141.
Harbeck, Nadia ; Saupe, Steffen ; Jäger, Elke ; Schmidt, Marcus ; Kreienberg, Rolf ; Müller, Lothar ; Otremba, Burkhard ; Waldenmaier, Dirk ; Dorn, Julia ; Warm, Mathias ; Scholz, Michael ; Untch, Michael ; Wit, Maike de ; Barinoff, Jana ; Lück, Hans-Joachim ; Harter, Philipp ; Augustin, Doris ; Harnett, Paul ; Beckmann, Matthias Wilhelm ; Batran, Salah-Eddin al-
Purpose: The PELICAN trial evaluates for the first time efficacy and safety of pegylated liposomal doxorubicin (PLD) versus capecitabine as first-line treatment of metastatic breast cancer (MBC).
Methods: This randomized, phase III, open-label, multicenter trial enrolled first-line MBC patients who were ineligible for endocrine or trastuzumab therapy. Cumulative adjuvant anthracyclines of 360 mg/m2 doxorubicin or equivalent were allowed. Left ventricular ejection fraction of >50 % was required. Patients received PLD 50 mg/m2 every 28 days or capecitabine 1250 mg/m2 twice daily for 14 days every 21 days. The primary endpoint was time-to-disease progression (TTP).
Results: 210 patients were randomized (n = 105, PLD and n = 105, capecitabine). Adjuvant anthracyclines were given to 37 % (PLD) and 36 % (capecitabine) of patients. No significant difference was observed in TTP [HR = 1.21 (95 % confidence interval, 0.838–1.750)]. Median TTP was 6.0 months for both PLD and capecitabine. Comparing patients with or without prior anthracyclines, no significant difference in TTP was observed in the PLD arm (log-rank P = 0.64). For PLD versus capecitabine, respectively, overall survival (median, 23.3 months vs. 26.8 months) and time-to-treatment failure (median, 4.6 months vs. 3.7 months) were not statistically significantly different. Compared to PLD, patients on capecitabine experienced more serious adverse events (P = 0.015) and more cardiac events among patients who had prior anthracycline exposure (18 vs. 8 %; P = 0.31).
Conclusion: Both PLD and capecitabine are effective first-line agents for MBC.
Bergmann, Lothar ; Grünwald, Viktor ; Maute, Luise ; Grimm, Marc-Oliver ; Weikert, Steffen ; Schleicher, Jan ; Klotz, Theodor ; Greiner, Jochen ; Flörcken, Anne ; Hartmann, Arndt ; Gauler, Thomas
Background: Non-clear cell renal cell cancers (nccRCC) are rare entities, and the optimal therapy in metastatic disease has still to be defined. Methods: In this small prospectively randomized phase IIa multicenter trial, we investigated temsirolimus (TEM) versus sunitinib (SUN) as first-line therapy in patients with metastatic nccRCC. The patients were randomized 1:1 to either TEM in a dose of 25 mg i.v. once a week or SUN with 50 mg p.o. daily for 4 weeks on and 2 weeks off. Primary endpoint was progression-free survival (PFS). In total, 22 patients were included with predominantly papillary RCC (16/22) followed by chromophobe RCC and others. Results: The male to female ratio was 16:6. The tumor control rate (CR + PR + SD) was 58% for TEM and 90% for SUN-treated patients. There was also a trend for improved PFS with 9.3 versus 13.2 months (HR 1.64; 95% CI 0.65–4.18) in favor of SUN. There was no trend for overall survival. Conclusions: Despite this trial had to be terminated earlier due to low recruitment, the results match the other studies published so far with the mTOR inhibitor everolimus and SUN, which show a trend in favor of SUN for ORR and PFS.
A randomised, double-blind, placebo-controlled trial of trichuris suis ova in active crohn's disease
(2017)
Schölmerich, Jürgen ; Fellermann, Klaus ; Seibold, Frank W. ; Rogler, Gerhard ; Langhorst, Jost ; Howaldt, Stefanie ; Novacek, Gottfried ; Petersen, Andreas Munk ; Bachmann, Oliver ; Matthes, Harald ; Hesselbarth, Norbert ; Teich, Niels ; Wehkamp, Jan ; Klaus, Jochen ; Ott, Claudia ; Dilger, Karin ; Greinwald, Roland ; Mueller, Ralph
BACKGROUND AND AIMS To investigate the efficacy and safety of three different dosages of embryonated, viable eggs of Trichuris suis [TSO] versus placebo for induction of remission in mildly-to-moderately active ileocolonic, uncomplicated Crohn's disease [CD].
METHODS Adults with active CD [n = 252] randomly received six fortnightly doses of 250, 2500, or 7500 TSO/15 ml suspension/day [TSO 250, TSO 2500, TSO 7500], or 15 ml placebo solution/day, in a double-blind fashion, with 4 weeks' follow-up. Primary endpoint was the rate of clinical remission [Crohn's Disease Activity Index [CDAI] < 150] at end of treatment, ie at Week 12 or withdrawal. Secondary endpoints included the course of clinical remission, rate of clinical response, change in CDAI, change in markers of inflammation, mucosal healing, and Physician's Global Assessment.
RESULTS Clinical remission at Week 12 occurred in 38.5%, 35.2%, and 47.2% of TSO 250, TSO 2500, and TSO 7500 patients, respectively, and in 42.9% of placebo recipients. TSO induced a dose-dependent immunological response. There was no response regarding laboratory markers of inflammation. Other secondary efficacy variables also showed no advantage of TSO over placebo for treatment of active CD. Administration of TSO did not result in any serious adverse drug reaction. Review of non-serious suspected adverse drug reactions following TSO did not reveal any safety concerns.
CONCLUSIONS Administration of 250-7500 TSO fortnightly over 12 weeks was safe and showed a dose-dependent immunological response, but no TSO dose showed a clinically relevant effect over placebo for induction of clinical remission or response in mildly-to-moderately active, ileocolonic CD.
Podda, Maurizio ; Kovács, Maximilian ; Hellmich, Martin ; Roth, Rebecca ; Marouan, Zarrouk ; Kraus, Daria Christina ; Prinz-Langenohl, Reinhild ; Cornely, Oliver Andreas
Background: Lipedema is a chronic disorder of the adipose tissue that affects mainly women, characterised by symmetrical, excessive fatty tissue on the legs and pain. Standard conservative treatment is long-term comprehensive decongestive therapy (CDT) to alleviate lipedema-related pain and to improve psychosocial well-being, mobility and physical activity. Patients may benefit from surgical removal of abnormally propagated adipose tissue by liposuction. The LIPLEG trial evaluates the efficacy and safety of liposuction compared to standard CDT.
Methods/design: LIPLEG is a randomised controlled multicentre investigator-blinded trial. Women with lipedema (n=405) without previous liposuction will be allocated 2:1 to liposuction or CDT. The primary outcome of the trial is leg pain reduction by ≥2 points on a visual analogue scale ranging 0–10 at 12 months on CDT or post-completion of liposuction. Secondary outcomes include changes in leg pain severity, health-related quality of life, depression tendency, haematoma tendency, prevalence of oedema, modification physical therapy scope, body fat percentage, leg circumference and movement restriction.
The primary analysis bases on intention-to-treat. Success proportions are compared using the Mantel-Haenszel test stratified by lipedema stage at a 5% two-sided significance level. If this test is statistically significant, the equality of the response proportions in the separate strata is evaluated by Fisher’s exact test in a hierarchical test strategy.
Discussion: LIPLEG assesses whether surgical treatment of lipedema is safe and effective to reduce pain and other lipedema-related health issues. The findings of this trial have the potential to change the standard of care in lipedema.
Trial registration: ClinicalTrials.gov NCT04272827. Registered on February 14, 2020.
Trial status: Protocol version is 02_0, December 17, 2019
A racionalização das tradições na modernidade: o diálogo entre Anthony Giddens e Jürgen Habermas
(2013)
Partindo das reflexões de Habermas e sua concepção de modernidade, compreendida como um projeto inacabado, Giddens salienta que, em todas as sociedades, a manutenção da identidade pessoal e sua conexão com identidades sociais mais amplas é um requisito primordial para a segurança ontológica. Para alcançar a segurança ontológica, a modernidade teve que (re)inventar tradições e se afastar de "tradições genuínas", isto é, aqueles valores radicalmente vinculados ao passado pré-moderno. Este é um caráter de descontinuidade da modernidade – a separação entre o que se apresenta como o novo e o que persiste como herança do velho. É sobre a relação entre tradição e modernidade e sobre um diálogo entre Giddens e Habermas que trata este texto. O objetivo é identificar os pontos de contato e as diferenças das teses defendidas por ambos, a fim de avaliar as contribuições de cada um para se pensar a racionalização das sociedades contemporâneas. A modernidade tardia ou reflexiva é um processo de mudanças ininterruptas que afetam as bases da sociedade ocidental. Frente a uma realidade em constante alteração, faz-se necessário escolher entre uma certeza do passado e uma nova realidade, em contínua mutação. Nesse sentido, e segundo a perspectiva habermasiana, o caráter reflexivo da modernidade está nesse processo de escolha entre as certezas herdadas do passado e as novas formas sociais que conduz à reflexão ou, até mesmo, à reformulação das práticas sociais, provocando a racionalização e a (re)invenção de diversos aspectos da vida em sociedade.
Relacionar a temática referente a Teoria do Reconhecimento de Axel Honnet e o direito humano ao trabalho, como direito humano com pretensão de validade universal, sob a perspectiva da Declaração dos Direitos e Princípios Fundamentais no Trabalho da OIT, com fins de fixar parâmetros de reconhecimento e de (re)inserção social da categoria de trabalhadores toxicodependentes é o principal objetivo do presente artigo. Para tanto, analisaremos o marco teórico em que a persecução da dignidade do homem pelo trabalho é o objetivo do Estado para que a seguir possamos tratar da dignidade do homem como direito cuja pretensão de validade é universal, com base da teoria do reconhecimento de Axel Honneth. Isto posto, podemos analisar a possível dignificação do homem pelo trabalho e no trabalho, em um contexto global a partir dos efeitos do reconhecimento de novos direitos, especialmente no que tange à categoria de trabalhadores que ocupam a parcela social de químico-dependentes, cuja participação no processo social está impedida, gerando uma categoria de trabalhadores socialmente excluídos, o que se pretende ultrapassar.