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Objective: Fluconazle or posaconazole is a standard of care in antifungal prophylaxis for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). However, many patients need to interrupt standard prophylaxis due to intolerability, drug‐drug interactions, or toxicity. Micafungin has come to prominence for these patients. However, the optimal biological dose of micafungin stays unclear.
Methods: We retrospectively evaluated the efficacy of micafungin as antifungal prophylaxis in HSCT patients. Micafungin was applied as bridging in patients who were not eligible to receive oral posaconazole. Micafungin was either given at a dose of 100 mg or 50 mg SID.
Results: A total of 173 patients received micafungin prophylaxis, 62 in the 100 mg and 111 in the 50 mg dose group. The incidence of probable or proven breakthrough IFDs during the observation period was one in the 100 mg and one in the 50 mg group. Fungal‐free survival after 100 days was 98% and 99% (P = .842), and overall survival after 365 days was 60% and 63% (P = .8) respectively. In both groups, micafungin was well tolerated with no grade 3 or 4 toxicities.
Conclusion: In this retrospective analysis, which was not powered to detect non‐inferiority, micafungin is effective and complements posaconazole as fungal prophylaxis in HSCT.
Review of: Vinzenz Brinkmann, Oliver Primavesi, Max Hollein (eds.), Circumlitio. The Polychromy of Antique and Medieval Sculpture. Proceedings of the Johann David Passavant Colloquium, 10-12 December 2008. Liebighaus Skulpturensammlung, Frankfurt am Main, 2010, 423 pp., 334 colour ill.,ISBN 978-3-7774-2871-0
New scientific methods now being applied to the analysis of traces of pigments and gilding on ancient Greek and Roman marble statuary, and other marble artefacts, have the potential to revolutionise our understanding of the relationship between form and colour in antiquity. At present the enquiry is still in its infancy, but the papers delivered at a conference held in Frankfurt in 2008, reviewed here, provide a general introduction to the subject and to a wide range of work in progress.
Characteristics and clinical outcome of breast cancer patients with asymptomatic brain metastases
(2020)
Simple Summary: The prognosis for patients with breast cancer that has spread to the brain is poor, and survival for these women hasn’t improved over the last few decades. We do not currently test for asymptomatic brain metastases in breast cancer patients, although this does happen in some other types of cancer. In this study we wanted to find out more about breast cancer that has spread to the brain and in particular to see whether there might be any advantage to spotting brain metastases before the development of neurological symptoms. Overall, our results suggest that women could be better off if their brain metastases are diagnosed before they begin to cause symptoms. We now need to carry out a clinical trial to see what happens if we screen high-risk breast cancer patients for brain metastases. This will verify whether doing so could increase survival, symptom control or quality of life.
Abstract: Background: Brain metastases (BM) have become a major challenge in patients with metastatic breast cancer. Methods: The aim of this analysis was to characterize patients with asymptomatic BM (n = 580) in the overall cohort of 2589 patients with BM from our Brain Metastases in Breast Cancer Network Germany (BMBC) registry. Results: Compared to symptomatic patients, asymptomatic patients were slightly younger at diagnosis (median age: 55.5 vs. 57.0 years, p = 0.01), had a better performance status at diagnosis (Karnofsky index 80–100%: 68.4% vs. 57%, p < 0.001), a lower number of BM (>1 BM: 56% vs. 70%, p = 0.027), and a slightly smaller diameter of BM (median: 1.5 vs. 2.2 cm, p < 0.001). Asymptomatic patients were more likely to have extracranial metastases (86.7% vs. 81.5%, p = 0.003) but were less likely to have leptomeningeal metastasis (6.3% vs. 10.9%, p < 0.001). Asymptomatic patients underwent less intensive BM therapy but had a longer median overall survival (statistically significant for a cohort of HER2-positive patients) compared to symptomatic patients (10.4 vs. 6.9 months, p < 0.001). Conclusions: These analyses show a trend that asymptomatic patients have less severe metastatic brain disease and despite less intensive local BM therapy still have a better outcome (statistically significant for a cohort of HER2-positive patients) than patients who present with symptomatic BM, although a lead time bias of the earlier diagnosis cannot be ruled out. Our analysis is of clinical relevance in the context of potential trials examining the benefit of early detection and treatment of BM.
The ecological validity of neuropsychological testing (NT) has been questioned in the sports environment. A frequent criticism is that NT, mostly consisting of pen and paper or digital assessments, lacks relevant bodily movement. This study aimed to identify the determinants of a newly developed testing battery integrating both cognitive and motor demands. Twenty active individuals (25 ± 3 years, 11 males) completed the new motor-cognitive testing battery (MC), traditional NT (Stroop test, Trail Making test, Digit Span test) and isolated assessments of motor function (MF; Y-balance test, 20m-sprint, counter-movement jump). Kendal’s tau and partial Spearman correlations were used to detect associations between MC and NT/MF. Except for two items (Reactive Agility A and counter-movement jump; Run-Decide and sprint time; r = 0.37, p < 0.05), MC was not related to MF. Similarly, MC and NT were mostly unrelated, even when controlling for the two significant motor covariates (p > 0.05). The only MC item with (weak to moderate) associations to NT was the Memory Span test (Digit Span backwards and composite; r = 0.43–0.54, p < 0.05). In sum, motor-cognitive function appears to be largely independent from its two assumed components NT and MF and may represent a new parameter in performance diagnostics.
Diverse extracellular signals induce plasma membrane translocation of sphingosine kinase-1 (SphK1), thereby enabling inside-out signaling of sphingosine-1-phosphate. We have shown before that Gq-coupled receptors and constitutively active Gαq/11 specifically induced a rapid and long-lasting SphK1 translocation, independently of canonical Gq/phospholipase C (PLC) signaling. Here, we further characterized Gq/11 regulation of SphK1. SphK1 translocation by the M3 receptor in HEK-293 cells was delayed by expression of catalytically inactive G-protein-coupled receptor kinase-2, p63Rho guanine nucleotide exchange factor (p63RhoGEF), and catalytically inactive PLCβ3, but accelerated by wild-type PLCβ3 and the PLCδ PH domain. Both wild-type SphK1 and catalytically inactive SphK1-G82D reduced M3 receptor-stimulated inositol phosphate production, suggesting competition at Gαq. Embryonic fibroblasts from Gαq/11 double-deficient mice were used to show that amino acids W263 and T257 of Gαq, which interact directly with PLCβ3 and p63RhoGEF, were important for bradykinin B2 receptor-induced SphK1 translocation. Finally, an AIXXPL motif was identified in vertebrate SphK1 (positions 100–105 in human SphK1a), which resembles the Gαq binding motif, ALXXPI, in PLCβ and p63RhoGEF. After M3 receptor stimulation, SphK1-A100E-I101E and SphK1-P104A-L105A translocated in only 25% and 56% of cells, respectively, and translocation efficiency was significantly reduced. The data suggest that both the AIXXPL motif and currently unknown consequences of PLCβ/PLCδ(PH) expression are important for regulation of SphK1 by Gq/11.
Crustal structure at the western end of the North Anatolian Fault Zone from deep seismic sounding
(2001)
The first deep seismic sounding experiment in Northwestern Anatolia was carried out in October 1991 as part of the "German - Turkish Project on Earthquake Prediction Research" in the Mudurnu area of the North Anatolian Fault Zone. The experiment was a joint enterprise by the Institute of Meteorology and Geophysics of Frankfurt University, the Earthquake Research Institute (ERI) in Ankara, and the Turkish Oil Company (TPAO). Two orthogonal profiles, each 120 km in length with a crossing point near Akyazi, were covered in succession by 30 short period tape recording seismograph stations with 2 km station spacing. 12 shots, with charge sizes between 100 and 250 kg, were fired and 342 seismograms out of 360 were used for evaluation. By coincidence an M b = 4.5 earthquake located below Imroz Island was also recorded and provided additional information on Moho and the sub-Moho velocity. A ray tracing method orginally developed by Weber (1986) was used for travel time inversion. From a compilation of all data two generalized crustal models were derived, one with velocity gradients within the layers and one with constant layer velocities. The latter consists of a sediment cover of about 2 km with V p » 3.6 km/s, an upper crystalline crust down to 13 km with V p » 5.9 km/s, a middle crust down to 25 km depth with V p » 6.5 km/s, a lower crust down to 39 km Moho depth with V p » 7.0 km/s and V p » 8.05 km/s below the Moho. The structure of the individual profiles differs slightly. The thickest sediment cover is reached in the Izmit-Sapanca-trough and in the Akyazi basin. Of particular interest is a step of about 4 km in the lower crust near Lake Sapanca and probably an even larger one in the Moho (derived from the Imroz earthquake data). After the catastrophic earthquake of Izmit on 17 August 1999 this significant heterogeneity in crustal structure appears in a new light with regard to the possible cause of the Izmit earthquake. Heterogeneities in structure are frequently also heterogeneities in strength and stress that impede or even lock rupture. The Izmit earthquake is discussed in relation to a large stepover or jog at the North Anatolian Fault.
Background: A large number of idiosyncratic drug induced liver injury (iDILI) and herb induced liver injury(HILI) cases of variable quality has been published but some are a matter of concern if the cases were not evaluated for causality using a robust causality assessment method (CAM) such as RUCAM (Roussel Uclaf Causality Assessment Method) as diagnostiinjuryc algorithm. The purpose of this analysis was to evaluate the worldwide use of RUCAM in iDILI and HILI cases. Methods: The PubMed database (1993–30 June 2020) was searched for articles by using the following key terms: Roussel Uclaf Causality Assessment Method; RUCAM; Idiosyncratic drug induced liver injury; iDILI; Herb induced liver injury; HILI. Results: Considering reports published worldwide since 1993, our analysis showed the use of RUCAM for causality assessment in 95,885 cases of liver injury including 81,856 cases of idiosyncratic DILI and 14,029 cases of HILI. Among the top countries providing RUCAM based DILI cases were, in decreasing order, China, the US, Germany, Korea, and Italy, with China, Korea, Germany, India, and the US as the top countries for HILI. Conclusion: Since 1993 RUCAM is certainly the most widely used method to assess causality in IDILI and HILI. This should encourage practitioner, experts, and regulatory agencies to use it in order to reinforce their diagnosis and to take sound decisions.
We model the decisions of young individuals to stay in school or drop out and engage in criminal activities. We build on the literature on human capital and crime engagement and use the framework of Banerjee (1993) that assumes that the information needed to engage in crime arrives in the form of a rumour and that individuals update their beliefs about the profitability of crime relative to education. These assumptions allow us to study the effect of social interactions on crime. In our model, we investigate informational spillovers from the actions of talented students to less talented students. We show that policies that decrease the cost of education for talented students may increase the vulnerability of less talented students to crime. The effect is exacerbated when students do not fully understand the underlying learning dynamics.
Various strategies have been employed to speed tissue regeneration using bioactive molecules. Interestingly, platelet concentrates derived from a patient’s own blood have been utilized as a regenerative strategy in recent years. In the present study, a novel liquid platelet formulation prepared without the use of anti-coagulants (injectable-platelet-rich fibrin, i-PRF) was compared to standard platelet-rich plasma (PRP) with gingival fibroblasts cultured on smooth and roughened titanium implant surfaces. Standard PRP and i-PRF (centrifuged at 700 rpm (60× g) for 3 min) were compared by assays for fibroblast biocompatibility, migration, adhesion, proliferation, as well as expression of platelet-derived growth factor (PDGF), transforming growth factor-β (TGF-β), collagen1 (COL1) and fibronectin (FN). The results demonstrate that i-PRF induced significantly higher cell migration, as well as higher messenger RNA (mRNA) levels of PDGF, TGF-β, collagen1 and fibronectin when compared to PRP. Furthermore, collagen1 synthesis was highest in the i-PRF group. These findings demonstrate that liquid platelet concentrates can be formulated without the use of anticoagulants and present much translational potential for future research. Future animal and clinical trials are now necessary to further investigate the potential of utilizing i-PRF for soft tissue regenerative protocols in combination with various biomaterials.
We aim to understand whether Greek and Italian, two null subject languages, differ in the use and interpretation of null subjects, based on evidence from both a production and a comprehension experiment. The results of the two experiments show that the two languages differ in the extent to which they comply with the Position of Antecedent Strategy as formulated by Carminati (2002). In order to account for this difference, we introduce a principle which defines prominence of sentence constituents in terms of hierarchical height, elaborating on a recent proposal by Rizzi (2018). Then we show that the prominence of subject and object constituents in Greek and Italian reflects word-order differences between the two languages (Roussou & Tsimpli 2006). In more general terms, this paper argues in favour of a multi-factorial approach to reference interpretation, in that syntactic factors interact with discourse factors, leading to a gradient variety of reference possibilities.
Background and objectives: Preoperative anaemia is an independent risk factor for a higher morbidity and mortality, a longer hospitalization and increased perioperative transfusion rates. Managing preoperative anaemia is the first of three pillars of Patient Blood Management (PBM), a multidisciplinary concept to improve patient safety. While various studies provide medical information on (successful) anaemia treatment pathways, knowledge of organizational details of diagnosis and management of preoperative anaemia across Europe is scarce.
Materials and methods: To gain information on various aspects of preoperative anaemia management including organization, financing, diagnostics and treatment, we conducted a survey (74 questions) in ten hospitals from seven European nations within the PaBloE (Patient Blood Management in Europe) working group covering the year 2016.
Results: Organization and activity in the field of preoperative anaemia management were heterogeneous in the participating hospitals. Almost all hospitals had pathways for managing preoperative anaemia in place, however, only two nations had national guidelines. In six of the ten participating hospitals, preoperative anaemia management was organized by anaesthetists. Diagnostics and treatment focused on iron deficiency anaemia which, in most hospitals, was corrected with intravenous iron.
Conclusion: Implementation and approaches of preoperative anaemia management vary across Europe with a primary focus on treating iron deficiency anaemia. Findings of this survey motivated the hospitals involved to critically evaluate their practice and may also help other hospitals interested in PBM to develop action plans for diagnosis and management of preoperative anaemia.
Aim: To provide distribution information and preliminary conservation assessments for all species of the pineapple family (Bromeliaceae), one of the most diverse and ecologically important plant groups of the American tropics—a global biodiversity hotspot. Furthermore, we aim to analyse patterns of diversity, endemism and the conservation status of the Bromeliaceae on the continental level in the light of their evolutionary history.
Location: The Americas.
Methods: We compiled a dataset of occurrence records for 3,272 bromeliad species (93.4% of the family) and modelled their geographic distribution using either climate‐based species distribution models, convex hulls or geographic buffers dependent on the number of occurrences available. We then combined this data with information on taxonomy and used the ConR software for a preliminary assessment of the conservation status of all species following Criterion B of the International Union for the Conservation of Nature (IUCN).
Results: Our results stress the Atlantic Forest in eastern Brazil, the Andean slopes, Central America and the Guiana Highlands as centres of bromeliad diversity and endemism. Phylogenetically ancient subfamilies of bromeliads are centred in the Guiana highlands whereas the large radiations of the group spread across different habitats and large geographic area. A total of 81% of the evaluated bromeliad species are Possibly Threatened with extinction. We provide range polygons for 3,272 species, as well as newly georeferenced point localities for 911 species in the novel “bromeliad” r package, together with functions to generate diversity maps for individual taxonomic or functional groups.
Main conclusions: Diversity centres of the Bromeliaceae agreed with macroecological patterns of other plant and animal groups, but show some particular patterns related to the evolutionary origin of the family, especially ancient dispersal corridors. A staggering 2/3rds of Bromeliaceae species might be threatened with extinction, especially so in tropical rain forests, raising concerns about the conservation of the family and bromeliad‐dependent animal species.
Colorectal cancer (CRC) is one of the most frequently diagnosed tumor in humans and one of the most common causes of cancer-related death worldwide. The pathogenesis of CRC follows a multistage process which together with somatic gene mutations is mainly attributed to the dysregulation of signaling pathways critically involved in the maintenance of homeostasis of epithelial integrity in the intestine. A growing number of studies has highlighted the critical impact of members of the tripartite motif (TRIM) protein family on most types of human malignancies including CRC. In accordance, abundant expression of many TRIM proteins has been observed in CRC tissues and is frequently correlating with poor survival of patients. Notably, some TRIM members can act as tumor suppressors depending on the context and the type of cancer which has been assessed. Mechanistically, most cancer-related TRIMs have a critical impact on cell cycle control, apoptosis, epithelial–mesenchymal transition (EMT), metastasis, and inflammation mainly through directly interfering with diverse oncogenic signaling pathways. In addition, some recent publications have emphasized the emerging role of some TRIM members to act as transcription factors and RNA-stabilizing factors thus adding a further level of complexity to the pleiotropic biological activities of TRIM proteins. The current review focuses on oncogenic signaling processes targeted by different TRIMs and their particular role in the development of CRC. A better understanding of the crosstalk of TRIMs with these signaling pathways relevant for CRC development is an important prerequisite for the validation of TRIM proteins as novel biomarkers and as potential targets of future therapies for CRC.
Summary
Wild relatives of crops thrive in habitats where environmental conditions can be restrictive for productivity and survival of cultivated species. The genetic basis of this variability, particularly for tolerance to high temperatures, is not well understood. We examined the capacity of wild and cultivated accessions to acclimate to rapid temperature elevations that cause heat stress (HS).
We investigated genotypic variation in thermotolerance of seedlings of wild and cultivated accessions. The contribution of polymorphisms associated with thermotolerance variation was examined regarding alterations in function of the identified gene.
We show that tomato germplasm underwent a progressive loss of acclimation to strong temperature elevations. Sensitivity is associated with intronic polymorphisms in the HS transcription factor HsfA2 which affect the splicing efficiency of its pre‐mRNA. Intron splicing in wild species results in increased synthesis of isoform HsfA2‐II, implicated in the early stress response, at the expense of HsfA2‐I which is involved in establishing short‐term acclimation and thermotolerance.
We propose that the selection for modern HsfA2 haplotypes reduced the ability of cultivated tomatoes to rapidly acclimate to temperature elevations, but enhanced their short‐term acclimation capacity. Hence, we provide evidence that alternative splicing has a central role in the definition of plant fitness plasticity to stressful conditions.
Aim: Predicting future changes in species richness in response to climate change is one of the key challenges in biogeography and conservation ecology. Stacked species distribution models (S‐SDMs) are a commonly used tool to predict current and future species richness. Macroecological models (MEMs), regression models with species richness as response variable, are a less computationally intensive alternative to S‐SDMs. Here, we aim to compare the results of two model types (S‐SDMS and MEMs), for the first time for more than 14,000 species across multiple taxa globally, and to trace the uncertainty in future predictions back to the input data and modelling approach used.
Location: Global land, excluding Antarctica.
Taxon: Amphibians, birds and mammals.
Methods: We fitted S‐SDMs and MEMs using a consistent set of bioclimatic variables and model algorithms and conducted species richness predictions under current and future conditions. For the latter, we used four general circulation models (GCMs) under two representative concentration pathways (RCP2.6 and RCP6.0). Predicted species richness was compared between S‐SDMs and MEMs and for current conditions also to extent‐of‐occurrence (EOO) species richness patterns. For future predictions, we quantified the variance in predicted species richness patterns explained by the choice of model type, model algorithm and GCM using hierarchical cluster analysis and variance partitioning.
Results: Under current conditions, species richness predictions from MEMs and S‐SDMs were strongly correlated with EOO‐based species richness. However, both model types over‐predicted areas with low and under‐predicted areas with high species richness. Outputs from MEMs and S‐SDMs were also highly correlated among each other under current and future conditions. The variance between future predictions was mostly explained by model type.
Main conclusions: Both model types were able to reproduce EOO‐based patterns in global terrestrial vertebrate richness, but produce less collinear predictions of future species richness. Model type by far contributes to most of the variation in the different future species richness predictions, indicating that the two model types should not be used interchangeably. Nevertheless, both model types have their justification, as MEMs can also include species with a restricted range, whereas S‐SDMs are useful for looking at potential species‐specific responses.
In 2010, the Conference of the Parties of the Convention on Biological Diversity agreedon the Strategic Plan for Biodiversity 2011–2020 in Aichi Prefecture, Japan. As this planapproaches its end, we discussed whether marine biodiversity and prediction studieswere nearing the Aichi Targets during the 4th World Conference on Marine Biodiversityheld in Montreal, Canada in June 2018. This article summarises the outcome of a five-day group discussion on how global marine biodiversity studies should be focusedfurther to better understand the patterns of biodiversity. We discussed and reviewedseven fundamental biodiversity priorities related to nine Aichi Targets focusing onglobal biodiversity discovery and predictions to improve and enhance biodiversitydata standards (quantity and quality), tools and techniques, spatial and temporal scaleframing, and stewardship and dissemination. We discuss how identifying biodiversityknowledge gaps and promoting efforts have and will reduce such gaps, including via theuse of new databases, tools and technology, and how these resources could be improvedin the future. The group recognised significant progress toward Target 19 in relationto scientific knowledge, but negligible progress with regard to Targets 6 to 13 whichaimed to safeguard and reduce human impacts on biodiversity.
Cardiac reactions to emotional words in adolescents and young adults with PTSD after child abuse
(2019)
Post‐traumatic stress disorder (PTSD) is associated with alterations in cardiac reactivity to threat cues. Meta‐analyses have summarized that adults with PTSD have increased heart rates in response to trauma‐related stimuli. However, the opposite effect (i.e., cardiac hyporeactivity) has recently been reported in subgroups of PTSD patients. In children and adolescents with PTSD, reports of cardiac alterations are rare and ambiguous. So far, most studies in adolescents and young adults are restricted to victims of accidents, even though PTSD is highly prevalent in victims of child maltreatment. The present study aimed at investigating cardiac reactions in adolescents and young adults with PTSD after child abuse. Cardiac responses to standardized emotional words were studied in 39 adolescent and young adult PTSD patients after childhood sexual and/or physical abuse as compared to 39 healthy control subjects (age range: 15–20 years). The experimental paradigm consisted of a passive reading task with neutral, positive, physically threatening, and socially threatening (swear) words. Results showed that cardiac reactions to negative stimuli, particularly physically threatening stimuli, were less pronounced in PTSD patients than in controls. Moreover, cardiac reactions in response to socially threatening words were less variable in the PTSD group. No differences between and within groups were present in reaction to neutral or positive stimuli. Findings suggest that a physiologically blunted subtype of PTSD may already manifest during adolescence and young adulthood. Moreover, the results of the present study emphasize the relevance of individual trauma history for physiological reactions.
Health economics of Patient Blood Management: a cost‐benefit analysis based on a meta‐analysis
(2019)
Background and Objectives: Patient Blood Management (PBM) is the timely application of evidence‐based medical and surgical concepts designed to improve haemoglobin concentration, optimize haemostasis and minimize blood loss in an effort to improve patient outcomes. The focus of this cost‐benefit analysis is to analyse the economic benefit of widespread implementation of a multimodal PBM programme.
Materials and Methods: Based on a recent meta‐analysis including 17 studies (>235 000 patients) comparing PBM with control care and data from the University Hospital Frankfurt, a cost‐benefit analysis was performed. Outcome data were red blood cell (RBC) transfusion rate, number of transfused RBC units, and length of hospital stay (LOS). Costs were considered for the following three PBM interventions as examples: anaemia management including therapy of iron deficiency, use of cell salvage and tranexamic acid. For sensitivity analysis, a Monte Carlo simulation was performed.
Results: Iron supplementation was applied in 3·1%, cell salvage in 65% and tranexamic acid in 89% of the PBM patients. In total, applying these three PBM interventions costs €129·04 per patient. However, PBM was associated with a reduction in transfusion rate, transfused RBC units per patient, and LOS which yielded to mean savings of €150·64 per patient. Thus, the overall benefit of PBM implementation was €21·60 per patient. In the Monte Carlo simulation, the cost savings on the outcome side exceeded the PBM costs in approximately 2/3 of all repetitions and the total benefit was €1 878 000 in 100·000 simulated patients.
Conclusion: Resources to implement a multimodal PBM concept optimizing patient care and safety can be cost‐effectively.
Objective: Novel treatments are needed to control treatment‐resistant status epilepticus (SE). We present a summary of clinical cases where oral topiramate (TPM) was used in refractory SE (RSE) and superrefractory SE (SRSE).
Methods: A review of medical records was carried out to detect TPM administration in SE patients treated in Frankfurt and Marburg between 2011 and 2016. The primary outcome question concerned SE resolution after TPM initiation.
Results: In total, TPM was used in 106 of 854 patients having a mean age of 67.4 ± 18.1 years, 61 of whom were female (57.5%). The median latency from SE onset to TPM initiation was 8.5 days. Patients with SE had previously failed a median of five other antiepileptic drugs. The median initial TPM dose was 100 mg/d, which was uptitrated to a median maintenance dose of 400 mg/d. Treatment with TPM was continued for a median time of 12 days. TPM was the last drug provided to 42 of 106 (39.6%) patients, with a resultant response attributed to TPM observed in 29 of 106 (27.4%) patients. A response was attributed to TPM in 21 (31.8%) of 66 RSE cases and eight (20%) of 40 SRSE cases. Treatment‐emergent adverse events were attributed to TPM usage in two patients, one each with pancreatitis and hyperchloremic acidosis, and in 38 patients (35.8%), hyperammonemia was seen. Thirty‐four of these patients received a combination of TPM and valproate and/or phenobarbital. The intrahospital mortality rate was 22.6% (n = 24).
Significance: The rate of SE cessation attributed to TPM treatment (27.4%) represents a relevant response given the late treatment position of TPM and the treatment latency of more than 8 days. Based on these results and in line with the findings of other case series, TPM can be considered an alternative option for treating RSE and SRSE.
This article discusses freedom of movement under the lens of shifting boundaries of membership and traces the tension between the political and the economic rationale of European integration. It first reflects on the normativity of free movement and links it to the foundations of modern democratic citizenship. Subsequently, it discusses the role of free movement in the construction of EU citizenship and argues that the genesis in market integration casts a long shadow which hinders EU citizenship's potential to fully display the logic of political and social equality. Under current conditions of huge wealth discrepancies between member states, the prevailing form of horizontal integration necessarily brings about a tension between mobility and solidarity, which in turn creates a barrier for further developing EU citizenship. It is concluded that strengthening an intra‐European dimension of solidarity is needed in order to substantiate the right to move as an equal European citizenship right.
Post‐traumatic stress disorder (PTSD) is associated with a hypersensitivity to potential threat. This hypersensitivity manifests through differential patterns of emotional information processing and has been demonstrated in behavioral and neurophysiological experimental paradigms. However, the majority of research has been focused on adult patients with PTSD. To examine possible differences in underlying neurophysiological patterns for adolescent patients with PTSD after childhood sexual and/or physical abuse (CSA/CPA), ERP correlates of emotional word processing in 38 healthy participants and 40 adolescent participants with PTSD after experiencing CSA/CPA were studied. The experimental paradigm consisted of a passive reading task with neutral, positive (e.g., paradise), physically threatening (e.g., torment), and socially threatening (i.e., swearing, e.g., son of a bitch) words. A modulation of P3 amplitudes by emotional valence was found, with positive words inducing less elevated amplitudes over both groups. Interestingly, in later processing, the PTSD group showed augmented early late positive potential (LPP) amplitudes for socially threatening stimuli, while there were no modulations within the healthy control group. Also, region‐specific emotional modulations for anterior and posterior electrode clusters were found. For the anterior LPP, highest activations have been found for positive words, while socially and physically threatening words led to strongest modulations in the posterior LPP cluster. There were no modulations by group or emotional valence at the P1 and EPN stage. The findings suggest an enhanced conscious processing of socially threatening words in adolescent patients with PTSD after CSA/CPA, pointing to the importance of a disjoined examination of threat words in emotional processing research.
A new giant species of the subfamily Rhynchoproctinae with strikingly bi-coloured, red-yellow legs contrasting with a black body is described: Alienostreptus bicoloripes sp. nov. from Vietnam. The new species is assigned to the genus Alienostreptus Pimvichai, Enghoff & Panha, 2010 hitherto comprising one species, A. alienus (Attems, 1936), and differing from other rhynchoproctine genera by having the femoral spine duplicated. Species of this genus share three synapomorphic characters of the subfamily, viz (1) anterior coxal fold forms deep concavity in posterior view, (2) posterior coxal fold very low, and (3) posterior coxal fold with mesal flap. A superficially very similar colourful species from Borneo, also with bi-coloured legs but clearly not belonging to Alienostreptus due to the position of ventral soft pads on male legs, is documented based on photographs.
Objectives: Whereas stationary stability of implants has been postulated for decades, recent studies suggested a phenomenon termed implant migration. This describes a change in position of implants as a reaction to applied forces. The present study aims at employing image registration of in vivo micro‐CT scans from different time points and to assess (a) if migration of continuously loaded implants is possible and (b) migration correlates with the force magnitude.
Material and methods: Two customized machined implants were placed in the dorsal portion of caudal vertebrae in n = 61 rats and exposed to standardized forces (0.5 N, 1.0 N, and 1.5 N) applied through a flat nickel–titanium contraction spring, or no forces (control). Micro‐CT scans were performed at 0, 1, 2, 4, 6, and 8 weeks after surgery. The baseline image was registered with the forthcoming scans. Implant migration was measured as the Euclidean distance between implant tips. Bone remodeling was assessed between the baseline and the forthcoming scans.
Results: The findings confirmed a positional change of the implants at 2 and 8 weeks of healing, and a linear association between applied force and velocity of movement (anterior implant: χ2 = 12.12, df = 3, and p = .007 and posterior implant: χ2 = 20.35, df = 3, and p < .001). Bone apposition was observed around the implants and accompanied by formation of load‐bearing trabeculae and a general cortical thickening close and also distant to the implants.
Conclusion: The present analysis confirmed that implants can migrate in bone. The applied forces seemed to stimulate bone thickening, which could explain why implants migrate without affecting stability.
Impairment in past tense production as well as interaction between tense and aspect have been found in both fluent and non-fluent aphasia (e.g. Dragoy & Bastiaanse, 2013). Inflection has been found to be relatively preserved in semantic dementia (SD) (Thompson et al., 2012). The aims of the present study are a) to compare the morphosyntactic abilities of patients with aphasia and SD in tense and aspect marking and b) to explore the interaction of lexical (+/- telic) and grammatical (perfective/imperfective) aspect in aphasia and SD. A sentence completion task was administered to 30 native speakers of Greek: 10 patients with aphasia (6 anomic, 2 Wernicke and 2 agrammatic), 10 age and education-matched controls, 5 patients with SD and 5 controls. The material consisted of unergative, unaccusative and transitive verbs (12 of each verb class) and the participants had to apply present (imperfective) and past (perfective) tense. Unergative and unaccusative verbs differ in terms of their aspectual properties with the unergative being [-telic], and unaccusative [+telic]. Transitive verbs vary. A principal distinction between the tested conditions was the standard ummarked combination ([+telic] verbs in past perfective and [–telic] verbs in present imperfective) vs. the marked one ([+telic] verbs in present imperfective and [–telic] in past perfective). Both control groups performed at ceiling in all conditions. Aphasic participants were significantly more impaired than the control group in all conditions. SD participants were significantly more impaired than the controls only in the production of present tense (M-W U= 1.5, p= 0.024). There was no difference between past perfective and present imperfective for neither group, but there was an interaction between verb class and tense for the aphasic participants, as performance in unaccusative verbs in past perfective (unmarked condition) was significantly better than in unergatives in past perfective (marked condition) (Z=2.512, p=0.012) but performance in unaccusatives in present imperfective (marked condition) was significantly worse than performance in unergatives in present imperfective (unmarked condition) (Z=2.680, p=0.004). In sum, aphasic participants performed significantly better in the unmarked than in the marked conditions. Such an interaction was not found for the SD group. Aphasic participants performed significantly worse than the SD subjects in past perfective tense (M-W U= 7.5, p=0.029) in total, and the difference was significant only for unaccusative verbs (M-W U= 6.5, p=0.021), although both groups performed very well in this condition. There was no difference in present, neither for each verb class separately nor for the total score. A general past tense deficit cannot be upheld for either group. Rather, SD participants appear relatively impaired in producing present tense. We argue for slight morphosyntactic impairment in SD, although with a different underlying cause than in aphasia. Moreover, our data suggest an effect of aspectual markedness in aphasia but not in SD. We discuss this finding in the light of the different neuropathology of the two populations.
Recent years have witnessed a revival of interest in Marcuse's critical theory. This can be partly ascribed to Marcuse's interdisciplinary approach to humanities and social sciences. Many of Marcuse's ideas and concepts are tacitly present in contemporary social and ecological movements. Contemporary literature on Marcuse is positively inclined to his theory while the critique of Marcuse dates back to the '70s, and remains largely unimpaired. This fact poses significant challenges to the revival of Marcuse's critical theory. This study sets out to report on current interest in Marcuse's critical theory trying to correct "past injustices" by responding to negative criticism. The main flaw of such criticism - as we see it - is in failing to perceive interdisciplinary character of Marcuse's critical theory. Marcuse's renaissance cannot be complete without, to use dialectical term, sublating the history of negative criticism.
This paper studies the link between bank recapitalization and welfare in a dynamic production economy. The model features financial frictions because banks benefit of a cost advantage at monitoring firms and face costly equity issuance. The competitive equilibrium outcome is inefficient because agents do not internalize the effects banks’ capitalization over the allocation of capital, its price and, in turn, firms investments. It follows, individual recapitalizations are sub-optimal and bailout policies may benefit social welfare in the long-run. Bailouts improve capital allocation in states where aggregate banks are poorly capitalized, therefore enhancing their market valuation, fostering investments, and stabilizing the economy recovery path.
Market fragmentation and technological advances increasing the speed of trading altered the functioning and stability of global equity limit order markets. Taking market resiliency as an indicator of market quality, we investigate how resilient are trading venues in a high-frequency environment with cross-venue fragmented order flow. Employing a Hawkes process methodology on high-frequency data for FTSE 100 stocks on LSE, a traditional exchange, and on Chi-X, an alternative venue, we find that when liquidity becomes scarce Chi-X is a less resilient venue than LSE with variations existing across stocks and time. In comparison with LSE, Chi-X has more, longer, and severer liquidity shocks. Whereas the vast majority of liquidity droughts on both venues disappear within less than one minute, the recovery is not lasting, as liquidity shocks spiral over the time dimension. Over half of the shocks on both venues are caused by spiralling. Liquidity shocks tend to spiral more on Chi-X than on LSE for large stocks suggesting that the liquidity supply on Chi-X is thinner than on LSE. Finally, a significant amount of liquidity shocks spill over cross-venue providing supporting evidence for the competition for order flow between LSE and Chi-X.
Deep-water species from the western Indian Ocean off the East African coast and Madagascar, belonging to the subfamily Photinae, are discussed and compared with species from the West Pacific. Phos elegantissimus Hayashi & Habe, 1965, P. hirasei Sowerby, 1913 and P. laevis Kuroda & Habe in Habe, 1961 are recorded from Mozambique and/or from Madagascar, hereby extending their known range considerably into the western Indian Ocean. The East African specimens formerly assigned to Phos roseatus Hinds, 1844 are found to differ from this West Pacific species. In total, five species are described as new: Phos ganii sp. nov., P. geminus sp. nov., P. ladoboides sp. nov., P. pulchritudus sp. nov. and P. testaceus sp. nov.
Features of the Maechidiini (Scarabaeidae: Melolonthinae) genera Maechidius Macleay, 1819, Epholcis Waterhouse, 1875 and Paramaechidius Frey, 1969 are critically revised and a new synonymy is proposed: Maechidius = Epholcis syn. nov. = Paramaechidius syn. nov. A key to and an annotated checklist of Maechidiini from the Indo-Australian transition zone are presented for the first time. Thirty-five new species are described, namely Maechidius aiyura sp. nov., M. alesbezdeki sp. nov., M. awu sp. nov., M. babyrousa sp. nov., M. bintang sp. nov., M. boessnecki sp. nov., M. brocki sp. nov., M. caperatus sp. nov., M. ciliatus sp. nov., M. crypticus sp. nov., M. dani sp. nov., M. deltouri sp. nov., M. dendrolagus sp. nov., M. hamatus sp. nov., M. kazantsevi sp. nov., M. konjo sp. nov., M. lapsus sp. nov., M. legalovi sp. nov., M. leucopsar sp. nov., M. longipes sp. nov., M. mailu sp. nov., M. maleo sp. nov., M. merdeka sp. nov., M. miklouhomaclayi sp. nov., M. nepenthephilus sp. nov., M. owenstanleyi sp. nov., M. riedeli sp. nov., M. similis sp. nov., M. skalei sp. nov., M. sougb sp. nov., M. suwawa sp. nov., M. trivialis sp. nov., M. ursus sp. nov., M. weigeli sp. nov. and M. yamdena sp. nov. Six new synonyms are proposed: Maechidius Macleay, 1819 = Epholcis Waterhouse, 1875 syn. nov. = Paramaechidius Frey, 1969 syn. nov., Maechidius esau Heller, 1914 = M. setosus Moser, 1920 syn. nov. = M. setosellus Frey, 1969 syn. nov., Maechidius heterosquamosus Heller, 1910 comb. rest. = Paramaechidius clypeatus Frey, 1969 syn. nov. and Maechidius paupianus Heller, 1910 = M. arrowi Frey, 1969 syn. nov. The first records of Maechidiini from the Tanimbar Islands (Yamdena), Sangihe Islands (Sangir) and Lesser Sunda Islands (Bali) are documented, of which the latter two are the northern- and westernmost known records of Maechidius and of the tribe Maechidiini. Lectotypes are designated for 23 species. Fifteen new combinations are proposed and the original combination to Maechidius is restored for four species. Ecological data are presented for the first time for selected Papuan and Wallacean species. Type material of Wallacean and Papuan Maechidiini is depicted for the first time. A key to species is given. In total, 78 species of Maechidiini are confirmed for the Indo-Australian transition zone.
This study reports and discusses new radiometric ages, petrographical and volcanological observations and whole rock geochemical data of the rocks of the Rudnik Mts. volcano-intrusive complex. The complex hosts a Pb-Zn-Ag deposit and belongs to the Serbo-Macedonian metallogenetic belt. Two distinct igneous events are distignuished. The first occurred >30 Ma and was mainly characterized by extrusive and shallow intrusive dacites and andesites and was unrelated to mineralization. The second igneous event occurred <23 Ma and was highly heterogeneous in terms of volcanic products and petrographic varieties, but with predominance of quartzlatites. The dacite-andesites (first event) and the quartzlatites (second event) are geochemically similar and display a calc-alkaline affinity and highly incompatible element enriched patterns on spider diagrams, but the younger quartzlatites are richer in K2O, Rb and Ba and poorer in Sr. This is taken as evidence that mixing between an ultrapotassic lamprophyre/lamproite magma and an acid calc-alkaline (dacite-like) magma was essential petrogenetic processes during the second event. The proposed simplified volcanological model suggests that this mixing was responsible for triggering strongly explosive volcanic activity as well as for providing conditions for active hydrothermal and mineralization processes. The observed link between a specific magmatic phase and ore deposit formation can be a general phennomenon in the Balkans, and must be addressed by further and more advanced studies.
The impact of columnar file formats on SQL‐on‐hadoop engine performance: a study on ORC and Parquet
(2019)
Columnar file formats provide an efficient way to store data to be queried by SQL‐on‐Hadoop engines. Related works consider the performance of processing engine and file format together, which makes it impossible to predict their individual impact. In this work, we propose an alternative approach: by executing each file format on the same processing engine, we compare the different file formats as well as their different parameter settings. We apply our strategy to two processing engines, Hive and SparkSQL, and evaluate the performance of two columnar file formats, ORC and Parquet. We use BigBench (TPCx‐BB), a standardized application‐level benchmark for Big Data scenarios. Our experiments confirm that the file format selection and its configuration significantly affect the overall performance. We show that ORC generally performs better on Hive, whereas Parquet achieves best performance with SparkSQL. Using ZLIB compression brings up to 60.2% improvement with ORC, while Parquet achieves up to 7% improvement with Snappy. Exceptions are the queries involving text processing, which do not benefit from using any compression.
The detection of cortical malformations in conventional MR images can be challenging. Prominent examples are focal cortical dysplasias (FCD), the most common cause of drug‐resistant focal epilepsy. The two main MRI hallmarks of cortical malformations are increased cortical thickness and blurring of the gray (GM) and white matter (WM) junction. The purpose of this study was to derive synthetic anatomies from quantitative T1 maps for the improved display of the above imaging characteristics in individual patients.
On the basis of a T1 map, a mask comprising pixels with T1 values characteristic for GM is created from which the local cortical extent (CE) is determined. The local smoothness (SM) of the GM‐WM junctions is derived from the T1 gradient. For display of cortical malformations, the resulting CE and SM maps serve to enhance local intensities in synthetic double inversion recovery (DIR) images calculated from the T1 map.
The resulting CE‐ and/or SM‐enhanced DIR images appear hyperintense at the site of cortical malformations, thus facilitating FCD detection in epilepsy patients. However, false positives may arise in areas with naturally elevated CE and/or SM, such as large GM structures and perivascular spaces.
In summary, the proposed method facilitates the detection of cortical abnormalities such as cortical thickening and blurring of the GM‐WM junction which are typical FCD markers. Still, subject motion artifacts, perivascular spaces, and large normal GM structures may also yield signal hyperintensity in the enhanced synthetic DIR images, requiring careful comparison with clinical MR images by an experienced neuroradiologist to exclude false positives.
Signal transduction and the regulation of gene expression are fundamental processes in every cell. RNA-binding proteins (RBPs) play a key role in the post-transcriptional modulation of gene expression in response to both internal and external stimuli. However, how signaling pathways regulate the assembly of RBPs with mRNAs remains largely unknown. Here, we summarize observations showing that the formation and composition of messenger ribonucleoprotein particles (mRNPs) is dynamically remodeled in space and time by specific signaling cascades and the resulting post-translational modifications. The integration of signaling events with gene expression is key to the rapid adaptation of cells to environmental changes and stress. Only a combined approach analyzing the signal transduction pathways and the changes in post-transcriptional gene expression they cause will unravel the mechanisms coordinating these important cellular processes.
Postoperative thrombotic thrombocytopenic purpura (TTP) shows clinical presentation similar to classical TTP, whereas exact pathophysiological contexts remain unexplained. In this study, we investigated intraoperative and postoperative changes in ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs, member 13), von Willebrand factor (VWF), large VWF multimers, and interleukin-6 (IL-6) in vascular surgery patients. The objective was to compare the impact of endovascular, peripheral, and aortic surgery on target parameters which are supposed to play a role in surgery-associated TTP. A total of 93 vascular surgery patients were included and divided into 4 groups according to the specific type of intervention they underwent. Blood samples were taken preoperatively, intraoperatively, and postoperatively on days 2 and 4. The ADAMTS-13 activity decreased significantly in 3 of the 4 groups during surgery (from median 81% to 49%, P < .001, in the group undergoing aortoiliacal interventions), whereas the percentage of large VWF multimers increased in all groups of patients. von Willebrand factor antigen increased significantly in all groups on postoperative day 2 and IL-6 increased significantly in the intraoperative and early postoperative period. There was no significant correlation between the intraoperative decrease in ADAMTS-13 and the increase in VWF or IL-6. No patient in this study showed clinical picture of TTP; the precise cause and clinical significance of moderately reduced ADAMTS-13 activity in the perioperative setting have not yet been definitely determined.
Background: Macrophage Migration Inhibitory Factor (MIF) is highly elevated after cardiac surgery and impacts the postoperative inflammation. The aim of this study was to analyze whether the polymorphisms CATT5–7 (rs5844572/rs3063368,“-794”) and G>C single-nucleotide polymorphism (rs755622,-173) in the MIF gene promoter are related to postoperative outcome. Methods: In 1116 patients undergoing cardiac surgery, the MIF gene polymorphisms were analyzed and serum MIF was measured by ELISA in 100 patients. Results: Patients with at least one extended repeat allele (CATT7) had a significantly higher risk of acute kidney injury (AKI) compared to others (23% vs. 13%; OR 2.01 (1.40–2.88), p = 0.0001). Carriers of CATT7 were also at higher risk of death (1.8% vs. 0.4%; OR 5.12 (0.99–33.14), p = 0.026). The GC genotype was associated with AKI (20% vs. GG/CC:13%, OR 1.71 (1.20–2.43), p = 0.003). Multivariate analyses identified CATT7 predictive for AKI (OR 2.13 (1.46–3.09), p < 0.001) and death (OR 5.58 (1.29–24.04), p = 0.021). CATT7 was associated with higher serum MIF before surgery (79.2 vs. 50.4 ng/mL, p = 0.008). Conclusion: The CATT7 allele associates with a higher risk of AKI and death after cardiac surgery, which might be related to chronically elevated serum MIF. Polymorphisms in the MIF gene may constitute a predisposition for postoperative complications and the assessment may improve risk stratification and therapeutic guidance.
Simple Summary: Glioblastomas are very malignant and essentially incurable brain tumors. One problem is the extensive penetration of tumor cells into the adjacent normal brain tissue. Thus, the testing of novel drugs requires appropriate tumor models, preferentially avoiding animal studies. This paper describes so-called brain tissue slice tandem-culture systems. They consist of a slice of normal brain tissue and a second layer of tumor tissue. The microscopic analysis of these slice tandem-cultures allows for the simultaneous assessment of single cells invading into the normal brain tissue and the space occupying growth of the total tumor mass. It is shown that the direct application of test drugs onto the slices exerts inhibitory effects on both mechanisms. We thus describe a system mimicking the situation in glioblastoma patients. It reduces animal studies, allows for the direct application of test drugs and the precise quantitation of their inhibitory effects on tumor growth and invasion.
Abstract: Glioblastomas (GBMs) are the most malignant brain tumors and are essentially incurable even after extensive surgery, radiotherapy, and chemotherapy, mainly because of extensive infiltration of tumor cells into the adjacent normal tissue. Thus, the evaluation of novel drugs in malignant glioma treatment requires sophisticated ex vivo models that approach the authentic interplay between tumor and host environment while avoiding extensive in vivo studies in animals. This paper describes the standardized setup of an organotypic brain tissue slice tandem-culture system, comprising of normal brain tissue from adult mice and tumor tissue from human glioblastoma xenografts, and explore its utility for assessing inhibitory effects of test drugs. The microscopic analysis of vertical sections of the slice tandem-cultures allows for the simultaneous assessment of (i) the invasive potential of single cells or cell aggregates and (ii) the space occupying growth of the bulk tumor mass, both contributing to malignant tumor progression. The comparison of tissue slice co-cultures with spheroids vs. tissue slice tandem-cultures using tumor xenograft slices demonstrates advantages of the xenograft tandem approach. The direct and facile application of test drugs is shown to exert inhibitory effects on bulk tumor growth and/or tumor cell invasion, and allows their precise quantitation. In conclusion, we describe a straightforward ex vivo system mimicking the in vivo situation of the tumor mass and the normal brain in GBM patients. It reduces animal studies and allows for the direct and reproducible application of test drugs and the precise quantitation of their effects on the bulk tumor mass and on the tumor’s invasive properties
In this paper we deal with an implementation as well as numerical experiments for the coupling of interior and exterior problems of the elastodynamic wave equation with transparent boundary conditions in 3D as described in a previous paper by this author. In more detail, the FEM‐BEM‐coupling as well as the time discretization by using leapfrog and convolution quadrature is considered. Our aim is to provide an insight into the necessary steps of the implementation. Based on this, we present numerical experiments for a non‐convex domain and analyze the errors.
Progression of pupil dilation (PD) in response to visual stimuli may indicate distinct internal processes. No study has been performed on PD progression during a social cognition task. Here, we describe PD progression during the Movie for the Assessment of Social Cognition (MASC) test in n = 23 adolescents with Autism Spectrum Disorder (ASD) and n = 24 age, IQ and sex‐matched neurotypical controls (NTC). The MASC consists of 43 video sequences depicting human social interactions, each followed by a multiple‐choice question concerning characters' mental states. PD progression data were extracted by eye tracking and controlled for fixation behavior. Segmenting PD progression during video sequences by principal component analysis, three sequential PD components were unveiled. In ASD compared with NTC, a distinct PD progression was observed with increased constriction amplitude, increased dilation latency, and increased dilation amplitude that correlated with PD progression components. These components predicted social cognition performance. The first and second PD components correlated positively with MASC behavioral performance in ASD but negatively in NTC. These PD components may be interpreted as indicators of sensory‐perceptual processing and attention function. In ASD, aberrant sensory‐perceptual processing and attention function could contribute to attenuated social cognition performance. This needs to be tested by additional studies combining the respective cognitive tests and the outlined PD progression analysis. Phasic activity of the locus coeruleus–norepinephrine system is discussed as putatively shared underlying mechanism.
This thesis investigates the acquisition pace and the typical developmental path in eL2 acquisition of selected phenomena of German morphosyntax and semantics and compared them to monolingual acquisition. In addition, the influence of ‘Age of Onset’ and of external factors on eL2 acquisition is examined.
To date, the most studies on eL2 acquisition focused on language production. Based on mostly longitudinal spontaneous speech data of only small number of children, they indicate that eL2 learners acquire sentence structure and subject-verb-agreement faster than monolingual children, whereas the acquisition of case marking causes them more difficulties. Moreover, similar developmental paths to those of monolingual children are claimed. Only several studies examined comprehension abilities in eL2 learners, however overwhelmingly in cross-sectional design. The findings from comprehension studies on telic and atelic verbs, and on wh-questions indicate that eL2 children acquire their target-like interpretation faster than monolingual children. The same acquisition stages towards target-like interpretation like in monolingual acquisition are assumed as well. Taking together, to date, no study exists, that examines comprehension and production abilities in a large group of eL2 learners of German in a longitudinal design.
This thesis extends the previous results by investigating pace of acquisition, impact of factors, and individual developmental paths in a longitudinal design with large groups of participants. Language data of 29 eL2 learners of German (age at T1: 3;7 years, LoE: 10 months) and 45 monolingual German-speaking children (age at T1: 3;7) are examined. The eL2 learners were tested in six test rounds (age at T6: 6;9 years). The monolingual children were tested in five test rounds (are at T5: 5;7). The standardized test LiSe-DaZ (Schulz & Tracy, 2011) was employed to examine children’s language skills.
eL2 learners show a significantly greater rate of change, thus faster acquisition pace, than monolingual children in the following scales: comprehension of telicity, comprehension of wh-questions, production of prepositions, and production of conjunctions. These phenomena are acquired early in monolingual children. No differences regarding acquisition pace between eL2 children and monolingual children are found for comprehension of negation, production of case marking, and production of focus particles. These phenomena are acquired late in monolingual development and involve semantic and pragmatic knowledge. The findings of faster acquisition pace of several phenomena are in line with several studies that reported that eL2 children develop faster than monolingual children.
Independent on whether a phenomenon is acquired early or late, no effects of external factors on eL2 children’s performance are found. These findings indicate that acquisition of core, rule-based phenomena is not sensitive to external factors if the first exposure to L2 takes place around the age of three.
Moreover, eL2 children show the same developmental stages and error types in comprehension of telicity, comprehension of negation, production of matrix and subordinate clauses. This is also independent on how fast they acquire a structure under consideration. Thus, these findings provide a further support for similar developmental paths of eL2 and monolingual children towards target-like comprehension and production.
Stanley Cavell is one of very few philosophers who systematically reflect on the impact and influence of autobiographical detail, experience, and preferences on their philosophical work. The aim of this essay is to show how Cavell’s use of autobiographical exploration is rooted in his early aesthetic theory, in particular his view of the similarities between philosophy and aesthetic criticism. Cavell argues that criticism starts by exploiting and incorporating a subjective vantage point, eventually bringing the reader to test the significance of a work on herself. In his ‘Aesthetic Problems of Modern Philosophy’, Cavell states exactly this form of appeal to the ‘We’ of author and reader as the basic move of his own version of ‘ordinary language philosophy’. It is because of the connections Cavell sees between criticism and philosophy that his aesthetic diagnosis harks back on his overall critical style of thinking.
The strictly anaerobic acetogenic bacterium Acetobacterium woodii is metabolically diverse and grows on variety of substrates which includes H2 + CO2, sugars, alcohols and diols. It is unique in producing bacterial microcompartments (BMC) during growth on different substrates such as 1,2-propanediol, 2,3-butanediol, ethanol or fructose. In this study, we analyzed the genetic organization and expression of the BMC genes within the A. woodii genome, the previously described 18 gene pdu cluster as well as four other cluster potentially encoding one or two shell proteins. Expression analysis of respective gene clusters revealed that the pdu gene cluster is highly expressed during growth on 1,2-PD, 2,3-BD, ethanol and ethylene glycol. The promoter region upstream of the pduA gene was identified and used to establish a reporter gene assay based on chloramphenicol acetyl transferase as a reporter protein. The reporter gene assay confirmed the qPCR data and demonstrated that 1,2-PD is superior over ethanol and ethylene glycol as inducer. BMCs were enriched from cells grown on 2,3- BD and 1,2-PD and shown to have typical structure in electron micrographs. Biochemical analyses revealed several of the protein encoded by the pdu cluster to be part of the isolated BMCs. These data demonstrate a very unique situation in A. woodii in which apparently one BMC gene cluster in expressed during growth on different substrates.
Background: Balloon pulmonary angioplasty is an evolving, interventional treatment option for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). Pulmonary hypertension at rest as well as exercise capacity is considered to be relevant outcome parameters. The aim of the present study was to determine whether measurement of pulmonary hemodynamics during exercise before and six months after balloon pulmonary angioplasty have an added value.
Methods: From March 2014 to July 2018, 172 consecutive patients underwent balloon pulmonary angioplasty. Of these, 64 consecutive patients with inoperable CTEPH underwent a comprehensive diagnostic workup that included right heart catheterization at rest and during exercise before balloon pulmonary angioplasty treatments and six months after the last intervention.
Results: Improvements in pulmonary hemodynamics at rest and during exercise, in quality of life, and in exercise capacity were observed six months after balloon pulmonary angioplasty: WHO functional class improved in 78% of patients. The mean pulmonary arterial pressure (mPAP) at rest was reduced from 41 ± 9 to 31 ± 9 mmHg (p < 0.0001). The mPAP/cardiac output slope decreased after balloon pulmonary angioplasty (11.2 ± 25.6 WU to 7.7 ± 4.1 WU; p < 0.0001), and correlated with N-terminal fragment of pro-brain natriuretic peptide (p = 0.035) and 6-minute walking distance (p = 0.01).
Conclusions: Exercise right heart catheterization provides valuable information on the changes of pulmonary hemodynamics after balloon pulmonary angioplasty in inoperable CTEPH patients that are not obtainable by measuring resting hemodynamics.
Resistance exercise has been demonstrated to improve brain function. However, the optimal workout characteristics are a matter of debate. This randomized, controlled trial aimed to elucidate differences between free-weight (REfree) and machine-based (REmach) training with regard to their ability to acutely enhance cognitive performance (CP). A total of n = 46 healthy individuals (27 ± 4 years, 26 men) performed a 45-min bout of REfree (military press, barbell squat, bench press) or REmach (shoulder press, leg press, chest press). Pre- and post-intervention, CP was examined using the Stroop test, Trail Making Test and Digit Span test. Mann–Whitney U tests did not reveal between-group differences for performance in the Digit Span test, Trail Making test and the color and word conditions of the Stroop test (p > 0.05). However, REfree was superior to REmach in the Stroop color-word condition (+6.3%, p = 0.02, R = 0.35). Additionally, REfree elicited pre-post changes in all parameters except for the Digit Span test and the word condition of the Stroop test while REmach only improved cognitive performance in part A of the Trail Making test. Using free weights seems to be the more effective RE method to acutely improve cognitive function (i.e., inhibitory control). The mechanisms of this finding merit further investigation.
Obstructive Sleep Apnea is emerging as a global health epidemic, particularly due to the obesity pandemic. However, comprehensive prevalence data are still lacking and global OSA research has not yet been structurally evaluated. Using the latest comprehensive age/gender-specific BMI and obesity data, a global landscape estimating the risk/burden of OSA was created. Results were presented in relation to an in-depth analysis of OSA research and countries’ socioeconomic/scientific background. While the USA, Canada, and Japan are the highest publishing countries on OSA, Iceland, Greece, and Israel appeared at the forefront when relating the scientific output to socioeconomic parameters. Conversely, China, India, and Russia showed relatively low performances in these relations. Analysis of the estimated population at risk (EPR) of OSA showed the USA, China, India, and Brazil as the leading countries. Although the EPR and OSA research correlated strongly, major regional discrepancies between the estimated demand and actual research performances were identified, mainly in, but not limited to, developing nations. Our study highlights regional challenges/imbalances in the global activity on OSA and allows targeted measures to mitigate the burden of undiagnosed/untreated OSA. Furthermore, the inclusion of disadvantaged countries in international collaborations could stimulate local research efforts and provide valuable insights into the regional epidemiology of OSA.
Four main informational elements have been suggested and studied as central aspects of narrative discourse: causality, character, location, time. The research that scholars have previously undertaken on these aspects has been primarily on Indo-European languages, and more specifically on the European side of that language family. The linguistic limitations have indicated that character is the aspect of narrative that readers/listeners attend to most closely. However, in examining narrative discourses from non-Indo-European languages, challenges to the presumed primacy of character emerge. In a partial report on field work conducted in Borneo in 2012-2015, I compare and contrast patterns in the rankings of the four main aspects of narrative in three languages, English, Hobongan and Daqan. I also note the strategies by which the languages make their respective rankings clear, including focus particles (Hobongan), specificity of description (each), and amount of information provided about the aspects (each). I suggest that analyses of the patterns and rankings of information in narrative be included in typological categorizations and linguistic descriptions of languages.
Objective: to systematize the strengths and challenges of Axel Honneth’s Theory of Recognition, and to reflect on these as support for research in health care. Method: this is a reflection article which considers the potential of incorporating the category of recognition in the Honnethian proposition for research, understanding, exercising of practice and management of health care. Results: the process of recognition promotes the exploration and understanding of relations of power and respect, above all in terms of conflict which are ascribed to these. As a result, it indicates support for diagnoses and structuring nuclei for overcoming oppressive and unequal practices, with consequences for dealing with situations of insecurity, weaknesses in self-esteem and vulnerabilities in the interactions between the subjects, which are configured as contemporary challenges. Conclusion: in the scientific exploration of care, management and public policies in health, this theoretical framework can assist in the visibility of the context and in its critical knots, in order to promote autonomy and human dignity, which are relevant for the interpersonal relations in the processes of care, with fruitful contributions to the qualification of the health care.
From reciprocal recognition to a society that is properly 'social' : on Axel Honneth's recent work
(2017)
This paper addresses Axel Honneth's recent endeavors to defend his theory of justice, broadly described in Freedom's right (2011) as an analysis of society. The paper begins by exposing Honneth's model as a theory of institutional intersubjectivity rather than a theory of the struggle for recognition. This model, however, was subject to criticism due to its supposed acceptance of the capitalistic market economy as a social order. In order to defend it from such objections, Honneth (2016) exposes the normative core of socialist ideals as a version of social freedom. Finally, he presents a distinction between two forms of political intervention: an internal and an external struggle for recognition – and asserts the advantages of the former.
Space optimizations in deterministic and concurrent call-by-need functional programming languages
(2020)
In this thesis the space consumption and runtime of lazy-evaluating functional programming languages are analyzed.
The typed and extended lambda-calculi LRP and CHF* as core languages for Haskell and Concurrent Haskell are used. For each LRP and CHF* compatible abstract machines are introduced.
Too lower the distortion of space measurement a classical implementable garbage collector is applied after each LRP reduction step. Die size of expressions and the space measure spmax as maximal size of all garbage-free expressions during an LRP-evaluation, are defined.
Program-Transformations are considered as code-to-code transformations. The notions Space Improvement and Space Equivalence as properties of transformations are defined. A Space Improvement does neither change the semantics nor it increases the needed space consumption, for a space equivalence the space consumption is required to remain the same. Several transformations are shown as Space Improvements and Equivalences.
An abstract machine for space measurements is introduced. An implementation of this machine is used for more complex space- and runtime-analyses.
Total Garbage Collection replaces subexpressions by a non-terminating constant with size zero, if the overall termination is not affected. Thereby the notion of improvement is more independent from the used garbage collector.
Analogous to Space Improvements and Equivalences the notions Total Space Improvement and Total Space Equivalence are defined, which use Total Garbage Collection during the space measurement. Several Total Space Improvements and Equivalences are shown.
Space measures for CHF* are defined, that are compatible to the space measure of LRP. An algorithm with sort-complexity is developed, that calculates the required space of independent processes that all start and end together. If a constant amount of synchronization restrictions is added and a constant number of processors is used, the runtime is polynomial, if arbitrary synchronizations are used, then the problem is NP-complete.
Abstract machines for space- and time-analyses in CHF* are developed and implementations of these are used for space and runtime analyses.
Viele Methoden wurden in dieser Arbeit vorgestellt, die sich mit dem Hauptziel der automatischen Dokumentenanalyse auf semantischer Ebene befassen. Um das Hauptziel zu erreichen, mussten wir jedoch zunächst eine solide Basis entwickeln, um das Gesamtbild zu vervollständigen. So wurden verschiedene Methoden und Werkzeuge entwickelt, die verschiedene Aspekte des NLP abdecken. Das Zusammenspiel dieser Methoden ermöglichte es, unser Ziel erfolgreich zu erreichen. Neben der automatischen Dokumentenanalyse legen wir großen Wert auf die drei Prinzipien von Effizienz, Anwendbarkeit und Sprachunabhängigkeit. Dadurch waren die entwickelten Tools für die Anwendungen bereit. Die Größe und Sprache der zu analysierenden Daten ist kein Hindernis mehr, zumindest für die im Bezug auf die von Wikipedia unterstützten Sprachen.
Einen großen Beitrag dazu leistete TextImager, das Framework, dass für die zugrunde liegende Architektur verschiedener Methoden und die gesamte Vorverarbeitung der Texte verantwortlich ist. TextImager ist als Multi-Server und Multi-Instanz-Cluster konzipiert, sodass eine verteilte Verarbeitung von Daten ermöglicht wird. Hierfür werden Cluster-Management-Dienste UIMA-AS und UIMA-DUCC verwendet. Darüber hinaus ermöglicht die Multi-Service-Architektur von TextImager die Integration beliebiger NLP-Tools und deren gemeinsame Ausführung. Zudem bietet der TextImager eine webbasierte Benutzeroberfläche, die eine Reihe von interaktiven Visualisierungen bietet, die die Ergebnisse der Textanalyse darstellen. Das Webinterface erfordert keine Programmierkenntnisse - durch einfaches Auswählen der NLP-Komponenten und der Eingabe des Textes wird die Analyse gestartet und anschließend visualisiert, so dass auch Nicht-Informatiker mit diesen Tools arbeiten können.
Zudem haben wir die Integration des statistischen Frameworks R in die Funktionalität und Architektur von TextImager demonstriert. Hier haben wir die OpenCPU-API verwendet, um R-Pakete auf unserem eigenen R-Server bereitzustellen. Dies ermöglichte die Kombination von R-Paketen mit den modernsten NLP-Komponenten des TextImager. So erhielten die Funktionen der R-Pakete extrahierte Informationen aus dem TextImager, was zu verbesserten Analysen führte.
Darüber hinaus haben wir interaktive Visualisierungen integriert, um die von R abgeleiteten Informationen zu visualisieren.
Einige der im TextImager entwickelten Visualisierungen sind besonders herausragend und haben in vielen Bereichen Anwendung gefunden. Ein Beispiel dafür ist PolyViz, ein interaktives Visualisierungssystem, das die Darstellung eines multipartiten Graphen ermöglicht. Wir haben PolyViz anhand von zwei verschiedenen Anwendungsfällen veranschaulicht.
SemioGraph, eine Visualisierungstechnik zur Darstellung multikodaler Graphen wurde auch vorgestellt. Die visuellen und interaktiven Funktionen von SemioGraph wurden mit einer Anwendung zur Visualisierung von Worteinbettungen vorgestellt. Wir haben gezeigt, dass verschiedene Modelle zu völlig unterschiedlichen Grafiken führen können. So kann Semiograph bei der Suche nach Worteinbettungen für bestimmte NLP-Aufgaben helfen.
Inspiriert von all den Textvisualisierungen im TextImager ist die Idee für text2voronoi geboren. Hier stellten wir einen neuartigen Ansatz zur bildgetriebenen Textklassifizierung vor, der auf einem Voronoi-Diagram linguistischer Merkmale basiert. Dieser Klassifikationsansatz wurde auf die automatische Patientendiagnose angewendet und wir haben gezeigt, dass wir das traditionelle Bag-Of-Words-Modell sogar übertreffen. Dieser Ansatz ermöglicht es, die zugrunde liegenden Merkmale anschließend zu analysieren und damit einen ersten Schritt zur Lösung der Black Box zu machen.
Wir haben text2voronoi auf literarische Werke angewendet und die entstandenen Visualisierungen auf einer webbasierten Oberfläche (LitViz) präsentiert. Hier ermöglichen wir den Vergleich von Voronoi-Diagrammen der verschiedenen Literaturen und damit den visuellen Vergleich der Sprachstile der zugrunde liegenden Autoren.
Mit unserer Kompetenz in der Vorverarbeitung und der Analyse von Texten sind wir unserem Ziel der semantischen Dokumentenanalyse einen Schritt näher gekommen. Als nächstes haben wir die Auflösung der Sinne auf der Wortebene untersucht. Hier stellten wir fastSense vor, ein Disambigierungsframework, das mit großen Datenmengen zurecht kommt. Um dies zu erreichen, haben wir einen Disambiguierungskorpus erstellt, der auf Wikipedias 221965 Disambiguierungsseiten basiert, wobei die sich auf 825179 Sinne beziehen. Daraus resultierten mehr als 50 Millionen Datensätze, die fast 50 GB Speicherplatz benötigten. Wir haben nicht nur gezeigt, dass fastSense eine so große Datenmenge problemlos verarbeiten kann, sondern auch, dass wir mit unseren Wettbewerbern mithalten und sie bei einigen NLP-Aufgaben sogar übertreffen können.
Jetzt, da wir den Wörtern Sinne zuordnen können, sind wir der semantischen Dokumentenanalyse einen weiteren Schritt näher gekommen. Je mehr Informationen wir aus einem Text und seinen Wörtern gewinnen können, desto genauer können wir seinen Inhalt analysieren. Wir stellten zudem einen netzwerktheoretischen Ansatz zur Modellierung der Semantik großer Textnetzwerke am Beispiel der deutschen Wikipedia vor. Zu diesem Zweck haben wir einen Algorithmus namens text2ddc entwickelt, um die thematische Struktur eines Textes zu modellieren. Dabei basiert das Modell auf einem etablierten Klassifikationsschema, nämlich der Dewey Decimal Classification. Mit diesem Modell haben wir gezeigt, wie man aus der Vogelperspektive die Hervorhebung und Verknüpfung von Themen, die sich in Millionen von Dokumenten manifestiert, darstellt. So haben wir eine Möglichkeit geschaffen, die thematische Dynamik von Dokumentnetzwerken automatisch zu visualisieren. Die Trainings- und Testdaten, die wir in diesem Kapitel hatten, bestanden jedoch hauptsächlich aus kurzen Textausschnitten. Zudem haben wir DDC Korpora erstellt, indem wir Informationen aus Wikidata, Wikipedia und der von der Deutschen Nationalbibliothek verwalteten Gemeinsamen Normdatei (GND) vereinigt haben. Auf diese Weise konnten wir nicht nur die Datenmenge erhöhen, sondern auch Datensätze für viele bisher unzugängliche Sprachen erstellen. Wir haben text2ddc so weit optimiert, dass wir einen F-score von 87.4% erzielen für die 98 Klassen der zweiten DDC-Stufe. Die Vorverarbeitung von TextImager und die Disambiguierung durch fastSense hatten einen großen Einfluss darauf. Für jedes Textstück berechnet text2ddc eine Wahrscheinlichkeitsverteilung über die DDC-Klassen berechnen
Der klassifikatorinduzierte semantische Raum von text2ddc wurde auch zur Verbesserung weiterer NLP-Methoden genutzt. Dazu gehört auch text2wiki, ein Framework für automatisches Tagging nach dem Wikipedia-Kategoriensystem. Auch hier haben wir einen klassifikatorinduzierten semantischen Raum, aber diesmal basiert er auf dem Wikipedia-Kategoriensystem. Ein großer Vorteil dieses Modells ist die Präzision und Tiefe der behandelten Themen und das sich ständig weiterentwickelnde Kategoriesystem. Damit sind auch die Kriterien eines offenen Themenmodells erfüllt. Um die Vorteile von text2wiki zu demonstrieren, haben wir anschließend die von text2wiki bereitgestellten Themenvektoren verwendet, um text2ddc zu verbessern, so dass sich beide Systeme gegenseitig verbessern können. Die Synergie zwischen den erstellten Methoden in dieser Dissertation war entscheidend für den Erfolg jeder einzelnen Methode.
Die CXCR4/CXCL12-Achse ist von entscheidender Bedeutung für die Entstehung und Aufrechterhaltung einer gesunden, reifen Hämatopoese. Erstmals beschrieben wurde der später als CXCR4 bezeichnete Rezeptor 1996 allerdings als Co-Rezeptor für den Eintritt humaner HI-Viren in Lymphozyten. Ein großes Interesse bestand daraufhin darin, sowohl natürliche Inhibitoren des G-Protein gekoppelten Rezeptors zu identifizieren, als auch synthetische herzustellen, um einen Eintritt des Virus in den menschlichen Organismus zu verhindern bzw. seine Ausbreitung zu unterbinden. Ein natürlich vorkommender CXCR4-Ligand, der 2015 von Zirafi und Kollegen erstmals beschrieben wurde, fand sich im Hämofiltrat von Dialysepatienten. Der im weiteren Verlauf als EPI-X4 bezeichnete CXCR4-Antagonist wurde als Spaltprodukt von Albumin identifiziert, welches über viele Spezies hochkonserviert ist. Diese Eigenschaft interpretieren wir als Hinweis auf eine relevante physiologische Funktion des Peptids. Da die Halbwertszeit von natürlich vorkommendem EPI-X4 beim Menschen vermutlich sehr kurz ist, sind in vivo- und darauffolgende in vitro-Analysen schwierig durchzuführen. In-vitro-Spike-Analysen von synthetischem EPI-X4 in humanem Plasma ergaben eine Halbwertszeit von nur 17 Minuten. Die geringen auftretenden Konzentrationen erschweren die Problematik zusätzlich. In dieser Arbeit sollen deshalb im Mausmodell in vivo-Analysen durchgeführt werden, um die Effekte von potentiell entstehendem EPI-X4 in verschiedenen experimentellen Ansätzen aufzudecken. Ein probates, hier verwendetes Mittel, ist die Analyse einer Knock-out (KO)-Maus. Die für die Bindung an CXCR4 entscheidende Aminosäure von EPI-X4, das am N-Terminus gelegene Leucin, wurde durch Alanin ersetzt, welches die Entstehung von EPI-X4 unterbindet und zusätzlich dessen Bindung an CXCR4 verhindert. Mit Hilfe zweier Mausmodelle können nun Analysen im EPI-X4-defizienten Modell durchgeführt werden, die im Umkehrschluss Informationen über die organismische Wirkung von EPI-X4 beinhalten. Zunächst wurde in beiden Modellen die physiologisch normale reife und unreife Hämatopoese charakterisiert. Hierbei zeigte sich kein signifikanter systematischer Einfluss von EPI-X4 auf reife Leukozyten (WBC), lediglich eine leichte Lymphozytose in der HR-Ala-Variante. Im weiteren Verlauf der homöostatischen Analyse der Hämatopoese der Ala-EPI-X4-Mäuse zeigten sich keine signifikanten Unterschiede zu wildtypischen Mäusen. Sowohl reife als auch unreife Zellen zeigten, außer in der T- und B-Zelllinie, keine zahlenmäßigen oder funktionalen Auffälligkeiten, weder im Blut, noch in der Milz oder im Knochenmark. Analysen der Zellzyklusaktivität unterschiedlicher Unreifestufen wiesen ebenfalls keine Auffälligkeiten auf. Diese Daten einer normalen, von einer C57Bl/6-Maus zu erwartenden Ergebnisse dienten als Grundlage zur Bewertung und Analyse von durchgeführten hämatopoetischen Stressmodellen. Hierfür wurden
zunächst hämatopoetische Stamm- und Vorläuferzellen (HSPC) mobilisiert. In den angewandten Mobilisierungsmodellen fanden sich lediglich unter G-CSF-Behandlung im Knochenmark eine größere Anzahl Granulozyten, was auf einen Einfluss von EPI-X4 auf HSPC schließen lässt. Um potentielle Auswirkungen von EPI-X4 im Knochenmark weiter zu untersuchen, wurde ein weiteres Stressmodell gewählt, welches ebenfalls mutmaßlich die Bedingungen zur EPI-X4-Generierung schafft: Subletale Bestrahlung der Mäuse sorgt für Schäden an allen Zellarten im Knochenmark, es wird ein steriles entzündliches Milieu kreiert. Unter diesen Umständen wurde die Regeneration von Blutzellen analysiert. Es zeigten sich keine nennenswerten Unterschiede sowohl in der akuten Phase des Schadens als auch in regelmäßigen Blutentnahmen während der Regenerierung.
Die Beschreibung von natürlich vorkommendem EPI-X4 in Vaginal- und Rektalschleimhaut zeigt seine Entstehung an Schleimhautbarrieren auf. Ala-EPI-X4-Muse werden deshalb auf deren Durchlässigkeit untersucht: LPS-Konzentrationen als Marker für eindringende pathogene Bakterien wurden im Plasma untersucht. Hierbei zeigten sich keine Unterschiede zwischen den Gruppen, eine Störung scheint hier nicht vorzuliegen. Zusätzlich wurde die Zusammensetzung des Mikrobioms im Darm untersucht, da beschrieben wurde, dass sich Mikrobiom und die Integrität der Darmschleimhaut gegenseitig beeinflussen. Im Falle der EPI-X4-defizienten Mäuse liegt zwar keine offensichtliche pathologische Veränderung vor, dennoch konnte in männlichen HR-Ala-Mäusen die Abwesenheit des Proteobakteriums Parasutterella nachgewiesen werden. Um eine mögliche Defizienz der Barrierefunktion weiter zu testen, wurden zwei Stressmodelle gewählt: Zunächst wurde den Mäusen eine akute, sterile Peritonitis zugefügt, woraufhin die Anzahl und Zusammensetzung der ins Peritoneum einströmenden Leukozyten analysiert wird. Die Reaktion auf diesen Entzündungsprozess war nicht verändert. Ähnliche Ergebnisse zeigten sich auch in einem akuten Colitis-Stressmodell.
Insgesamt konnte in dieser Arbeit mithilfe zweier KO-Mausmodelle die Rolle von EPI-X4 in der Hämatopoese und der Immunologie von Mäusen beginnend charakterisiert werden. Die homöostatische Hämatopoese scheint kaum von EPI-X4 abhängig zu sein, lediglich die Zahl der B- und T-Zellen, insbesondere der regulatorischen T-Zellen, scheint beeinflusst. Damit einhergehend konnten Veränderungen in Zytokinlevels bei inflammatorischen Ereignissen gezeigt werden. Experimente zur beeinflussten, eventuell gestörten Barrierefunktion von Ala-EPI-X4-Mäusen zeigten vielversprechende Ansätze und sollten in Zukunft weiter analysiert werden.
Natural science is only just beginning to understand the complex processes surrounding transcription. Epitranscriptional regulation is in large parts conveyed by transcription factors (TFs) and two recently discovered small RNA (smRNA) species: microRNAs (miRNAs) and transfer RNA fragments (tRFs). As opposed to the fairly well-characterised function of TFs in shaping the phenotype of the cell, the effects and mechanism of action of smRNA species is less well understood. In particular, the multi-levelled combinatorial interaction (many-to-many) of smRNAs presents new challenges to molecular biology. This dissertation contributes to the study of smRNA dynamics in mammalian cells in several ways, which are presented in three main chapters.
I) The exhaustive analysis of the many-to-many network of smRNA regulation is reliant on bioinformatic support. Here, I describe the development of an integrative database capable of fast and efficient computation of complex multi-levelled transcriptional interactions, named miRNeo. This infrastructure is then applied to two use cases. II) To elucidate smRNA dynamics of cholinergic systems and their relevance to psychiatric disease, an integrative transcriptomics analysis is performed on patient brain sample data, single-cell sequencing data, and two closely related in vitro human cholinergic cellular models reflecting male and female phenotypes. III) The dynamics between small and large RNA transcripts in the blood of stroke victims are analysed via a combination of sequencing, analysis of sorted blood cell populations, and bioinformatic methods based on the miRNeo infrastructure. Particularly, importance and practicality of smRNA:TF:gene feedforward loops are assessed.
In both analytic scenarios, I identify the most pertinent regulators of disease-relevant processes and biological pathways implicated in either pathogenesis or responses to the disease. While the examples described in chapters three and four of this dissertation are disease-specific applications of miRNeo, the database and methods described have been developed to be applicable to the whole genome and all known smRNAs.
The subject matter of this article is Axel Honneth’s theory of recognition as it has been exposed in his more recent book, Das Recht der Freiheit. Throughout the paper his attempts to describe injustices within modern capitalist societies using the notions of pathologies and anomie will be analyzed and criticized, especially from the viewpoint of their inability to deal with processes and contexts of disrecognition (Aberkennung). With help of this category, Honneth’s diagnosis regarding the moral progress in modern societies, as well as his notion of second order disorders, as injustices will be confronted and, hopefully, complemented.
While liberal, redistributive views seek to correct and compensate for past injustices, by resorting to compensatory, procedural arguments for corrective justice, the recognition-based, communitarian arguments tend to promote by means of social movements and struggles for recognition a society free from prejudice and disrespect. In developing democratic societies such as Brazil, Axel Honneth’s contribution to the ongoing debates on Affirmative Action has been evoked, confirming that the dialectics of recognition does not merely seek a theoretical solution to the structural and economic inequalities that constitute some of their worst social pathologies, but allows for practices of self-respect and subjectivation that defy all technologies of social control, as pointed out in Foucault’s critique of power. The phenomenological deficit of critical theory consists thus in recasting the critique of power with a view to unveiling lifeworldly practices that resist systemic domination.
This paper describes the revision of the Vietnamese version of the Multilingual Assessment Instrument for Narratives (LITMUS-MAIN). We first introduce the Vietnamese language and Vietnamese-speaking populations after which we describe the translation and adaptation process of the Vietnamese MAIN and present results from monolingual and bilingual children.
The Multilingual Assessment Instrument for Narratives (MAIN), an assessment tool in the Language Impairment Testing in Multilingual Settings (LITMUS) battery, aims to improve the assessment of bilingual children. This paper describes the process of adapting MAIN to Urdu. Given the lack of language assessment tools for Urdu-speaking children, the Urdu MAIN is an important new instrument that is made widely and freely accessible to researchers and practitioners, allowing them to examine the narrative abilities of children acquiring Urdu as a first, heritage, second, or additional language.
This paper presents a short overview of Turkey and the Turkish language, and then outlines the process of adapting the Multilingual Assessment Instrument for Narratives (MAIN) to Turkish and how the Turkish MAIN has been used with monolingual and bilingual children. The grammatical features of Turkish, the critical points in the adaptation process of MAIN to Turkish and our experiences of extensive piloting of the Turkish MAIN with typically developing monolingual children are described.
Torwali, a Dardic language of the Indo-Aryan family spoken in the District Swat in Pakistan, is an endangered language that lacks a literary tradition. This paper gives a background on the Torwali language and people, and describes the development of an orthography for Torwali and the establishment of Torwali-medium schools by the local organization Idara Baraye Taleem-o-Taraqi ‘institute for education and development’ (IBT). Finally, the process of adapting the Multilingual Assessment Instruments for Narratives (MAIN) to Torwali is outlined.
This paper briefly presents the current situation of bilingualism in the Philippines, specifically that of Tagalog-English bilingualism. More importantly, it describes the process of adapting the Multilingual Assessment Instrument for Narratives (LITMUS-MAIN) to Tagalog, the basis of Filipino, which is the country’s national language. Finally, the results of a pilot study conducted on Tagalog-English bilingual children and adults (N=27) are presented. The results showed that Story Structure is similar across the two languages and that it develops significantly with age.
In this paper, we present some features of the European Spanish adaptation of the Multilingual Assessment Instrument for Narratives (LITMUS-MAIN), most of them related to specificities of the Spanish grammar as compared to English, the source language of the original MAIN (Gagarina et al., 2012). These two languages differ in e.g. 1) the use of 3rd grammatical person to address the hearer; 2) the ways of maintaining nominal cohesion: English (non-pro drop) vs. Spanish (pro-drop); 3) the verbal paradigm with regard to morphological tense and aspect morphology. Finally, preliminary results for micro- and macrostructure measures in the narratives of children with Spanish as L1 and L2 confirm their consistency across MAIN stories and procedures.
Using MAIN in South Africa
(2020)
South Africa is a country marked by cultural and linguistic diversity with 11 official languages. The majority of school children do not receive their formal schooling in their home language. There is a need for language assessment tools in education and rehabilitation contexts to distinguish between children with language learning problems and/or SLI, and language delay as a result of limited exposure to the language of learning. The Multilingual Assessment Instrument for Narratives (LITMUS-MAIN) provides clinicians and researchers with an appropriate and culturally relevant tool to assess bilingual children in both languages. So far MAIN has been widely used in Afrikaans-English bilingual children. However, translating and adapting MAIN to our other nine official languages to achieve functional and cultural equivalence is more challenging.
The adaptation of the Multilingual Assessment Instrument for Narratives (LITMUS-MAIN) for use with Slovak speaking children is a vital step in the process of creating a transparent evaluation of children’s narrative abilities. Since its first translation and adaptation in 2012, new pilot data from different groups of children has been collected in Slovakia. This paper describes the process of adapting the instrument to fit the Slovak language and reports on analyses of narrative production in monolingual (103 Slovak-speaking children) and bilingual (37 Slovak-English speaking) pre-school children. Within a pilot study, the story elicitation method was also compared (telling vs. retelling) within a small sample of 10 monolingual Slovak-speaking children. All results show transparent and detailed possibilities in terms of finding a meaningful evaluation that can evaluate a child’s complex narrative abilities.
This paper provides the background to the process of translation and piloting of the Serbian version of the Multilingual Assessment Instrument for Narratives (LITMUS-MAIN), Multilingvalni Test za Procenu Narativa (MTPN). Our review of the sparse research literature on Serbian children’s narrative abilities reveals a need for a well-designed narrative instrument, which will enable researchers and practitioners to assess the production and comprehension of narratives in children of a wide age range, typically and atypically developing, monolingual and bilingual, crucially allowing for cross-linguistic comparisons. We encountered two kinds of challenges during the process of translation and adaptation of the instrument from English into Serbian. The first concerned the lack of established Serbian technical terminology needed to describe test administration to the future users of the test: researchers and practitioners working in different disciplines such as linguistics, psychology, Speech and Language Therapy. The second challenge concerned the translation of linguistic structures required to produce a successful rendition of the narrative: in contrast to English, but in line with other Slavic languages, Serbian relies heavily on verbs marked for perfective aspect in story-telling. Our discussion of preliminary data from four Serbian monolingual children, aged 5;5-10, demonstrates that MTPN is a successful tool in assessing narrative abilities in children acquiring Serbian.
A translation process is often seen as only a simple code exchange, but, in fact, it always requires an adaptation of terms, expressions, and structures, which is not exactly straightforward. This paper describes the process of translating and adapting the Multilingual Assessment Instrument for Narratives (LITMUS-MAIN) to Brazilian Portuguese. A brief description of the project, concerning both historic and linguistic aspects, was done in order to emphasize the cultural and linguistic challenges faced during the process.
This paper describes in detail the development of the Polish version of the Multilingual Assessment Instrument for Narratives (LITMUS-MAIN). We first describe its two earlier versions, the unpublished version and the published version, developed in 2012, as well as the revised version. We also justify the differences between the unpublished Polish version developed in 2012 and the original MAIN. Then we summarize the results from studies that used the unpublished version of the Polish MAIN. We end with outlining a study that could be conducted to compare the two slightly different procedures in order to examine whether the results obtained with MAIN are resistant to changes in the procedure details.
This paper describes the experience of using the Norwegian and Russian versions of LITMUS-MAIN to elicit narrative data from bilingual Norwegian-Russian children as well as from Norwegian- and Russian-speaking monolinguals (Rodina 2017, 2018). The paper reports on the slight adaptations to the standardized design, procedure and analysis that were done to make the tasks more suitable for this specific population. It highlights the advantages, challenges, and potential associated with the task against a backdrop of the research conducted with Norwegian-Russian bilinguals in Norway.
This paper introduces the Mandarin version of the Multilingual Assessment Instrument for Narratives (LITMUS-MAIN) and describes the adaptation process. The Mandarin MAIN not only extends the empirical coverage of MAIN by including one of the most widely spoken languages in the world, but also offers an important tool to assess the narrative abilities of monolingual and bi-/ multi- lingual children acquiring Mandarin as a first, heritage, second, or additional language across the globe.
This paper describes the addition of Luxembourgish to the language versions of MAIN, the adaption process and the use of MAIN in Luxembourg. A short description of Luxembourg’s multilingual society and trilingual school system as well as an overview of selected morphosyntactic and syntactic features of Luxembourgish introduce the Luxembourgish version of MAIN.
This paper introduces the Kam version of the Multilingual Assessment Instrument for Narratives (LITMUS-MAIN). Kam is a minority language in southern China which belongs to the Kam-Tai language family and is spoken by the Kam ethnic minority people. Adding Kam to MAIN not only enriches the typological diversity of MAIN but also allows researchers to study children’s narrative development in a sociocultural context vastly distinctly different from the frequently examined WEIRD (Western, Educated, Industrialized, Rich, and Democratic) societies. Moreover, many Kam-speaking children are bilingual ethnic minority children who are “left-behind” children living in Mainland China, growing up in a unique socio-communicative environment
This paper presents the Italian version of the Multilingual Assessment tool for Narratives (MAIN), describes how it was developed and reports on some recent uses of MAIN within the Italian context. The Italian MAIN has been used in different research projects and for clinical purposes; results have been presented at conferences and in peer reviewed papers. The results indicate that MAIN is an appropriate assessment tool for evaluating children’s narrative competence, in production and comprehension from preschool age (5 years) to school age (8 years) in typical language development, bilingual development and language delay/disorders.
Irish (Gaeilge) is the first official language of the Republic of Ireland. It is a fast-changing, endangered language. Almost universal bilingualism (i.e. almost all Irish speakers also speak English), frequent code-switching to English, and loan words are features of the sociolinguistic context in which the language is spoken. This paper describes the adaptation of the Language Impairment Testing in Multilingual Settings - Multilingual Assessment Instrument for Narratives (LITMUS-MAIN, Gagarina et al., 2019) to Irish. Data was collected using the retell mode (Cat story) and the comprehension questions. Eighteen children participated ranging in age from 5;3 to 8;7 (six female and 12 male). Results suggest that story structure is not sensitive to exposure to Irish at home and indicate that MAIN Gaeilge (Irish) is a promising tool for assessing language in Irish-speaking children from a range of Irish language backgrounds.
Immigration in Iceland has a short history and so does the Icelandic language as an L2. This paper gives a brief introductory overview of this history and of some characteristics of the Icelandic language that constitute a challenge for L2 learners but also make it an interesting testing ground for cross-linguistic comparisons of L1 and L2 language acquisition. It then describes the adaptation process of the Multilingual Assessment Instrument for Narratives (LITMUS-MAIN) to Icelandic. The Icelandic MAIN is expected to fill a gap in available assessment tools for multilingual Icelandic speaking children.
The Multilingual Assessment Instrument for Narratives (LITMUS-MAIN) was developed to assess the narrative abilities of bi- and multilingual children in the various languages that they speak. This paper presents the details of the adaptation of MAIN to three Indian languages, Kannada, Hindi and Malayalam. We describe some typological features of these languages and discuss the challenges faced during the process of adaptation. Finally, we give an overview of results for narrative comprehension and production from Kannada-English and Hindi-English bilinguals aged 7 to 9.
This paper presents an overview of the adaptation of the Multilingual Assessment Instrument for Narratives in Greek, focusing on its use in Greek academic and diagnostic settings. A summary of the properties of the Greek language and the concomitant challenges these language-specific properties posed to MAIN adaptation are presented along with a summary of published studies with monolingual Greek-speaking children and bilingual children with Greek as L2, with and without Developmental Language Disorder.
This paper presents the adaptation of MAIN to Gondi (Dantewada), Halbi and Hindi for Gondi-Hindi and Halbi-Hindi bilinguals. The Gondi and Halbi communities and the context in which Gondi-Hindi and Halbi-Hindi bilingual children are growing up are described, and the adaptation process is outlined together with its theoretical underpinnings. Finally, results from a study of 54 Halbi-Hindi bilinguals from Grade 3 (Mean age = 8.5 years), Grade 5 (Mean age = 10.9 years) and Grade 7 (Mean age = 12.9 years) are presented. The results showed that, for the macrostructure of Grade 3 and Grade 5, L1 retelling was significantly better than L2 retelling, though this pattern was not found in Grade 7 where the performance was at the same level across languages for retelling. Narrative macrostructure was consistently higher in tellings than in the retellings regardless of languages and grades.
This paper describes the rationale for the adaptation of the Multilingual Assessment Instrument for Narratives (LITMUS-MAIN) (Gagarina et al., 2012, 2015, 2019) to Scottish Gaelic (Gaelic) and presents some preliminary results from the macrostructure measures. Gaelic is a heritage minority language in Scotland being revitalised through immersion education, which spans across all levels of compulsory education (preschool, primary and secondary level). MAIN was adapted to Gaelic for two reasons: (i) to gauge the language abilities of children attending Gaelic immersion schools using an ecologically valid test, and (ii) to help identify areas of language impairment in children with Developmental Language Disorders within a broader battery of language tasks. Preliminary results from the macrostructure component indicate a wider range of Gaelic language abilities in six- to eight-year-old typically developing children in Gaelic-medium education. These results set the stage for future use of the tool within this context.
This paper describes the current state of affairs concerning the West Frisian adaptation of the Multilingual Assessment Instrument for Narratives (MAIN). We provide a short description of the West Frisian language, the process of adapting MAIN into West Frisian and the results of recent research using this adaptation.
This paper describes Estonian version of the Multilingual Assessment Instrument for Narratives (LITMUS-MAIN) to Estonian. A short description of Estonian, some challenges in the adapting MAIN to Estonian, the first experiences of using the Estonian MAIN and a summary of the first results are presented.
This contribution provides an overview of the current state of affairs with respect to the Dutch version of the Multilingual Assessment Instrument for Narratives (MAIN). We describe properties of the Dutch MAIN, the creation of the Dutch MAIN, and the results of recent research with this new instrument to measure narrative competence.
This paper describes the process of adapting the Multilingual Assessment Instrument for Narratives (LITMUS-MAIN) to Danish and the use of MAIN in a Danish context. First, there is a brief description of the Danish language followed by details of the process of translating and adapting the MAIN manual to Danish. Finally, we briefly describe some of the research contexts in which the current and previous MAIN materials have been piloted and applied.
This paper presents the Croatian version of the Multilingual Assessment tool for Narratives (MAIN), outlines its development and describes the research that has used it to assess narrative skills in monolingual and bilingual speakers. The Croatian version of MAIN has so far been used in three research projects and results have been presented in five peer-reviewed articles (published or in press) covering a total of 175 children in the age range from 5;0 to 9;0 (20 with developmental language disorder) and 60 adults, age range from 22 to 76. The accumulated results indicate that MAIN can differentiate narrative skills of speakers in distinct age groups and can distinguish children with language disorders form children with typical language development.
The adaptation of the Multilingual Assessment Instrument for Narratives (LITMUS-MAIN; Gagarina, et al., 2019) to Catalan contributes to advancing our knowledge of the development of children’s narrative skills in a diversity of languages using the same protocol, making it possible to evaluate narratives also in Catalan-speakers. The adaptation of MAIN will be very useful in Catalonia, because it is a region where two official languages (Catalan and Spanish) coexist, Catalan being the language of schooling, so that most of the population is bilingual. However, currently there is no instrument for assessing narrative skills that allows for parallel assessment of Catalan in bilingual children. For these reasons, this adaptation will be of great value to promote the study of narratives in the bilingual population considering Catalan within the possible language combinations. The present paper describes the process of adapting MAIN to Catalan and reports results from the first pilot study using the Catalan MAIN.
This paper gives an introduction to the Cantonese adaptation of Multilingual Assessment Instrument for Narratives (MAIN), which is part of the Language Impairment Testing in Multilingual Settings (LITMUS) battery. We here discuss the motivation for adapting this assessment instrument into Cantonese, the adaptation process itself and potential contexts for use of the Cantonese MAIN.
Bulgarian belongs to the South Slavic language group but exhibits specific linguistic features shared with the non-Slavic languages of the Balkan Sprachbund. In this paper, we discuss linguistic and cultural aspects relevant for the Bulgarian adaptation of the revised English version of The Multilingual Assessment Instrument for Narratives (LITMUS-MAIN). We address typological properties of the verbal system pertaining to a differentiated aspectual system and to a paradigm of verbal forms for narratives grammaticalized as renarrative mood in Bulgarian. Further, we consider lexical, derivational and discourse cohesive means in contrast to the English markers of involvement and perspective taking in the MAIN stories.
Adapting MAIN to Arabic
(2020)
Preface: New language versions of MAIN: Multilingual Assessment Instrument for Narratives - revised
(2020)
The Multilingual Assessment Instrument for Narratives (MAIN) is a theoretically grounded toolkit that employs parallel pictorial stimuli to explore and assess narrative skills in children in many different languages. It is part of the LITMUS (Language Impairment Testing in Multilingual Settings) battery of tests that were developed in connection with the COST Action IS0804 Language Impairment in a Multilingual Society: Linguistic Patterns and the Road to Assessment (2009−2013). MAIN has been designed to assess both narrative production and comprehension in children who acquire one or more languages from birth or from early age. Its design allows for the comparable assessment of narrative skills in several languages in the same child and in different elicitation modes: Telling, Retelling and Model Story. MAIN contains four parallel stories, each with a carefully designed six-picture sequence based on a theoretical model of multidimensional story organization. The stories are controlled for cognitive and linguistic complexity, parallelism in macrostructure and microstructure, as well as for cultural appropriateness and robustness. As a tool MAIN had been used to compare children’s narrative skills across languages, and also to help differentiate between children with and without developmental language disorders, both monolinguals and bilinguals.
This volume consists of two parts. The main content of Part I consists of 33 papers describing the process of adapting and translating MAIN to a large number of languages from different parts of the world. Part II contains materials for use for about 80 languages, including pictorial stimuli, which are accessible after registration.
MAIN was first published in 2012/2013 (ZASPiL 56). Several years of theory development and material construction preceded this launch. In 2019 (ZASPiL 63), the revised English version (revised on the basis of over 2,500 transcribed MAIN narratives as well as ca 24,000 responses to MAIN comprehension questions, collected from around 700 monolingual and bilingual children in Germany, Russia and Sweden between 2013-2019) was published together with revised versions in German, Russian, Swedish, and Turkish for the bilingual Turkish-Swedish population in Sweden. The present 2020 (ZASPiL 64) volume contains new and revised language versions of MAIN.
Sea pens (Cnidaria: Anthozoa: Pennatulacea) constitute a distinctive group of colonial marine invertebrates. They inhabit the world`s oceans, from shallow to deep waters. Studies about this group in Argentina are scarce, and no species have been described in the area in over a decade. Based on samples collected in Mar del Plata Submarine Canyon at about 3000 m deep we describe a new species of sea pen, Umbellula pomona Risaro, Williams & Lauretta sp. nov. This is a spiculate Umbellula that differs from other species of Umbellula with sclerites, by the number, development and distribution of the autozooids in its terminal cluster, as well as the shape of its axis. Molecular data also distinguishes it from other known species. Of the forty-three described species approximately ten are considered valid for the genus Umbellula, four of them are registered for the South Atlantic Ocean and only three are described for the Antarctic region. Since sampling efforts in this area have been scarce, the number of species of sea pens from the region is likely to increase substantially in the coming years.
The p38α mitogen-activated protein kinase (MAPK) is activated through stress stimuli such as heat shock or hypoxia. In the nucleus, p38α modulates the activity of other kinases and transcription factors, a process that regulates the expression of specific target genes, most importantly pro-inflammatory cytokines. Dysregulation of p38α therefore plays a major role in the development of inflammatory diseases such as rheumatoid arthritis. Despite many years of intensive research, no p38 small-molecule inhibitors have been approved yet. Several inhibitor design strategies have been reported, leading to >100-fold selective compounds for α/β over the γ and δ isoforms. Achieving such a selectivity among the two structurally most related α and β isoforms, however, remains a challenging task. Targeting an inactive DFG-out conformation offers another strategy for the development of potent kinase inhibitors (type-II), exemplified by the BCR/ABL-inhibitor Imatinib. Achieving selectivity with type-II binders is challenging, because many kinases can adopt an inactive DFG-out conformation. This is exemplified by the p38 type-II inhibitor BIRB-796, which exhibits picomolar on-target affinity but only a poor kinome-wide selectivity. A potent and selective type-II chemical probe for p38α/β was still lacking at the start of this thesis.
The promising hit VPC-00628, was chosen for a combinatorial synthetic approach to develop a type-II chemical probe. The studies covered the optimization of the hinge-binding head group, the hydrophobic region I and the DFG-out deep pocket of the lead compound VPC-00628. Selectivity for the p38α and p38β isoforms was monitored during the optimization process, which identified several inhibitors with favorable isoform selectivity, providing valuable insights into the potential of isoform-selective inhibitor design for p38. A potent and highly selective p38 MAPK probe (SR-318) was discovered, which showed IC50 values in the low nanomolar range in HEK293T cells. An unusual P-loop conformation induced upon binding of SR-318 to p38α contributed most likely to the impressive selectivity profile within the kinome that surpassed both the parent compound and BIRB-796. A negative control compound, SR-321, was developed, to distinguish between on-target effects and non-specific effects due to cross-reactivity with other cellular proteins. Studies of the metabolic stability in human liver microsomes revealed a high stability of the compounds, with only a small amount of metabolites formed over several hours. Compound SR-318 also exhibited a good in vitro efficacy, quantitatively reducing the LPS-stimulated TNF-α release in whole blood. Taken together, SR-318 is a highly potent and selective type-II p38α/β chemical probe, which will help to gain a better understanding of the catalytic and non-catalytic functions of these key signaling kinases in physiology and pathology.
The next studies focused on the exploration of the highly dynamic allosteric back pocket of p38 MAPK, and allosteric BIRB-796 derived compounds for targeting the αC- and DFG-out pockets were synthesized. Kinase activities of allosteric pyrazole-urea fragments were analyzed against a comprehensive set of 47 diverse kinases by differential scanning fluorimetry (DSF), revealing that BIRB-796 off-targets remain a problem when targeting this back-pocket binding motif. Revisiting the recently published compound MCP-081, which combines the allosteric part of BIRB-796 with the active-site directed part of VPC-00628, showed that it displays a clean selectivity profile in our kinase panel. Because the potency of MCP-081 was slightly reduced compared with VPC-00628 and the allosteric tert-butyl pyrazole moiety seemed suboptimal, a set of VPC-00628 derivatives for targeting the αC-out pocket region was synthesized. Through structure-guided extension of the terminal amide of VPC-00628 toward this allosteric site, the potent and selective compound SR-43 was developed, which showed excellent cellular activity on p38 MAPK in NanoBRETTM assays (IC50 [p38α/β] = 14.0 ± 0.1/ 16.8 ± 0.1 nM). SR-43 showed a dose-dependent inhibition of activating phosphorylation of p38 in HCT-15 cells as well as inhibition of phosphorylation of p38 downstream substrates MK2 and Hsp27. In addition, SR-43 induced an anti-inflammatory response by blocking TNF-α release in whole blood and displayed a high metabolic stability. Selectivity profiling of SR-43 revealed a narrow selectivity for additional targets such as the discoidin domain receptor kinases (DDR1/2). DDR kinases play a central role in fibrotic disorders, such as renal and pulmonale fibrosis, atherosclerosis and different forms of cancer. Since selective and potent inhibitors for these important therapeutic targets are largely lacking and the existing inhibitors are of low scaffold diversity, the next study focused on the optimization of SR-43 toward DDR1/2 kinase inhibition. The synthetic work covered the optimization of the hinge-binding head group and the allosteric part of SR-43 toward DDR1/2 kinase inhibition. These studies provided novel insights into the P-loop folding process of p38 MAPK and how targeting of non-conserved amino acids affects inhibitor selectivity. Importantly, they led to the development of a selective dual DDR/p38 inhibitor probe, SR-302, with picomolar affinity for DDR2. SR-302 was efficient in vitro and showed a destabilizing effect on the surface adhesion protein E-cadherin in epithelial cells. In summary, SR-302 and its negative control SR-301 provide a valuable tool set for studying the phenotypic effects of DDR1/2 signaling, e.g., in cancer cell lines.
Dichromatobolus, a new genus of spirobolidan millipedes from Madagascar (Spirobolida, Pachybolidae)
(2020)
A new genus, Dichromatobolus gen. nov., belonging to the genus-rich mainly southern hemisphere family Pachybolidae of the order Spirobolida, is described based on D. elephantulus gen. et sp. nov., illustrated with color pictures, line drawings, and scanning electron micrographs. The species is recorded from the spiny bush of southwestern Madagascar. Dichromatobolus elephantulus gen. et sp. nov. shows an unusual color pattern, sexual dichromatism with males being red with black legs and females being grey. Males seem to be more surface active, as mainly males were collected with pitfall traps. Females mainly come from the pet trade. The body of this species is short and very wide, being only 8 times longer than wide in the males. Live observations show the species is a very slow mover, digging in loose soil almost as fast as walking on the surface. The posterior gonopods of Dichromatobolus gen. nov. are unusually simple and well-rounded, displaying some similarities to the genera Corallobolus Wesener, 2009 and Granitobolus Wesener, 2009, from which the new genus differs in numerous other characters, e.g., size, anterior gonopods and habitus. Despite several attempts with fresh tissue samples and different primers, molecular barcoding did not work for Dichromatobolus gen. nov. Any relationships to the other 15 genera of Pachybolidae indigenous to Madagascar remain unknown.
Background: Zolpidem is a non-benzodiazepine hypnotic agent which has been shown to be effective in inducing and maintaining sleep in adults and is one of the most frequently prescribed hypnotics in the world. For drugs that are used to treat sleeping disorders, the time to reach the maximum concentration (Tmax) of the drug in plasma is important to achieving a fast onset of action and this must be maintained when switching from one product to another.
Objectives: The main objective of the present work was to create a PBPK/PD model for zolpidem and establish a clinically relevant “safe space” for dissolution of zolpidem from the commercial immediate release (IR) formulation. A second objective was to analyze literature pharmacokinetic data to verify the negative food effect ascribed to zolpidem and consider its ramifications in terms of the “safe space” for dissolution.
Methods: Using dissolution, pharmacokinetic and pharmacodynamic data, an integrated PBPK/PD model for immediate release zolpidem tablets was constructed in Simcyp®. This model was used to identify the clinically relevant dissolution specifications necessary to ensure efficacy.
Results: According to the simulations, as long as 85% of the drug is released in 45 minutes or less, the impact on the PK and PD profiles of zolpidem would be minimal. According to the FDA, the drug has to dissolve from the test and reference products at a similar rate and to an extent of 85% in not more than 30 minutes to pass bioequivalence via the BCS-biowaiver test. Thus, the BCS-biowaiver specifications are somewhat more stringent than the “safe space” based on the PBPK/PD model. Published data from fasted and fed state pharmacokinetic studies suggest but do not prove a negative food effect of zolpidem.
Conclusions: A PBPK/PD model indicates that current BCS biowaiver criteria are more restrictive for immediate release zolpidem tablets than they need to be. In view of the close relationship between PK and PD, it remains advisable to avoid taking zolpidem tablets with or immediately after a meal, as indicated by the Stilnox® labeling.
In this study, we examine 500 specimens of Anaplecta collected from China, of which 26 samples were used for COI sequencing. We confirm eight new species, i.e., Anaplecta corneola Deng & Che sp. nov., Anaplecta staminiformis Deng & Che sp. nov., Anaplecta arcuata Deng & Che sp. nov., Anaplecta strigata Deng & Che sp. nov., Anaplecta furcata Deng & Che sp. nov., Anaplecta cruciata Deng & Che sp. nov., Anaplecta nigra Deng & Che sp. nov. and Anaplecta bicolor Deng & Che sp. nov. based on morphological and molecular data using ABGD and GMYC analyses. The results of ABGD and GMYC were basically consistent with the morphospecies of Anaplecta. The intraspecific and interspecific genetic distances of Anaplecta ranged from 0 to 6.6% and 16.8% to 31.8%, respectively. We found the male genitalia of Anaplecta to exhibit intraspecific variation, especially in the phallomeres.
Background: While systemic inflammation is recognized as playing a central role in the pathogenesis of organ failures in patients with liver cirrhosis, less is known about its relevance in the development of classical hepatic decompensation. Aim: To characterize the relationship between systemic inflammation, hemodynamics, and anemia with decompensation of liver cirrhosis. Methods: This is a post-hoc analysis of a cohort study of outpatients with advanced liver fibrosis or cirrhosis. Results: Analysis included 338 patients of whom 51 patients (15%) were hospitalized due to decompensation of liver cirrhosis during a median follow-up time of six months. In univariate analysis, active alcoholism (p = 0.002), model of end-stage liver disease (MELD) score (p = 0.00002), serum IL-6 concentration (p = 0.006), heart rate (p = 0.03), low arterial blood pressure (p < 0.05), maximal portal venous flow (p = 0.008), and low hemoglobin concentration (p < 0.00001) were associated with hospitalization during follow-up. Multivariate analysis revealed an independent association of low hemoglobin (OR = 0.62, 95% CI = 0.51–0.78, p = 0.001) and serum IL-6 concentration (OR = 1.02, 95% CI = 1.01–1.04, p = 0.03)—but not of hemodynamic parameters—with hepatic decompensation. An inverse correlation between hemoglobin concentration and portal venous flow (R = −0.362, p < 0.0001) was detected for the non-hospitalized patients. Accuracy of baseline hemoglobin levels for predicting hospitalization (AUC = 0.84, p < 0.000001) was high. Conclusion: Anemia and systemic inflammation, rather than arterial circulatory dysfunction, are strong and independent predictors of hepatic decompensation in outpatients with liver cirrhosis.
Background: Sepsis frequently occurs after major trauma and is closely associated with dysregulations in the inflammatory/complement and coagulation system. Thrombin-activatable fibrinolysis inhibitor (TAFI) plays a dual role as an anti-fibrinolytic and anti-inflammatory factor by downregulating complement anaphylatoxin C5a. The purpose of this study was to investigate the association between TAFI and C5a levels and the development of post-traumatic sepsis. Furthermore, the predictive potential of both TAFI and C5a to indicate sepsis occurrence in polytraumatized patients was assessed. Methods: Upon admission to the emergency department (ED) and daily for the subsequent ten days, circulating levels of TAFI and C5a were determined in 48 severely injured trauma patients (injury severity score (ISS) ≥ 16). Frequency matching according to the ISS in septic vs. non-septic patients was performed. Trauma and physiologic characteristics, as well as outcomes, were assessed. Statistical correlation analyses and cut-off values for predicting sepsis were calculated. Results: Fourteen patients developed sepsis, while 34 patients did not show any signs of sepsis (no sepsis). Overall injury severity, as well as demographic parameters, were comparable between both groups (ISS: 25.78 ± 2.36 no sepsis vs. 23.46 ± 2.79 sepsis). Septic patients had significantly increased C5a levels (21.62 ± 3.14 vs. 13.40 ± 1.29 ng/mL; p < 0.05) and reduced TAFI levels upon admission to the ED (40,951 ± 5637 vs. 61,865 ± 4370 ng/mL; p < 0.05) compared to the no sepsis group. Negative correlations between TAFI and C5a (p = 0.0104) and TAFI and lactate (p = 0.0423) and positive correlations between C5a and lactate (p = 0.0173), as well as C5a and the respiratory rate (p = 0.0266), were found. In addition, correlation analyses of both TAFI and C5a with the sequential (sepsis-related) organ failure assessment (SOFA) score have confirmed their potential as early sepsis biomarkers. Cut-off values for predicting sepsis were 54,857 ng/mL for TAFI with an area under the curve (AUC) of 0.7550 (p = 0.032) and 17 ng/mL for C5a with an AUC of 0.7286 (p = 0.034). Conclusion: The development of sepsis is associated with early decreased TAFI and increased C5a levels after major trauma. Both elevated C5a and decreased TAFI may serve as promising predictive factors for the development of sepsis after polytrauma.
Low-to-moderate quality meta-analytic evidence shows that motor control stabilisation exercise (MCE) is an effective treatment of non-specific low back pain. A possible approach to overcome the weaknesses of traditional meta-analyses would be that of a prospective meta-analyses. The aim of the present analysis was to generate high-quality evidence to support the view that motor control stabilisation exercises (MCE) lead to a reduction in pain intensity and disability in non-specific low back pain patients when compared to a control group. In this prospective meta-analysis and sensitivity multilevel meta-regression within the MiSpEx-Network, 18 randomized controlled study arms were included. Participants with non-specific low back pain were allocated to an intervention (individualized MCE, 12 weeks) or a control group (no additive exercise intervention). From each study site/arm, outcomes at baseline, 3 weeks, 12 weeks, and 6 months were pooled. The outcomes were current pain (NRS or VAS, 11 points scale), characteristic pain intensity, and subjective disability. A random effects meta-analysis model for continuous outcomes to display standardized mean differences between intervention and control was performed, followed by sensitivity multilevel meta-regressions. Overall, 2391 patients were randomized; 1976 (3 weeks, short-term), 1740 (12 weeks, intermediate), and 1560 (6 months, sustainability) participants were included in the meta-analyses. In the short-term, intermediate and sustainability, moderate-to-high quality evidence indicated that MCE has a larger effect on current pain (SMD = −0.15, −0.15, −0.19), pain intensity (SMD = −0.19, −0.26, −0.26) and disability (SMD = −0.15, −0.27, −0.25) compared with no exercise intervention. Low-quality evidence suggested that those patients with comparably intermediate current pain and older patients may profit the most from MCE. Motor control stabilisation exercise is an effective treatment for non-specific low back pain. Sub-clinical intermediate pain and middle-aged patients may profit the most from this intervention.