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Sex differences in the relationship between conduct disorder and cortical structure in adolescents
(2017)
Objective: Previous studies have reported reduced cortical thickness and surface area and altered gyrification in frontal and temporal regions in adolescents with conduct disorder (CD). Although there is evidence that the clinical phenotype of CD differs between males and females, no studies have examined whether such sex differences extend to cortical and subcortical structure.
Method: As part of a European multisite study (FemNAT-CD), structural magnetic resonance imaging (MRI) data were collected from 48 female and 48 male participants with CD and from 104 sex-, age-, and pubertal-status−matched controls (14–18 years of age). Data were analyzed using surface-based morphometry, testing for effects of sex, diagnosis, and sex-by-diagnosis interactions, while controlling for age, IQ, scan site, and total gray matter volume.
Results: CD was associated with cortical thinning and higher gyrification in ventromedial prefrontal cortex in both sexes. Males with CD showed lower, and females with CD showed higher, supramarginal gyrus cortical thickness compared with controls. Relative to controls, males with CD showed higher gyrification and surface area in superior frontal gyrus, whereas the opposite pattern was seen in females. There were no effects of diagnosis or sex-by-diagnosis interactions on subcortical volumes. Results are discussed with regard to attention-deficit/hyperactivity disorder, depression, and substance abuse comorbidity, medication use, handedness, and CD age of onset.
Conclusion: We found both similarities and differences between males and females in CD–cortical structure associations. This initial evidence that the pathophysiological basis of CD may be partly sex-specific highlights the need to consider sex in future neuroimaging studies and suggests that males and females may require different treatments.
Background: Few studies have evaluated the impact of pre-treatment drug resistance (PDR) on response to combination antiretroviral treatment (cART) in children. The objective of this joint EuroCoord-CHAIN-EPPICC/PENTA project was to assess the prevalence of PDR mutations and their association with virological outcome in the first year of cART in children.
Methods: HIV-infected children <18 years initiating cART between 1998 and 2008 were included if having at least one genotypic resistance test prior to cART initiation. We used the World Health Organization 2009 resistance mutation list and Stanford algorithm to infer resistance to prescribed drugs. Time to virological failure (VF) was defined as the first of two consecutive HIV-RNA > 500 copies/mL after 6 months cART and was assessed by Cox proportional hazards models. All models were adjusted for baseline demographic, clinical, immunology and virology characteristics and calendar period of cART start and initial cART regimen.
Results: Of 476 children, 88 % were vertically infected. At cART initiation, median (interquartile range) age was 6.6 years (2.1–10.1), CD4 cell count 297 cells/mm3 (98–639), and HIV-RNA 5.2 log10copies/mL (4.7–5.7). Of 37 children (7.8 %, 95 % confidence interval (CI), 5.5–10.6) harboring a virus with ≥1 PDR mutations, 30 children had a virus resistant to ≥1 of the prescribed drugs. Overall, the cumulative Kaplan-Meier estimate for virological failure was 19.8 % (95 %CI, 16.4–23.9). Cumulative risk for VF tended to be higher among children harboring a virus with PDR and resistant to ≥1 drug prescribed than among those receiving fully active cART: 32.1 % (17.2–54.8) versus 19.4 % (15.9–23.6) (P = 0.095). In multivariable analysis, age was associated with a higher risk of VF with a 12 % reduced risk per additional year (HR 0.88; 95 %CI, 0.82–0.95; P < 0.001).
Conclusions: PDR was not significantly associated with a higher risk of VF in children in the first year of cART. The risk of VF decreased by 12 % per additional year at treatment initiation which may be due to fading of PDR mutations over time. Lack of appropriate formulations, in particular for the younger age group, may be an important determinant of virological failure.
Background: Posttraumatic Stress Disorder (PTSD) related to childhood sexual abuse (CSA) is often associated with a wide range of trauma-related aversive emotions such as fear, disgust, sadness, shame, guilt, and anger. Intense experience of aversive emotions in particular has been linked to higher psychopathology in trauma survivors. Most established psychosocial treatments aim to reduce avoidance of trauma-related memories and associated emotions. Interventions based on Dialectical Behavior Therapy (DBT) also foster radical acceptance of the traumatic event.
Methods: This study compares individual ratings of trauma-related emotions and radical acceptance between the start and the end of DBT for PTSD (DBT-PTSD) related to CSA. We expected a decrease in trauma-related emotions and an increase in acceptance. In addition, we tested whether therapy response according to the Clinician Administered PTSD-Scale (CAPS) for the DSM-IV was associated with changes in trauma-related emotions and acceptance. The data was collected within a randomized controlled trial testing the efficacy of DBT-PTSD, and a subsample of 23 women was included in this secondary data analysis.
Results: In a multilevel model, shame, guilt, disgust, distress, and fear decreased significantly from the start to the end of the therapy whereas radical acceptance increased. Therapy response measured with the CAPS was associated with change in trauma-related emotions.
Conclusions: Trauma-related emotions and radical acceptance showed significant changes from the start to the end of DBT-PTSD. Future studies with larger sample sizes and control group designs are needed to test whether these changes are due to the treatment.
Trial registration: ClinicalTrials.gov, number NCT00481000
The former and current multiple sclerosis (MS) classifications are essential for describing different phenotypes and disease dynamics. To establish personalized treatment regimes, further clinical and paraclinical parameters have to be considered such as imaging, cerebrospinal fluid (CSF) findings, past disease-modifying therapies (DMTs), and disease activity under these therapies. In clinical practice, this information is often difficult to overview. Especially, patients with a long course of disease offer an extensive medical history so that comprehending all of the necessary information can be very time consuming.
Influence of the sFlt-1/PlGF ratio on clinical decision-making in women with suspected preeclampsia
(2016)
Objective: To evaluate the influence of the soluble fms-like tyrosine kinase 1/placental growth factor ratio in physicians’ decision making in pregnant women with signs and symptoms of preeclampsia in routine clinical practice.
Methods: A multicenter, prospective, open, non-interventional study enrolled pregnant women presenting with preeclampsia signs and symptoms in several European perinatal care centers. Before the soluble fms-like tyrosine kinase 1/placental growth factor ratio result was known, physicians documented intended clinical procedures using an iPad® application (data locked/time stamped). After the result was available, clinical decisions were confirmed or revised and documented. An independent adjudication committee evaluated the appropriateness of decisions based on maternal/fetal outcomes. Clinician decision making with regard to hospitalization was the primary outcome.
Results: In 16.9% of mothers (20/118) the hospitalization decision was changed after knowledge of the ratio. In 13 women (11.0%), the initial decision to hospitalize was changed to no hospitalization. In seven women (5.9%) the revised decision was hospitalization. All revised decisions were considered appropriate by the panel of adjudicators (McNemar test; p < 0.0001).
Conclusions: The use of the soluble fms-like tyrosine kinase 1/placental growth factor test influenced clinical decision making towards appropriate hospitalization in a considerable proportion of women with suspected preeclampsia. This is the first study to demonstrate the impact of angiogenic biomarkers on decision making in a routine clinical practice.
Background: Hemodynamic instability is frequent and outcome-relevant in critical illness. The understanding of complex hemodynamic disturbances and their monitoring and management plays an important role in treatment of intensive care patients. An increasing number of treatment recommendations and guidelines in intensive care medicine emphasize hemodynamic goals, which go beyond the measurement of blood pressures. Yet, it is not known to which extent the infrastructural prerequisites for extended hemodynamic monitoring are given in intensive care units (ICUs) and how hemodynamic management is performed in clinical practice. Further, it is still unclear which factors trigger the use of extended hemodynamic monitoring.
Methods: In this multicenter, 1-day (November 7, 2013, and the preceding 24 h) cross-sectional study, we retrieved data on patient monitoring from ICUs in Germany, Austria, and Switzerland by means of a web-based case report form. One hundred and sixty-one intensive care units contributed detailed information on availability of hemodynamic monitoring. In addition, detailed information on hemodynamic monitoring of 1789 patients that were treated on due date was collected, and independent factors triggering the use of extended hemodynamic monitoring were identified by multivariate analysis.
Results: Besides basic monitoring with electrocardiography (ECG), pulse oximetry, and blood pressure monitoring, the majority of patients received invasive arterial (77.9 %) and central venous catheterization (55.2 %). All over, additional extended hemodynamic monitoring for assessment of cardiac output was only performed in 12.3 % of patients, while echocardiographic examination was used in only 1.9 %. The strongest independent predictors for the use of extended hemodynamic monitoring of any kind were mechanical ventilation, the need for catecholamine therapy, and treatment backed by protocols. In 71.6 % of patients in whom extended hemodynamic monitoring was added during the study period, this extension led to changes in treatment.
Conclusions: Extended hemodynamic monitoring, which goes beyond the measurement of blood pressures, to date plays a minor role in the surveillance of critically ill patients in German, Austrian, and Swiss ICUs. This includes also consensus-based recommended diagnostic and monitoring applications, such as echocardiography and cardiac output monitoring. Mechanical ventilation, the use of catecholamines, and treatment backed by protocol could be identified as factors independently associated with higher use of extended hemodynamic monitoring.
Nerve tissue contains a high density of chemical synapses, about 1 per µm3 in the mammalian cerebral cortex. Thus, even for small blocks of nerve tissue, dense connectomic mapping requires the identification of millions to billions of synapses. While the focus of connectomic data analysis has been on neurite reconstruction, synapse detection becomes limiting when datasets grow in size and dense mapping is required. Here, we report SynEM, a method for automated detection of synapses from conventionally en-bloc stained 3D electron microscopy image stacks. The approach is based on a segmentation of the image data and focuses on classifying borders between neuronal processes as synaptic or non-synaptic. SynEM yields 97% precision and recall in binary cortical connectomes with no user interaction. It scales to large volumes of cortical neuropil, plausibly even whole-brain datasets. SynEM removes the burden of manual synapse annotation for large densely mapped connectomes.
Target-specific treatment modalities are currently not available for triple-negative breast cancer (TNBC), and acquired chemotherapy resistance is a primary obstacle for the treatment of these tumors. Here we employed derivatives of BT-549 and MDA-MB-468 TNBC cell lines that were adapted to grow in the presence of either 5-Fluorouracil, Doxorubicin or Docetaxel in an aim to identify molecular pathways involved in the adaptation to drug-induced cell killing. All six drug-adapted BT-549 and MDA-MB-468 cell lines displayed cross resistance to chemotherapy and decreased apoptosis sensitivity. Expression of the anti-apoptotic co-chaperone BAG3 was notably enhanced in two thirds (4/6) of the six resistant lines simultaneously with higher expression of HSP70 in comparison to parental controls. Doxorubicin-resistant BT-549 (BT-549rDOX20) and 5-Fluorouracil-resistant MDA-MB-468 (MDA-MB-468r5-FU2000) cells were chosen for further analysis with the autophagy inhibitor Bafilomycin A1 and lentiviral depletion of ATG5, indicating that enhanced cytoprotective autophagy partially contributes to increased drug resistance and cell survival. Stable lentiviral BAG3 depletion was associated with a robust down-regulation of Mcl-1, Bcl-2 and Bcl-xL, restoration of drug-induced apoptosis and reduced cell adhesion in these cells, and these death-sensitizing effects could be mimicked with the BAG3/Hsp70 interaction inhibitor YM-1 and by KRIBB11, a selective transcriptional inhibitor of HSF-1. Furthermore, BAG3 depletion was able to revert the EMT-like transcriptional changes observed in BT-549rDOX20 and MDA-MB-468r5-FU2000 cells. In summary, genetic and pharmacological interference with BAG3 is capable to resensitize TNBC cells to treatment, underscoring its relevance for cell death resistance and as a target to overcome therapy resistance of breast cancer.
Germany Inc. was an idiosyncratic form of industrial organization that put financial institutions at the center. This paper argues that the consumption of private benefits in related party transactions by these key agents can be understood as a compensation for their coordinating and monitoring function in Germany Inc. As a consequence, legal tools apt to curb tunneling remained weak in Germany from the perspective of outside shareholders. While banks were in a position to use their firm-level knowledge and influence to limit rent-seeking by other related parties, their own behavior was not subject to meaningful controls. With the dismantling of Germany Inc. banks seized their monitoring function and left an unprecedented void with regard to related party transactions. Hence, a “traditionalist” stance which opposes law reform for related party transactions in Germany negatively affects capital market development, growth opportunities and ultimately social welfare.
We characterize the optimal linear tax on capital in an Overlapping Generations model with two period lived households facing uninsurable idiosyncratic labor income risk. The Ramsey government internalizes the general equilibrium feedback of private precautionary saving. For logarithmic utility our full analytical solution of the Ramsey problem shows that the optimal aggregate saving rate is independent of income risk. The optimal time-invariant tax on capital is increasing in income risk. Its sign depends on the extent of risk and on the Pareto weight of future generations. If the Ramsey tax rate that maximizes steady state utility is positive, then implementing this tax rate permanently generates a Pareto-improving transition even if the initial equilibrium is dynamically efficient. We generalize our results to Epstein-Zin-Weil utility and show that the optimal steady state saving rate is increasing in income risk if and only if the intertemporal elasticity of substitution is smaller than 1.
This paper investigates the roles psychological biases play in empirically estimated deviations between subjective survival beliefs (SSBs) and objective survival probabilities (OSPs). We model deviations between SSBs and OSPs through age-dependent inverse S-shaped probability weighting functions (PWFs), as documented in experimental prospect theory. Our estimates suggest that the implied measures for cognitive weakness, likelihood insensitivity, and those for motivational biases, relative pessimism, increase with age. We document that direct measures of cognitive weakness and motivational attitudes share these trends. Our regression analyses confirm that these factors play strong quantitative roles in the formation of subjective survival beliefs. In particular, cognitive weakness is an increasingly important contributor to the overestimation of survival chances in old age.
This paper is the national report for Germany prepared for the to the 20th General Congress of the International Academy of Comparative Law 2018 and gives an overview of the regulation of crowdfunding in Germany and the typical design of crowdfunding campaigns under this legal framework. After a brief survey of market data, it delineates the classification of crowdfunding transactions in German contract law and their treatment under the applicable conflict of laws regime. It then turns to the relevant rules in prudential banking regulation and capital market law. It highlights disclosure requirements that flow from both contractual obligations of the initiators of campaigns vis-à-vis contributors and securities regulation (prospectus regime). After sketching the most important duties of the parties involved in crowdfunding, the report also looks at the key features of the respective transactions’ tax treatment.
This paper revisits the macroeconomic effects of the large-scale asset purchase programmes launched by the Federal Reserve and the Bank of England from 2008. Using a Bayesian VAR, we investigate the macroeconomic impact of shocks to asset purchase announcements and assess changes in their effectiveness based on subsample analysis. The results suggest that the early asset purchase programmes had significant positive macroeconomic effects, while those of the subsequent ones were weaker and in part not significantly different from zero. The reduced effectiveness seems to reflect in part better anticipation of asset purchase programmes over time, since we find significant positive macroeconomic effects when we consider shocks to survey expectations of the Federal Reserve’s last asset purchase programme. Finally, in all estimations we find a significant and persistent positive impact of asset purchase shocks on stock prices.
Working memory and conscious perception are thought to share similar brain mechanisms, yet recent reports of non-conscious working memory challenge this view. Combining visual masking with magnetoencephalography, we investigate the reality of non-conscious working memory and dissect its neural mechanisms. In a spatial delayed-response task, participants reported the location of a subjectively unseen target above chance-level after several seconds. Conscious perception and conscious working memory were characterized by similar signatures: a sustained desynchronization in the alpha/beta band over frontal cortex, and a decodable representation of target location in posterior sensors. During non-conscious working memory, such activity vanished. Our findings contradict models that identify working memory with sustained neural firing, but are compatible with recent proposals of ‘activity-silent’ working memory. We present a theoretical framework and simulations showing how slowly decaying synaptic changes allow cell assemblies to go dormant during the delay, yet be retrieved above chance-level after several seconds.
Aim: To evaluate the long-term outcome of catheter ablation of atrial fibrillation (AF) facilitated by preprocedural three-dimensional (3-D) transesophageal echocardiography.
Methods: In 50 patients, 3D transesophageal echocardiography (3D TEE) was performed immediately prior to an ablation procedure (paroxysmal AF: 30 patients, persistent AF: 20 patients). The images were available throughout the ablation procedure. Two different ablation strategies were used. In most of the patients with paroxysmal AF, the cryoablation technique was used (Arctic Front Balloon, CryoCath Technologies/Medtronic; group A2). In the other patients, a circumferential pulmonary vein ablation was performed using the CARTO system [Biosense Webster; group A1 (paroxysmal AF), group B (persistent AF)]. Success rates and complication rates were analysed at 4-year follow-up.
Results: A 3D TEE could be performed successfully in all patients prior to the ablation procedure and all four pulmonary vein ostia could be evaluated in 84% of patients. The image quality was excellent in the majority of patients and several variations of the pulmonary vein anatomy could be visualized precisely (e.g., common pulmonary vein ostia, accessory pulmonary veins, varying diameter of the left atrial appendage and its distance to the left superior pulmonary vein). All ablation procedures could be performed as planned and almost all pulmonary veins could be isolated successfully. At 48-mo follow-up, 68.0% of all patients were free from an arrhythmia recurrence (group A1: 72.7%, group A2: 73.7%, group B: 60.0%). There were no major complications.
Conclusion: 3D TEE provides an excellent overview over the left atrial anatomy prior to AF ablation procedures and these procedures are associated with a favourable long-term outcome.
Disturbed homeostasis as a result of tissue stress can provoke leukocyte responses enabling recovery. Since mild hypothermia displays specific clinically relevant tissue-protective properties and interleukin (IL)-22 promotes healing at host/environment interfaces, effects of lowered ambient temperature on IL-22 were studied. We demonstrate that a 5-h exposure of endotoxemic mice to 4°C reduces body temperature by 5.0° and enhances splenic and colonic il22 gene expression. In contrast, tumor necrosis factor-α and IL-17A were not increased. In vivo data on IL-22 were corroborated using murine splenocytes and human peripheral blood mononuclear cells (PBMC) cultured upon 33°C and polyclonal T cell activation. Upregulation by mild hypothermia of largely T-cell-derived IL-22 in PBMC required monocytes and associated with enhanced nuclear T-cell nuclear factor of activated T cells (NFAT)-c2. Notably, NFAT antagonism by cyclosporin A or FK506 impaired IL-22 upregulation at normothermia and entirely prevented its enhanced expression upon hypothermic culture conditions. Data suggest that intact NFAT signaling is required for efficient IL-22 induction upon normothermic and hypothermic conditions. Hypothermia furthermore boosted early signal transducer and activator of transcription 3 activation by IL-22 and shaped downstream gene expression in epithelial-like cells. Altogether, data indicate that hypothermia supports and fine-tunes IL-22 production/action, which may contribute to regulatory properties of low ambient temperature.
Objective: The influence of the jaw position on postural control, body posture, walking and running pattern has been reported in the literature. All these movements have in common that a relatively small, but well controlled muscle activation is required. The induced effects on motor output through changed jaw positions have been small. Therefore, it has been questioned if it could still be observed in maximal muscle activation.
Method: Twenty-three healthy, mid age recreational runners (mean age = 34.0 ± 10.3 years) participated in this study. Three different jump tests (squat jump, counter movement jump, and drop jumps from four different heights) and three maximal strength tests (trunk flexion and extension, leg press of the right and left leg) were conducted. Four different dental occlusion conditions and an additional familiarization condition were tested. Subjects performed the tests on different days for which the four occlusion conditions were randomly changed.
Results: No familiarization effect was found. Occlusion conditions with a relaxation position and with a myocentric condylar position showed significantly higher values for several tests compared to the neutral condition and the maximal occlusion position. Significance was found in the squat jump, countermovement jump, the drop jump from 32cm and 40cm, trunk extension, leg press force and rate of force development. The effect due to the splint conditions is an improvement between 3% and 12% (min and max). No influence of the jaw position on symmetry or balance between extension and flexion muscle was found.
Conclusion: An influence of occlusion splints on rate of force development (RFD) and maximal strength tests could be confirmed. A small, but consistent increase in the performance parameters could be measured. The influence of the occlusion condition is most likely small compared to other influences as for example training status, age, gender and circadian rhythm.
Background: Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement ‘hotspot’ loci. However, microdeletion burden not overlapping these regions or within different epilepsy subtypes has not been ascertained.
Objective: To decipher the role of microdeletions outside hotspots loci and risk assessment by epilepsy subtype.
Methods: We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases. Microdeletions were assessed in a combined and subtype-specific approaches against 6746 controls.
Results: When hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted p=1.06×10−6,OR 1.89, 95% CI 1.51 to 2.35). Epilepsy subtype-specific analyses showed that hotspot microdeletions in the GGE subgroup contribute most of the overall signal (adjusted p=9.79×10−12, OR 7.45, 95% CI 4.20–13.5). Outside hotspots , microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted p=9.13×10−3,OR 2.85, 95% CI 1.62–4.94). No additional signal was observed for RE and AFE. Still, gene-content analysis identified known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes across epilepsy subtypes that were not deleted in controls.
Conclusions: Our results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor contribution in the aetiology of RE and AFE.
Background: The Ebola virus has been responsible for numerous outbreaks since the 1970s, with the most recent outbreak taking place between 2014 and 2016 and causing an international public health emergency. Ebola virus disease (EVD) has a high mortality rate and no approved targeted treatment exists to date. A number of established drugs are being considered as potential therapeutic agents for the treatment of EVD.
Objective: We aimed to identify potential drug repositioning candidates and to assess the scientific evidence available on their efficacy.
Methods: We conducted a systematic literature search in MEDLINE, Embase, and other relevant trial registry platforms for studies published between January 1976 and January 2017. We included drug screening, preclinical studies, and clinical studies on repurposed drugs for the treatment of EVD. The risk of bias for animal studies and nonrandomized clinical studies was assessed. The quality of reporting for case series and case reports was evaluated. Finally, we selected drugs approved by established regulatory authorities, which have positive in vitro study outcomes and at least one additional animal or clinical trial.
Results: We identified 3301 publications, of which 37 studies fulfilled our inclusion criteria. Studies were highly heterogeneous in terms of study type, methodology, and intervention. The risk of bias was high for 13 out of 14 animal studies. We selected 11 drugs with potential anti-EVD therapeutic effects and summarized their evidence.
Conclusions: Several established drugs may have therapeutic effects on EVD, but the quality and quantity of current scientific evidence is lacking. This review highlights the need for well-designed and conducted preclinical and clinical research to establish the efficacy of potential repurposed drugs against EVD.
We describe 70 cases of monocled cobra (Naja kaouthia) bite admitted to Chittagong Medical College Hospital, Bangladesh. The biting snakes were identified by examining the dead snake and/or detecting N. kaouthia venom antigens in patients' serum. Bites were most common in the early morning and evening during the monsoon (May-July). Ligatures were routinely applied to the bitten limb before admission. Thirty-seven patients consulted traditional healers, most of whom made incisions around the bite site. Fifty-eight patients experienced severe neurotoxicity and most suffered swelling and pain of the bitten limb. The use of an Indian polyvalent antivenom in patients exhibiting severe neurotoxicity resulted in clinical improvement but most patients experienced moderate-to-severe adverse reactions. Antivenom did not influence local blistering and necrosis appearing in 19 patients; 12 required debridement. Edrophonium significantly improved the ability of patients to open the eyes, endurance of upward gaze, and peak expiratory flow rate suggesting that a longer-acting anticholinesterase drug (neostigmine) could be recommended for first aid. The study suggested that regionally appropriate antivenom should be raised against the venoms of the major envenoming species of Bangladesh and highlighted the need to improve the training of staff of local medical centers and to invest in the basic health infrastructure in rural communities.
Resistance formation after initial therapy response (acquired resistance) is common in high-risk neuroblastoma patients. YM155 is a drug candidate that was introduced as a survivin suppressant. This mechanism was later challenged, and DNA damage induction and Mcl-1 depletion were suggested instead. Here we investigated the efficacy and mechanism of action of YM155 in neuroblastoma cells with acquired drug resistance. The efficacy of YM155 was determined in neuroblastoma cell lines and their sublines with acquired resistance to clinically relevant drugs. Survivin levels, Mcl-1 levels, and DNA damage formation were determined in response to YM155. RNAi-mediated depletion of survivin, Mcl-1, and p53 was performed to investigate their roles during YM155 treatment. Clinical YM155 concentrations affected the viability of drug-resistant neuroblastoma cells through survivin depletion and p53 activation. MDM2 inhibitor-induced p53 activation further enhanced YM155 activity. Loss of p53 function generally affected anti-neuroblastoma approaches targeting survivin. Upregulation of ABCB1 (causes YM155 efflux) and downregulation of SLC35F2 (causes YM155 uptake) mediated YM155-specific resistance. YM155-adapted cells displayed increased ABCB1 levels, decreased SLC35F2 levels, and a p53 mutation. YM155-adapted neuroblastoma cells were also characterized by decreased sensitivity to RNAi-mediated survivin depletion, further confirming survivin as a critical YM155 target in neuroblastoma. In conclusion, YM155 targets survivin in neuroblastoma. Furthermore, survivin is a promising therapeutic target for p53 wild-type neuroblastomas after resistance acquisition (neuroblastomas are rarely p53-mutated), potentially in combination with p53 activators. In addition, we show that the adaptation of cancer cells to molecular-targeted anticancer drugs is an effective strategy to elucidate a drug’s mechanism of action.
Background: Community acquired viruses (CRVs) may cause severe disease in cancer patients. Thus, efforts should be made to diagnose CRV rapidly and manage CRV infections accordingly.
Methods: A panel of 18 clinicians from the Infectious Diseases Working Party of the German Society for Haematology and Medical Oncology have convened to assess the available literature and provide recommendations on the management of CRV infections including influenza, respiratory syncytial virus, parainfluenza virus, human metapneumovirus and adenovirus.
Results: CRV infections in cancer patients may lead to pneumonia in approximately 30% of the cases, with an associated mortality of around 25%. For diagnosis of a CRV infection, combined nasal/throat swabs or washes/aspirates give the best results and nucleic acid amplification based-techniques (NAT) should be used to detect the pathogen. Hand hygiene, contact isolation and face masks have been shown to be of benefit as general infection management. Causal treatment can be given for influenza, using a neuraminidase inhibitor, and respiratory syncytial virus, using ribavirin in addition to intravenous immunoglobulins. Ribavirin has also been used to treat parainfluenza virus and human metapneumovirus, but data are inconclusive in this setting. Cidofovir is used to treat adenovirus pneumonitis.
Conclusions: CRV infections may pose a vital threat to patients with underlying malignancy. This guideline provides information on diagnosis and treatment to improve the outcome.
Background: Shortening duration of peginterferon-based HCV treatment reduces associated burden for patients. Primary objectives of this study were to assess the efficacy against the minimally acceptable response rate 12 weeks post-treatment (SVR12) and safety of simeprevir plus PR in treatment-naïve HCV GT1 patients treated for 12 weeks. Additional objectives included the investigation of potential associations of rapid viral response and baseline factors with SVR12.
Methods: In this Phase III, open-label study in treatment-naïve HCV GT1 patients with F0–F2 fibrosis, patients with HCV-RNA <25 IU/mL (detectable/undetectable) at Week 2, and undetectable HCV-RNA at Weeks 4 and 8, stopped all treatment at Week 12. All other patients continued PR for a further 12 weeks. Baseline factors significantly associated with SVR12 were identified through logistic regression.
Results: Of 163 patients who participated in the study, 123 (75%) qualified for 12-week treatment; of these, 81 (66%) achieved SVR12. Baseline factors positively associated with SVR12 rates in patients receiving the 12-week regimen were: IL28B CC genotype: (94% SVR12); HCV RNA ≤800,000 IU/mL (82%); F0–F1 fibrosis (74%). Among all 163 patients, 94% experienced ≥1 adverse event (AE), 4% a serious AE, and 2.5% discontinued due to an AE. Reduced impairment in patient-reported outcomes was observed in the 12-week vs >12-week regimen.
Conclusions: Overall SVR12 rate (66%) was below the target of 80%, indicating that shortening of treatment with simeprevir plus PR to 12 weeks based on very early response is not effective. However, baseline factors associated with higher SVR12 rates were identified. Therefore, while Week 2 response alone is insufficient to predict efficacy, GT1 patients with favourable baseline factors may benefit from a shortened simeprevir plus PR regimen.
Trial Registration: ClinicalTrials.gov NCT01846832
Core Facilities (CF) for advanced light microscopy (ALM) have become indispensable support units for research in the life sciences. Their organizational structure and technical characteristics are quite diverse, although the tasks they pursue and the services they offer are similar. Therefore, throughout Europe, scientists from ALM‐CFs are forming networks to promote interactions and discuss best practice models. Here, we present recommendations for ALM‐CF operations elaborated by the workgroups of the German network of ALM‐CFs, German Bio‐Imaging (GerBI). We address technical aspects of CF planning and instrument maintainance, give advice on the organization and management of an ALM‐CF, propose a scheme for the training of CF users, and provide an overview of current resources for image processing and analysis. Further, we elaborate on the new challenges and opportunities for professional development and careers created by CFs. While some information specifically refers to the German academic system, most of the content of this article is of general interest for CFs in the life sciences.
In dieser Arbeit wurde das Protein OR1 ausführlich charakterisiert und die Grundlage für weitere Studien an diesem Protein gelegt. Die Zielsetzung dieser Arbeit bestand primär in der biophysikalischen Analyse eines eukaryotischen Proteorhodopsins, da bislang keine Daten zu diesen vorlagen. Dieser Ansatz ist vergleichbar mit der Studie am BR ähnlichen Rhodopsin aus dem Pilz Leptosphaeria maculans (Waschuk et al. 2005). Auch wenn man aus den Eigenschaften von OR1 keine Signatur für eukaryotische PRs herausfiltern kann, so weist OR1 eine Reihe von Charakteristika auf, die es wert sind weiterbearbeitet zu werden. Zu den hervorzuhebenden Ergebnissen dieser Arbeit zählen:
(1) OR1 zeigte in der methylotrophen Hefe Pichia pastoris ein hohes Expressionsniveau weit über der gewohnten Ausbeute bei Membranproteinen.
(2) OR1 offenbarte sich als Proteorhodopsin mit BR ähnlichen Eigenschaften wie dem niedrigen pKs-Wert des Protonenakzeptors und damit guten Protonenpumpeigenschaften über einen großen pH-Bereich. Auch bindet OR1 keinen zweiten Chromophor, was die nahen Verwandten GR und XR hingegen tun.
(3) OR1 demonstriert, dass die Konfiguration des komplexen Gegenions von Proteorhodopsinen stark variiert und sich anscheinend flexibel den physiologischen Erfordernissen des jeweiligen Organismus anpasst. In diesem Zusammenhang spielt auch das konservierte Histidin eine Rolle, da es den primären Protonenakzeptor beeinflusst. Bei OR1 stellte sich heraus, dass das Histidin den pKs Wert der D100 Position nicht signifikant beeinflusst.
(4) OR1 wurde mit 13C und 15N Atomen erfolgreich markiert und das entwickelte Protokoll für die Rekonstitution bewährte sich. Die Proteoliposomen des Wildtyps gaben sehr gut aufgelöste Festkörper-NMR Spektren. In Zukunft sind somit ausführliche NMR Studien an OR1 möglich.
"A really well-made Buttonhole is the only link between Art and Nature", war eine der dekadenten, subversiven und paradoxen Weisheiten, die der Schriftsteller und Dandy Oscar Wilde (1854–1900), der selbst das Haus nie ohne Knopflochblume verließ, 1894 der Jugend auf den Weg gab, als er seine 'Phrases and Philosophy for the Use of the Young' für die Zeitschrift 'Chameleon' verfasste. Die Belle Époque war die Hochzeit der Boutonnière. Heute lamentieren die Männermodezeitschriften, sie werde nur noch bei der eigenen Hochzeit getragen. Die kulturelle Bedeutung der zum Accessoire verkommenen Blume im Knopfloch des Herrenanzuges geht sehr weit über die Kostümgeschichte hinaus. Sie ist der einzige Link zwischen Kleidung und Philosophie.
Im Jahr 1926 landete Coco Chanel ihre vielleicht folgenreichste Kreation. Nach den Verwüstungen und radikalen politischen Umwälzungen des Ersten Weltkrieges feierte man in den 'Roaring Twenties' emphatisch das eigene Überleben. Frauen kleideten sich beim Besuch von Variété-Theatern, Lichtspielen und Bars, lasziv Zigarettenspitzen haltend, jetzt bevorzugt in Schwarz - in Klein und Schwarz. Auch wenn Coco als geniale Erfinderin dieses Outfits gilt, wäre der Erfolg ihrer Innovation ohne die historisch-politischen Umstände vermutlich undenkbar geblieben.
Blaustrumpf
(2015)
Der Blaustrumpf ist ein merkwürdiges Textil, das bereits auf den ersten Blick eher geschriebener denn gestrickter Natur ist. Studieren lassen sich an ihm dennoch die enge Verwobenheit von Kleider- und Geschlechterordnungen ebenso wie verschiedene Übersetzungsvorgänge zwischen vestimentären und anderen kulturellen Codes.
Von der nackten Wahrheit zur rätselhaften Wahrheit des Strumpfes : Walter Benjamins Bilddenken
(2015)
Mit der Unterscheidung zwischen Erkenntnis und Wahrheit findet sich in Benjamins frühen erkenntnistheoretischen Überlegungen eine Entsprechung zu den beiden Seiten der Sprache. Unter 'Erkenntnis' versteht er in diesem Zusammenhang durch Begriffe mitteilbare Sachverhalte, welche den Bereich propositionalen Wissens bilden und in der Semantik der Sprache aufgehen. Erkenntnisse können prädikativ erfasst und verbal vermittelt werden. Von der Wahrheit könne es hingegen kein Wissen geben. Da die Wahrheit weder in Begriffen darstellbar noch durch Aussagen mitteilbar ist, ist ihre Darstellung auf die symbolische Seite der Sprache verwiesen. Folgerichtig findet sich für diese Vorstellung von Wahrheit in Benjamins Schriften kein Begriff, sondern ein 'Bild', nämlich das des Strumpfes - vermutlich nicht zufällig. Denn dieser steht als ein Kleidungsstück exemplarisch für den Zusammenhang von Funktion und Symbol in der menschlichen Kultur.
Frontal fibrosierende Alopezie: Literaturanalyse und Vergleich des eigenen Patientenkollektivs
(2017)
Seit Steven Kossard 1994 das Krankheitsbild der frontal fibrosierenden Alopezie bei 6 postmenopausalen Frauen erstmals beschrieb, wurden zunehmend mehr Fälle und Beschreibungen größerer Kohorten publiziert. Die Diagnose wird vorrangig klinisch gestellt. Typischerweise zeigt sich eine meist asymptomatische, vernarbende Regression des temporo-frontalen Haaransatzes mit Verlust der Haarfollikel und einem perifollikulären Erythem. Des Weiteren kann es auch zu einem Haarausfall in anderen Regionen des Capillitiums, im Bereich der Augenbrauen und anderer Körperregionen kommen. Histologisch zeigen sich eine perifollikuläre Fibrose und ein lymphozytisches Infiltrat. Die Pathogenese der frontal fibrosierenden Alopezie ist ungeklärt. Da es für die Therapie kein Konzept gibt, beruhen Therapieansätzen meistens auf Behandlungskonzepten anderer Alopezieformen.
In dieser Arbeit wurden weltweit erschienene Daten von insgesamt 932 Patienten mit frontal fibrosierenden Alopezie zusammengefasst und klinische Charakteristika, Komorbiditäten, sowie krankheitsbegünstigende- und auslösende Faktoren identifiziert und Therapien und deren Erfolge systematisch erhoben und ausgewertet. Diese wurden mit Daten von 12 Patientinnen des eigenen Kollektivs verglichen.
Hier ergaben sich für die Kriterien Geschlecht, Status der Menopause, Alter bei Auftreten, Erkrankungsdauer und Ethnie ähnliche Ergebnisse. Bezüglich der Beteiligung einzelner Areale fanden sich für die Bereiche frontaler Haaransatz und Augenbrauen ähnliche Werte, während die Beteiligung der übrigen Körperstellen zum Teil stark differierte. Auch die Charakteristika perifollikuläres Erythem, Verlust von Haarfollikeln und die histologischen Kriterien perifollikuläre Fibrose und lymphozytäres Infiltrat kamen in der Gruppe der eigenen Patienten häufiger vor als in der Gruppe der Literaturpatienten. Bezüglich der Komorbiditäten fiel in beiden Gruppen eine im Vergleich zur Normalbevölkerung erhöhte Prävalenz von Schilddrüsenerkrankungen auf.
Die Auswertung der Therapieversuche ergab in beiden Gruppen in den meisten Fällen einen fortschreitenden Verlauf, allenfalls eine Stabilisierung, wobei kein Therapieversuch positiv herausstach. In Ausnahmefällen konnte ein erneutes Haarwachstum, vorrangig im Bereich der Augenbrauen, beobachtet werden.
Für die Patienten des eigenen Patientenkollektivs wurde das Vorliegen einer atopischen Hautdiathese gemessen am Erlanger Atopiescore erhoben. Hierbei konnte jedoch kein Zusammenhang gefunden werden. Mit Hilfe zweier Fragebögen- dem Functional Assessment of Non-Life Threatening Conditions (FANLTC) und dem modifizierten Hairdex- wurde die Lebensqualität in Abhängigkeit der Ausprägung der frontal fibrosierenden Alopezie und der Erkrankungsdauer ausgewertet. Die These, dass die Ausprägung der Alopezie und die Erkrankungsdauer negativ in linearem Zusammenhang mit der Lebensqualität stehen, bestätigte sich hierbei nicht. Die Lebensqualität von Patienten mit frontal fibrosierender Alopezie ist unabhängig von der Ausprägung und der Erkrankungsdauer bis auf eine Ausnahme sehr gut, was darauf hindeutet, dass sich die Erkrankung auf die Lebensqualität nicht negativ auswirkt.
The efficacy of antiviral treatment for chronic hepatitis C virus (HCV) infection is determined by measuring HCV RNA at specific time points throughout therapy using highly sensitive and accurate HCV RNA assays. This study compared the performances of two recently developed real-time PCR HCV RNA assays, cobas HCV for use on the cobas 6800/8800 systems (cobas 6800/8800 HCV) and cobas HCV for use on the cobas 4800 system (cobas 4800 HCV), with those of two established assays, the Cobas AmpliPrep/Cobas TaqMan HCV quantitative test, version 2 (CAP/CTM v2) and the Cobas TaqMan HCV test, version 2 for use with the High Pure system (HPS/CTM v2). The limits of detection (LODs) and linearity at lower concentrations (5 to 1000 IU/ml) were assessed for cobas 6800/8800 HCV and cobas 4800 HCV using WHO standard traceable panels representing HCV genotypes (GT) 1 to 4. Pairwise assay comparisons were also performed using 245 clinical samples representing HCV GT 1 to GT 4. Results from cobas 6800/8800 HCV and cobas 4800 HCV were linear at low HCV RNA concentrations (<0.3 log10 IU/ml difference between expected and observed results) with LODs of 8.2 IU/ml and 11.7 IU/ml, respectively, for GT 1. The new assays showed excellent agreement with results from CAP/CTM v2 and HPS/CTM v2 in samples with quantifiable viral loads. The concordances using the 6 million IU/ml cutoff were high among all four assays (90 to 94%). In conclusion, the cobas 6800/8800 HCV and cobas 4800 HCV tests are sensitive and linear and correlate well with the established Roche assays used in clinical practice.
Establishing a yeast-based screening system for discovery of human GLUT5 inhibitors and activators
(2017)
Human GLUT5 is a fructose-specific transporter in the glucose transporter family (GLUT, SLC2 gene family). Its substrate-specificity and tissue-specific expression make it a promising target for treatment of diabetes, metabolic syndrome and cancer, but few GLUT5 inhibitors are known. To identify and characterize potential GLUT5 ligands, we developed a whole-cell system based on a yeast strain deficient in fructose uptake, in which GLUT5 transport activity is associated with cell growth in fructose-based media or assayed by fructose uptake in whole cells. The former method is convenient for high-throughput screening of potential GLUT5 inhibitors and activators, while the latter enables detailed kinetic characterization of identified GLUT5 ligands. We show that functional expression of GLUT5 in yeast requires mutations at specific positions of the transporter sequence. The mutated proteins exhibit kinetic properties similar to the wild-type transporter and are inhibited by established GLUT5 inhibitors N-[4-(methylsulfonyl)-2-nitrophenyl]-1,3-benzodioxol-5-amine (MSNBA) and (−)-epicatechin-gallate (ECG). Thus, this system has the potential to greatly accelerate the discovery of compounds that modulate the fructose transport activity of GLUT5.
Two missense mutations of the DYRK1B gene have recently been found to co-segregate with a rare autosomal-dominant form of metabolic syndrome. This gene encodes a member of the DYRK family of protein kinases, which depend on tyrosine autophosphorylation to acquire the catalytically active conformation. The mutations (H90P and R102C) affect a structural element named DYRK homology (DH) box and did not directly interfere with the conformation of the catalytic domain in a structural model of DYRK1B. Cellular assays showed that the mutations did not alter the specific activity of mature kinase molecules. However, a significant part of the mutant DYRK1B protein accumulated in detergent-insoluble cytoplasmic aggregates and was underphosphorylated on tyrosine. The mutant DYRK1B variants were more vulnerable to the HSP90 inhibitor ganetespib and showed enhanced binding to the co-chaperone CDC37 as compared to wild type DYRK1B. These results support the hypothesis that the mutations in the DH box interfere with the maturation of DYRK1B by tyrosine autophosphorylation and compromise the conformational stability of the catalytic domain, which renders the kinase susceptible to misfolding.
Spatial attention allows us to make more accurate decisions about events in our environment. Decision confidence is thought to be intimately linked to the decision making process as confidence ratings are tightly coupled to decision accuracy. While both spatial attention and decision confidence have been subjected to extensive research, surprisingly little is known about the interaction between these two processes. Since attention increases performance it might be expected that confidence would also increase. However, two studies investigating the effects of endogenous attention on decision confidence found contradictory results. Here we investigated the effects of two distinct forms of spatial attention on decision confidence; endogenous attention and exogenous attention. We used an orientation-matching task, comparing the two attention conditions (endogenous and exogenous) to a control condition without directed attention. Participants performed better under both attention conditions than in the control condition. Higher confidence ratings than the control condition were found under endogenous attention but not under exogenous attention. This finding suggests that while attention can increase confidence ratings, it must be voluntarily deployed for this increase to take place. We discuss possible implications of this relative overconfidence found only during endogenous attention with respect to the theoretical background of decision confidence.
A new Mexican species of Ochraethes Chevrolat, 1860 (Coleoptera, Cerambycidae, Cerambycinae, Clytini) is described: Ochraethes skillmani Wappes, Santos-Silva and Botero. Plocaederus mirim Martins and Monné, 2002 (Cerambycini) is redescribed and its female is figured for the first time. New geographical records in Plocaederus Dejean, 1835 are also provided.
A taxonomic revision of Panamanian species of the genus Dasymutilla Ashmead (Hymenoptera, Mutillidae) is presented and a key for the six species is given, all recognized from both sexes. Dasymutilla colorado Cambra, Williams and Quintero sp. nov., from central and eastern Panama, is described and illustrated. Sex associations permitted us to make the following five synonymies: D. sleipniri Manley and Pitts, 2007 (male) under D. phya (Cameron, 1895) (female); D. deyrollesi Mickel, 1937 (male) and Sphaerophthama [sic.] temaxensis Cameron, 1895 under Dasymutilla araneoides (Smith, 1862) (female); D. ionothorax Manley and Pitts, 2007 (male) under Dasymutilla spilota Manley and Pitts, 2007 (female); and D. guanacaste Manley and Pitts, 2007 (male) under D. paradoxa (Gerstaecker, 1874) (female). Seasonal flight activity for Dasymutilla from six years of continuous malaise trappings in Barro Colorado Island is presented.
Embedding spanning structures into the random graph G(n,p) is a well-studied problem in random graph theory, but when one turns to the random r-uniform hypergraph H(r)(n,p) much less is known. In this thesis we will examine this topic from different perspectives, providing insights into various aspects of the theory of random graphs. Our results cover the determination of existence thresholds in two models, as well as an algorithmic approach. For the embeddings, we work with random and pseudorandom structures.
Together with Person we first notice that a general result of Riordan can be adapted from random graphs to hypergraphs and provide sufficient conditions for when H(r)(n,p) contains a given spanning structure asymptotically almost surely. As applications, we discuss several spanning structures such as cubes, lattices, spheres, and Hamilton cycles in hypergraphs.
Moreover, we study universality, i.e. when does an r-uniform hypergraph contain every hypergraph on n vertices with maximum vertex degree bounded by [delta]? For H(r)(n,p), it is shown with Person that this holds for p = w(ln n/n)1/[delta]) asymptotically almost surely by combining approaches taken by Dellamonica, Kohayakawa, Rödl, and Ruciński, of Ferber, Nenadov, and Peter, and of Kim and Lee.
Any hypergraph that is universal for the family of bounded degree r-uniform hypergraphs has to contain [omega](nr-r/[delta]) edges. With Hetterich and Person we exploit constructions of Alon and Capalbo to obtain universal r-uniform hypergraphs with the optimal number of edges O(nr-r/[delta]) when r is even, r | [delta], or [delta] = 2. Furthermore, we generalise the result of Alon and Asodi about optimal universal graphs for the family of graphs with at most m edges and no isolated vertices to hypergraphs.
In an r-uniform hypergraph on n vertices a tight Hamilton cycle consists of n edges such that there exists a cyclic ordering of the vertices where the edges correspond to consecutive segments of r vertices. In collaboration with Allen, Koch, and Person we provide a first deterministic polynomial time algorithm, which finds asymptotically almost surely tight Hamilton cycles in random r-uniform hypergraphs with edge probability at least C log3 n/n. This result partially answers a question of Nenadov and Skorić and of Dudek and Frieze who proved that tight Hamilton cycles exist already for p = w(1/n) for r = 3 and p [größer/gleich] (e + o(1))/n for r [größer/gleich] 4 using a second moment argument. Moreover our algorithm is superior to previous results of Allen, Böttcher, Kohayakawa, and Person and Nenadov and Skorić.
Lastly, we study the model of randomly perturbed dense graphs introduced by Bohman, Frieze and Martin, that is, the union of any n-vertex graph G[alpha] with minimum degree at least [alpha]n and G(n,p). For any fixed [alpha] > 0, and p = w(n-2/([delta]+1)), we show with Böttcher, Montgomery, and Person that G[alpha] UG(n,p) almost surely contains any single spanning graph with maximum degree [delta], where [delta] [größer/gleich] 5. As in previous results concerning this model, the bound used for p is lower by a log-term in comparison to the conjectured threshold for the general appearance of such subgraphs in G(n,p) alone. The new techniques we introduce also give simpler proofs of related results in the literature on trees and factors.
In modern welfare states, family policies may resolve the tension between employment and care-focused demands. However these policies sometimes have adverse consequences for distinct social groups. This study examined gender and educational differences in working parents’ perceived work–family conflict and used a comparative approach to test whether family policies, in particular support for child care and leave from paid work, are capable of reducing work–family conflict as well as the gender and educational gaps in work–family conflict. We use data from the European Social Survey 2010 for 20 countries and 5296 respondents (parents), extended with information on national policies for maternity and parental leave and child care support from the OECD Family Database. Employing multilevel analysis, we find that mothers and the higher educated report most work–family conflict. Policies supporting child care reduce the level of experienced work–family conflict; family leave policy appears to have no alleviating impact on working parents’ work–family conflict. Our findings indicate that family policies appear to be unable to reduce the gender gap in conflict perception and even widen the educational gap in work–family conflict.
The pathological skin phenotype caused by hyperglycemia is an important indicator for the progress of diabetes mellitus. An early detection of diabetes assures an early intervention to regulate the carbohydrate metabolism. In this publication a non-invasive detection principle based on the measurement of complex scattering parameters in the millimeter-wave frequency range is presented. The measurement principle provides evidence of the applicability for the identification of different glycemic states in animal models. The method proposed here can be used to predict diabetes status in animal models and is interesting for application on humans in view of safeness of millimeter-wave radiation. Furthermore the complex scattering parameters give important information about the anatomic varieties between the analyzed skin samples of the different mice strains. In contrast to other methods, our approach is less sensitive to skin variations between animals.
Das World Wide Web (Web) als die wohl wichtigste Entwicklung von Informations- und Kommunikationstechnologien (engl. information and communication technologies, ICTs) Ende des 20. Jahrhunderts bietet uns Zugang zu einer unbegrenzten Fülle an Informationen. Doch um es als reichhaltige Informationsquelle effektiv nutzen zu können, benötigen wir spezifische ICT-Fähigkeiten. Die Dissertation Development of Interactive Performance Measures for two Components of ICT Literacy: Successfully Accessing and Evaluating Information befasst sich daher mit der Untersuchung zweier grundlegender ICT Fähigkeiten für die erfolgreiche Nutzung des Web als Informationsquelle: der Fähigkeit, auf die gewünschten Information zugreifen zu können, also basale Computerfähigkeiten (engl. basic computer skills, BCS), sowie der Fähigkeit, die Online-Informationen in Bezug auf ihre Glaubwürdigkeit bewerten zu können. Hierzu werden zunächst anhand der Betrachtung des theoretischen Hintergrundes beider ICT-Fähigkeiten Definitionen der Konstrukte vorgestellt. Ziel der Arbeit stellt die Entwicklung zweier Testverfahren zur interaktiven, computer-basierten Erfassung basaler Computerfähigkeiten sowie der Fähigkeit zur Bewertung der Glaubwürdigkeit von Online-Informationen dar. Die den Testverfahren zugrundeliegende faktorielle Struktur sowie die Beziehung beider ICT-Fähigkeiten zu verwandten Konstrukten werden untersucht. Des Weiteren werden Ergebnisse aus der praktischen Anwendung des neu entwickelten Tests zur Evaluation von Online-Informationen (TEO) genutzt, um zu einem tieferen Verständnis über den Suchprozess im Web (engl. web search proccess) zu gelangen und Faktoren zu identifizieren, die diesen beeinflussen. Dabei wird sowohl der Einfluss sogenannter Aufgabencharakteristika (engl. task characteristics) untersucht, die den Kontext des Suchprozesses bestimmen, als auch der Einfluss individueller Prozesscharakteristika (engl. individual process characteristics), welche durch die jeweilige Person bestimmt sind, die die Informationssuche vornimmt.
Um den Forschungszielen der Arbeit gerecht zu werden, wurden drei Studien durchgeführt. Die erste Studie befasst sich mit der Entwicklung der Skala zur Erfassung basaler Computerfähigkeiten (BCS). Im Konkreten wurden Hypothesen über die Zusammenhänge der BCS-Skala mit praktischem Computerwissen, Worterkennung, einer Selbsteinschätzung der eigenen Computerfähigkeiten sowie elektronischer Lesefähigkeit formuliert und analysiert. Die zweite Studie behandelt die Entwicklung des Tests zur Evaluation von Online-Informationen (TEO) und exploriert sowohl die latente Struktur des Konstruktes der Bewertung der Glaubwürdigkeit von Online-Informationen als auch den Zusammenhang mit basalen Computerfähigkeiten, Worterkennung und logischem Denken. In der dritten Studie wird der Suchprozess im Web näher beleuchtet und mögliche Einflussgrößen einer erfolgreichen Bewertung von Online-Informationen erforscht, wobei der Einfluss von Aufgabencharakteristika, individuellen Prozesscharakteristika und deren Interaktion ergründet wird. Im Speziellen wurde der Einfluss dreier Aufgabencharakteristika geprüft, die sich auf die Komplexität einer Aufgabe beziehen: die Anzahl der Suchergebnisse (Links auf der Ergebnisseite einer Suchmaschinenabfrage), die Attraktivität der weniger glaubwürdigen Links auf der Ergebnisseite einer Suchmaschinenabfrage im Vergleich zum glaubwürdigsten Link sowie die Kongruenz zwischen den Glaubwürdigkeitsmerkmalen in den Links auf der Ergebnisseite der Suchmaschinenabfrage und auf den dazugehörigen Webseiten. Dabei war die Attraktivität eines Links definiert als die Gesamtanzahl der Glaubwürdigkeitsmerkmale, welche auf eine hohe Glaubwürdigkeit der Informationen hinweisen. Je mehr Merkmale eines Links hohe Glaubwürdigkeit indizieren, desto attraktiver ist ein Link. Von Kongruenz zwischen den Glaubwürdigkeitsmerkmalen wurde ausgegangen, wenn diese sowohl in einem Link auf der Ergebnisseite der Suchmaschinenabfrage als auch auf der korrespondierenden Webseite gleichermaßen hohe oder gleichermaßen geringe Glaubwürdigkeit anzeigen. Inkongruenz hingegen wurde angenommen, wenn die Glaubwürdigkeitsmerkmale in einem Link auf der Ergebnisseite hohe Glaubwürdigkeit und jene auf der korrespondierenden Webseite geringe Glaubwürdigkeit anzeigen und vice versa. Weiterhin wurde der Einfluss dreier individueller Prozesscharakteristika auf den Bewertungserfolg untersucht: die Anzahl besuchter unterschiedlicher Webseiten, die auf der Ergebnisseite der Suchmaschinenabfrage verbrachte Zeit sowie die auf den korrespondierenden Webseiten verbrachte Zeit.
Zusammengefasst präsentiert die Arbeit reliable Instrumente zur Erfassung basaler Computerfähigkeiten sowie der Fähigkeit zur Bewertung der Glaubwürdigkeit von Online-Informationen. Sie zeigt die hohe Relevanz basaler Lesefähigkeiten (Worterkennung) für beide Konstrukte auf und offenbart die Fähigkeit zum logischen Denken als Prädiktor für die Bewertungskompetenz. Während eine erfolgreiche Bewertung von Online-Informationen durch eine hohe Anzahl von Suchergebnissen negativ beeinflusst wurde, wirkte sich Kongruenz der Glaubwürdigkeitsmerkmale sowie eine hohe Anzahl besuchter unterschiedlicher Webseiten positiv auf den Bewertungserfolg aus. Die Attraktivität der weniger glaubwürdigen Links sowie die zeitbezogenen Prozesscharakteristika beeinflussten den Bewertungserfolg wider Erwarten nicht. Die Anzahl besuchter unterschiedlicher Webseiten erwies sich bei einer hohen Anzahl von Suchergebnissen als weniger prädiktiv für den Bewertungserfolg als bei einer geringen Anzahl von Suchergebnissen.
A full understanding of the origin, formation and degradation of volatile compounds that contribute to wine aroma is required before wine style can be effectively managed. Fractionation of grapes represents a convenient and robust method to simplify the grape matrix to enhance our understanding of the grape contribution to volatile compound production during yeast fermentation. In this study, acetone extracts of both Riesling and Cabernet Sauvignon grape berries were fractionated and model wines produced by spiking aliquots of these grape fractions into model grape juice must and fermented. Non-targeted SPME-GCMS analyses of the wines showed that several medium chain fatty acid ethyl esters were more abundant in wines made by fermenting model musts spiked with certain fractions. Further fractionation of the non-polar fractions and fermentation of model must after addition of these fractions led to the identification of a mixture of polyunsaturated triacylglycerides that, when added to fermenting model must, increase the concentration of medium chain fatty acid ethyl esters in wines. Dosage-response fermentation studies with commercially-available trilinolein revealed that the concentration of medium chain fatty acid ethyl esters can be increased by the addition of this triacylglyceride to model musts. This work suggests that grape triacylglycerides can enhance the production of fermentation-derived ethyl esters and show that this fractionation method is effective in segregating precursors or factors involved in altering the concentration of fermentation volatiles.
In recent decades the embryo of Gallus g. domesticus has been widely used as a model for the study of early sexual development and the potential impact of substances affecting development, including endocrine disrupting chemicals (EDCs). Since there is no standardized procedure available for experiments with the chicken embryo, the objective of our project is to expedite the protocol to assess the potential effects of EDCs on early sexual differentiation. The main aim of the present study was to systematically investigate the natural variability of individual developmental and histological key parameters in untreated and solvent-treated control groups, since this has been insufficiently addressed so far. A further aim was to provide robust values for all parameters investigated in control and substance experiments, using two known estrogenic compounds, bisphenol A (75/150/300 μg/g egg) and 17α-ethinylestradiol (20 ng/g egg). On embryonic day 1 eggs were injected with the estrogenic compounds. On embryonic day 19 histological gonadal data as well as morphological parameters were noted. In baseline experiments with control groups the selected endpoints showed reproducible results with low variabilities. Furthermore, gonadal endpoints responded sensitively to the treatment with the two model EDCs. Thus, these endpoints are recommended for the assessment of suspected EDCs in which the values provided for all parameters can serve as validity criteria in future experiments. The embryo of G. domesticus has shown to be a suitable alternative to currently accepted mammalian bioassays for the impact assessment of EDCs on reproductive tissues.
Drugs may cause liver injury in a few susceptible individuals, but the molecular events that lead to this idiosyncratic, largely dose-independent and non-predictable drug-induced liver injury (DILI) are mostly unknown, since animal models to explore the pathogenetic mechanisms of human idiosyncratic DILI are not yet reliable.
"Sehet her !" Auf dem Frontispiz des Ehrenbuches der Familie Fugger fordert die Figur des in prachtvollem Ornat gekleideten Hohepriesters Jesus Sirach den Betrachter und Lesenden mit direktem Blick und erhobenem Zeigefinger auf, dieser Familiengeschichte Respekt und Aufmerksamkeit entgegenzubringen. Auf der folgenden Seite ist es ein Herold, der das Wappen der Fugger präsentierend an das Hinsehen appelliert: "Secht an das ist das Buch der Eern". Schon auf diesen ersten Seiten deutet sich an: es geht um Sehen und Gesehenwerden und um Selbst- und Fremdwahrnehmung in diesem "Ehrenbuch" der Familie mit dem größten Handelsund Bankimperium des 16. Jahrhunderts. Gregor Rohmann hat sich in einer zweibändigen, reich bebilderten Studie einer grundlegenden Untersuchung und Kommentierung des Fuggerschen Familienbuches aus dem 16. Jahrhundert gewidmet. Diese Studie ist bereits der zweite Teil von Rohmanns Dissertation: Wo der erste, 2001 veröffentlichte Teil über den Geschichtsschreiber Clemens Jäger die Historiographie des 16. Jh. thematisiert, beschäftigt sich dieser zweite mit den Prinzipien sozialer Mobilität, Memoria und gesellschaftlicher Legitimation, Herkunft, "Herkommen" und der Konstruktion einer Genealogie am konkreten "Fallbeispiel" des Ehrenbuches. Aufgeteilt ist das ambitionierte Werk in einen Textund einen Bildband. ...
Brachiopod shells are the most widely used geological archive for the reconstruction of the temperature and the oxygen isotope composition of Phanerozoic seawater. However, it is not conclusive whether brachiopods precipitate their shells in thermodynamic equilibrium. In this study, we investigated the potential impact of kinetic controls on the isotope composition of modern brachiopods by measuring the oxygen and clumped isotope compositions of their shells. Our results show that clumped and oxygen isotope compositions depart from thermodynamic equilibrium due to growth rate-induced kinetic effects. These departures are in line with incomplete hydration and hydroxylation of dissolved CO2. These findings imply that the determination of taxon-specific growth rates alongside clumped and bulk oxygen isotope analyses is essential to ensure accurate estimates of past ocean temperatures and seawater oxygen isotope compositions from brachiopods.
Background: The objective of the FAVOR study was to evaluate the effect of indacaterol/glycopyrronium (IND/GLY) versus tiotropium on peak forced expiratory volume in 1 s (FEV1) and also to investigate patient satisfaction and treatment preference.
Methods: Patients with moderate-to-severe airflow limitation (FEV1/forced vital capacity ratio of <0.70), those with a COPD assessment test score of ≥10, and those who were maintained on tiotropium HandiHaler® therapy prior to enrollment were recruited for the study, and randomized (1:1) to receive either 4 weeks open-label IND/GLY (110/50 µg) once daily followed by 4 weeks of tiotropium (18 µg) once daily or vice versa. The primary endpoint was FEV1 1 h post-inhalation after 4 weeks of treatment. Other endpoints included patient’s and physician’s preference for treatment, patient’s satisfaction evaluated using a study-specific questionnaire and the abbreviated Treatment Satisfaction Questionnaire for Medication, and safety and tolerability.
Results: Eighty-seven out of 88 randomized patients completed the study and showed significantly higher FEV1 1 h post-inhalation after 4 weeks of treatment with IND/GLY versus tiotropium (treatment difference =0.081 L; p=0.0017). IND/GLY was preferred over tiotropium among the patients (69.4% versus 30.6%, p=0.0004) and the physicians (81.6% versus 18.4%, p<0.0001). A higher proportion of the patients stated they were very satisfied or satisfied with IND/GLY versus tiotropium with regard to dyspnea reduction (79.3% versus 58.0%, respectively) and reduction of dyspnea on exertion (72.4% versus 43.2%, respectively). Patients treated with IND/GLY showed significant improvement in Treatment Satisfaction Questionnaire for Medication domain scores versus tiotropium. IND/GLY demonstrated a good safety and tolerability profile.
Conclusion: This study indicated that, beyond FEV1, important patient-reported outcomes improved with the open-label dual bronchodilator IND/GLY when compared with tiotropium. This study suggests that individual patients felt the lung function benefits with IND/GLY compared with tiotropium, which, in turn, may also have contributed to the preference for IND/GLY.
Characterizing the hologenome of Lasallia pustulata and tracing genomic footprints of lichenization
(2017)
The lichen symbiosis – consisting of fungal mycobionts and photoautotroph photobionts (green algae or cyanobacteria) – is globally successful. It covers an estimated 6% of the global surface with habitats ranging from deserts to the arctic. This success is reflected in the diversity of the mycobionts, with around 21% of all fungal species participating in lichen symbioses that can be facultative or obligate. Lichenization is furthermore evolutionary old, with fossil evidence for lichens reaching back 415 million years. For an individual fungal lineage, the Lecanoromycetes, the lichenization happened around 300 million years ago. This longstanding symbiotic relationship and the diversity of observed symbiotic dependency make them promising models to study the genomic consequences that follow the establishment of symbioses. Despite this, only little is known about the genomic effects of lichenization and extreme symbiotic dependency. To fill this gap we sequenced the hologenome of the lichen Lasallia pustulata, where the mycobiont could so far not been cultivated, suggesting that it might be more dependent on its symbionts.
As the poor culturability of lichen symbionts renders their genomes inaccessible to standard sequencing practices, we evaluated the extent to which different metagenome sequencing- and de novo assembly-strategies can be used to sequence and reconstruct the genomes of the individual symbionts. We find that the abundances of individual genomes present in the L. pustulata hologenome vary substantially, with the mycobiont being most abundant. Using in silico generated data sets and real Illumina sequencing data for L. pustulata we observe that the skewed abundances prevent a contiguous assembly of the underrepresented genomes when using only short-read sequencing. We conclude that short-read sequencing can offer first insights into lichen hologenomes. The fragmentation of the reconstructions hinders downstream analyses into the genomic consequences of lichenization though, as these are focused on identifying the gain and loss of genes.
We thus demonstrate a hybrid genome assembly strategy that is based on both short- and long-read sequencing. We show that this strategy is capable of creating highly contiguous genome reconstructions, not only for the L. pustulata mycobiont but also its photobiont Trebouxia sp., along with substantial amounts of the bacterial microbiome. A subsequent analysis of the microbiome of L. pustulata – performed over nine different samples collected in Germany and Italy – showed a stable taxonomic composition across the geographic range. We find that Acidobacteriaceae, which are known to thrive in nutrient poor habitats, are the dominant taxa. These would make them well adapted for the co-habitation with L. pustulata, which largely grows on rocks. Whether the Acidobacteriaceae are functionally involved in the lichen symbiosis is unclear so far.
As further comparative genomic studies rely on comprehensive genome annotations, we evaluate the completeness and fidelity of the gene annotations for the mycobiont L. pustulata as well as four further Lecanoromycetes. This reveals that un- and mis-annotated genes impact all evaluated genomes, with artificially joined genes and unannotated genes having the largest impact. In addition to these factors we find that the sequence composition – especially G/C-rich inverted repeats – lead to sequencing errors that interfere with the gene prediction. We minimize the effects of these artifacts through a rigorous curation.
Given the extremely sparse taxon sampling of available green alga genomes, we focus our search for the genomic footprints of lichenization on the mycobionts. We compare the genomes of the Lecanoromycetes to their closest relatives, the Eurotiomycetes and Dothideomycetes. This reveals that the last common ancestor of the Lecanoromycetes has lost around 10% of its genes after they split from the non-lichenized ancestor they share with the Eurotiomycetes. These losses are furthermore enriched, showing an excessive loss of genes involved with the degradation of polysaccharides. The loss of these genes fits a change from an ancestral saprotrophic lifestyle that depends on degrading complex plant matter, to the symbiotic lifestyle that relies on simpler nutrients provided by the photobionts. While the last common ancestor of the Lecanoromycetes additionally gained around 400 genes these could so far not be further characterized due to a lack of functionally annotated reference data.
As the mycobiont L. pustulata could so far not been grown in axenic culture, we initially expected to find an extensive genomic remodeling compared to the other mycobionts that easily grow in culture. We do not find evidence for this. Analyzing both the contraction of gene families and the loss of genes, we observe that L. pustulata and Umbilicaria muehlenbergii – its close relative that is easily grown in culture – share most of these. Furthermore, L. pustulata does not show an excessive loss of evolutionary old and well-conserved genes. These effects are mirrored on the functional level, as neither gene family contractions nor gene losses show a functional enrichment. This is partially due to the lack of functional reference data, analogous to the genes gained in the Lecanoromycetes, rendering their characterization hard. Thus, further studies on the genomic consequences of lichenization and differences in symbiotic dependence will have to be conducted, including larger taxon sets. This will be even more important for the photobionts, as the Chlorophyta are even more sparsely sampled today, hindering an effective functional and evolutionary study.
Die Habilitationsschrift des Frankfurter Historikers Gregor Rohmann will keine Ideengeschichte des krankhaften Tanzens präsentieren, sondern wählt einen diskursiven, semiotischen Ansatz zur Deutung und Bewertung eines mittelalterlichen Phänomens, das unter dem Begriff der »Tanzwut« in der interdisziplinären Forschung sehr unterschiedliche Bewertungen erfahren hat. Galt die Tanzwut in der Wissenschaft des 19. Jahrhunderts vorwiegend als physisch bedingte Krankheit (Chorea Huntington, Veitstanz) bzw. psychische Epidemie, wird die Tanzwut unter der Prämisse einer diskursiven Körpergeschichte zunehmend als kulturell beeinflusstes, dynamisches Krankheitskonzept interpretiert, das sich durch Einbettung in verschiedene Beziehungsgeflechte in einem stetigen Deutungswandel befindet. Daran anknüpfend zielt Rohmanns Studie auf ein neues Verständnis der Tanzwut auf der Basis umfangreicher epochenübergreifender Quellenbelege. ...
In dieser Arbeit soll identifiziert werden, welcher der zahlreichen Vertreter einer Arzneistoffklasse sich letztlich auf dem Markt durchsetzen kann und ob bestimmte pharmakokinetische, pharmakodynamische, klinische oder praktische Substanzeigenschaften retrospektiv für den Markterfolg einer Substanz verantwortlich gemacht werden können. Zudem stellt sich die Frage, ob und in wie fern Analogpräparate einen Nutzen in der Arzneimitteltherapie mit sich bringen, obwohl ihnen zum Zeitpunkt ihrer Markteinführung nur ein geringer Innovationsgrad zugebilligt wurde. Um derartige Rückschlüsse ziehen zu können wurden exemplarisch folgende fünf Arzneistoffklassen untersucht, die sich durch eine Vielzahl an Vertretern auszeichnen: Arsphenamine, Sulfonamide, Benzodiazepine, Glucocorticoide sowie Betablocker. Der Untersuchungszeitraum bemisst sich folglich vom Anfang des 20. Jahrhunderts, als industriell gefertigte, chemisch definierte hochpotente Wirkstoffe die Therapie zu bestimmen begannen, bis etwa zum letzten Drittel des 20. Jahrhunderts als Preise und Kostenerstattungsfragen zusätzlich zu Substanzeigenschaften für den Markterfolg mitbestimmend wurden.
Exploring biophysical properties of virus-encoded components and their requirement for virus replication is an exciting new area of interdisciplinary virological research. To date, spatial resolution has only rarely been analyzed in computational/biophysical descriptions of virus replication dynamics. However, it is widely acknowledged that intracellular spatial dependence is a crucial component of virus life cycles. The hepatitis C virus-encoded NS5A protein is an endoplasmatic reticulum (ER)-anchored viral protein and an essential component of the virus replication machinery. Therefore, we simulate NS5A dynamics on realistic reconstructed, curved ER surfaces by means of surface partial differential equations (sPDE) upon unstructured grids. We match the in silico NS5A diffusion constant such that the NS5A sPDE simulation data reproduce experimental NS5A fluorescence recovery after photobleaching (FRAP) time series data. This parameter estimation yields the NS5A diffusion constant. Such parameters are needed for spatial models of HCV dynamics, which we are developing in parallel but remain qualitative at this stage. Thus, our present study likely provides the first quantitative biophysical description of the movement of a viral component. Our spatio-temporal resolved ansatz paves new ways for understanding intricate spatial-defined processes central to specfic aspects of virus life cycles.
Plasma fibronectin is a circulating protein that facilitates phagocytosis by connecting bacteria to immune cells. A fibronectin isoform, which includes a sequence of 90 AA called extra-domain B (EDB), is synthesized de novo at the messenger RNA (mRNA) level in immune cells, but the reason for its expression remains elusive. We detected an 80-fold increase in EDB-containing fibronectin in the cerebrospinal fluid of patients with bacterial meningitis that was most pronounced in staphylococcal infections. A role for this isoform in phagocytosis was further suggested by enhanced EDB fibronectin release after internalization of Staphylococcus aureus in vitro. Using transgenic mouse models, we established that immune cell production of fibronectin contributes to phagocytosis, more so than circulating plasma fibronectin, and that accentuated release of EDB-containing fibronectin by immune cells improved phagocytosis. In line with this, administration of EDB fibronectin enhanced in vitro phagocytosis to a larger extent than plasma fibronectin. This enhancement was mediated by αvβ3 integrin as shown using inhibitors or cells from β3 integrin knockout mice. Thus, we identified both a novel function for EDB fibronectin in augmenting phagocytosis over circulating plasma fibronectin, as well as the mediating receptor. Our data also establish for the first time, a direct role for β3 integrin in bacterial phagocytosis in mammals.
Inhalt
1. Strauß, Johann (Vater:/Sr.) (* 14.3.1804 – † 25.9.1849) [3]
2. Strauß, Johann (Sohn:/Jr.) (* 25.10.1825 – † 3.6.1899) [6]
3. Die Operetten-Adaptionen [12]
3.1 Die Fledermaus (Operette in 3 Akten, Johann Strauß, Sohn) :/:/ UA: 5.4.1874 [12]
3.2 Eine Nacht in Venedig (Operette in 3 Akten, Johann Strauß, Sohn) :/:/ UA: 3.10.1883 [17]
3.3 Der Zigeunerbaron (Operette in 3 Akten, Johann Strauß, Sohn) :/:/ UA: 24.10.1885 [18]
3.4 Wiener Blut (Johann Strauß, Sohn) :/:/ UA: 25.10.1899 [19]
3.5 Frühlingsluft (Jose. Strauß) :/:/ UA: 9.5.1903 [
Die Arbeit mit Rechnungen bietet den Vorteil, dass es sich dabei fast immer um Originalquellen handelt. Rechnungen wurden üblicherweise nicht in Kompilationen aufgenommen oder nicht in Urkunden inseriert. Wenn sie abgeschrieben wurden, geschah das höchstens im Zuge des Abrechnungsprozesses und nicht, wie etwa bei Chroniken, um für ihre weitere Verbreitung zu sorgen. Unter den schriftlichen Quellen kommen die Rechnungen damit wohl der Definition eines Überrestes am nächsten: Sie wurden für die Mit-, nicht die Nachwelt erstellt. Das bringt allerdings den Nachteil mit sich, dass wir selten genau wissen, zu welchem Zweck eine Rechnung eigentlich verfertigt wurde. Keine Arenga klärt den Forscher über die Vorgeschichte und den Zusammenhang der Niederschrift auf. Erklärende Dokumente sind fast nie überliefert. Die Menschen, die Rechnungen erstellten und mit ihnen arbeiteten, lernten das durch und bei ihrer Arbeit, eventuell unter mündlicher Anleitung. ...
Wirtschafts- und Rechnungsbücher bieten mehrdimensionale Zugänge und erfordern multidisziplinäre Annäherungen. Dass sie weit mehr sind als Einnahmen- und Ausgabeverzeichnisse zeigen die hier vorliegenden 17 Beiträge mit Beispielen von Lübeck bis Lyon. Sie vereinen die Ergebnisse eines Workshops, der diese Gattung serieller Quellen von Seiten der Geschichtswissenschaft und der Historischen Sprachforschung, der Editions- und Medienwissenschaft sowie der historischen Wirtschafts- und Betriebswirtschaftswissenschaft in den Blick genommen hat.
The behavioral sciences, including most of psychology, seek to explain and predict behavior with the help of theories and models that involve concepts (e.g., attitudes) that are subsequently translated into measures. Currently, some subdisciplines such as social psychology focus almost exclusively on measures that demand reflection or even introspection when administered to persons. We argue that such a focus hinders progress in explaining behavior. One major reason is that such an exclusive focus on reflections results in common method bias, which then produces spurious relations, or in other words, low discriminant validity. Without the valid measurement of theoretical concepts, theoretical assumptions cannot be tested, and hence, theory development will be hampered. We argue that the use of a greater variety of methods would reduce these problems and would in turn foster theory building. Using a representative sample of N = 472 participants (age: M = 51.0, SD = 17.7; 54% female), we compared the validity of a classical introspective attitude measure (i.e., the New Ecological Paradigm) with that of an alternative attitude measure (i.e., the General Ecological Behavior scale). The latter measure, which was based on self-reported behavior, showed substantially better validity that we argue could aid theory development.
Tumor progression largely depends on the presence of alternatively polarized (M2) tumor-associated macrophages (TAMs), whereas the classical M1-polarized macrophages can promote anti-tumorigenic immune responses. Thus, selective inhibition of M2-TAMs is a desirable anti-cancer approach in highly resistant tumor entities such as hepatocellular carcinoma (HCC) or breast cancer. We here examined whether a peptide that selectively binds to and is internalized by in vitro-differentiated murine M2 macrophages as compared to M1 macrophages, termed M2pep, could be used to selectively target TAMs in HCC and breast carcinoma. We confirmed selectivity of M2pep for in vitro M2 polarized macrophages. Upon incubation of suspended mixed 4T1 tumor cells with M2pep, high amounts of the TAMs were found to be associated with M2pep, whereas in mixed tumor cell suspensions from two HCC mouse models, M2pep showed only low-degree binding to TAMs. M2pep also showed low-degree targeting of liver macrophages. This indicates that the TAMs in different tumor entities show different targeting of M2pep and that M2pep is a very promising approach to develop selective M2-TAM-targeting in tumor entities containing M2-TAMs with significant amounts of the so far elusive M2pep receptor(s).
Les Blank
(2017)
Hans-Joachim Schlegel
(2017)
Knowledge about the biogeographic affinities of the world’s tropical forests helps to better understand regional differences in forest structure, diversity, composition, and dynamics. Such understanding will enable anticipation of region-specific responses to global environmental change. Modern phylogenies, in combination with broad coverage of species inventory data, now allow for global biogeographic analyses that take species evolutionary distance into account. Here we present a classification of the world’s tropical forests based on their phylogenetic similarity. We identify five principal floristic regions and their floristic relationships: (i) Indo-Pacific, (ii) Subtropical, (iii) African, (iv) American, and (v) Dry forests. Our results do not support the traditional neo- versus paleotropical forest division but instead separate the combined American and African forests from their Indo-Pacific counterparts. We also find indications for the existence of a global dry forest region, with representatives in America, Africa, Madagascar, and India. Additionally, a northern-hemisphere Subtropical forest region was identified with representatives in Asia and America, providing support for a link between Asian and American northern-hemisphere forests.
Background: Current approved drugs for Alzheimer’s disease (AD) only attenuate symptoms, but do not cure the disease. The pirinixic acid derivate MH84 has been characterized as a dual gamma-secretase/proliferator activated receptor gamma (PPARγ) modulator in vitro. Pharmacokinetic studies in mice showed that MH84 is bioavailable after oral administration and reaches the brain. We recently demonstrated that MH84 improved mitochondrial dysfunction in a cellular model of AD. In the present study, we extended the pharmacological characterization of MH84 to 3-month-old Thy-1 AβPPSL mice (harboring the Swedish and London mutation in human amyloid precursor protein (APP)) which are characterized by enhanced AβPP processing and cerebral mitochondrial dysfunction, representing a mouse model of early AD.
Methods: Three-month-old Thy-1 AβPPSL mice received 12 mg/kg b.w. MH84 by oral gavage once a day for 21 days. Mitochondrial respiration was analyzed in isolated brain mitochondria, and mitochondrial membrane potential and ATP levels were determined in dissociated brain cells. Citrate synthase (CS) activity was determined in brain tissues and MitoTracker Green fluorescence was measured in HEK293-AβPPwt and HEK293-AβPPsw cells. Soluble Aβ1–40 and Aβ1–42 levels were determined using ELISA. Western blot analysis and qRT-PCR were used to measure protein and mRNA levels, respectively.
Results: MH84 reduced cerebral levels of the β-secretase-related C99 peptide and of Aβ40 levels. Mitochondrial dysfunction was ameliorated by restoring complex IV (cytochrome-c oxidase) respiration, mitochondrial membrane potential, and levels of ATP. Induction of PPARγ coactivator-1α (PGC-1α) mRNA and protein expression was identified as a possible mode of action that leads to increased mitochondrial mass as indicated by enhanced CS activity, OXPHOS levels, and MitoTracker Green fluorescence.
Conclusions: MH84 modulates β-secretase processing of APP and improves mitochondrial dysfunction by a PGC-1α-dependent mechanism. Thus, MH84 seems to be a new promising therapeutic agent with approved in-vivo activity for the treatment of AD.
Damage control resuscitation may lead to postoperative intra-abdominal hypertension or abdominal compartment syndrome. These conditions may result in a vicious, self-perpetuating cycle leading to severe physiologic derangements and multiorgan failure unless interrupted by abdominal (surgical or other) decompression. Further, in some clinical situations, the abdomen cannot be closed due to the visceral edema, the inability to control the compelling source of infection or the necessity to re-explore (as a “planned second-look” laparotomy) or complete previously initiated damage control procedures or in cases of abdominal wall disruption. The open abdomen in trauma and non-trauma patients has been proposed to be effective in preventing or treating deranged physiology in patients with severe injuries or critical illness when no other perceived options exist. Its use, however, remains controversial as it is resource consuming and represents a non-anatomic situation with the potential for severe adverse effects. Its use, therefore, should only be considered in patients who would most benefit from it. Abdominal fascia-to-fascia closure should be done as soon as the patient can physiologically tolerate it. All precautions to minimize complications should be implemented.
The contribution of upper body movements to dynamic balance regulation during challenged locomotion
(2018)
Recent studies suggest that in addition to movements between ankle and hip joints, movements of the upper body, in particular of the arms, also significantly contribute to postural control. In line with these suggestions, we analyzed regulatory movements of upper and lower body joints supporting dynamic balance regulation during challenged locomotion. The participants walked over three beams of varying width and under three different verbally conveyed restrictions of arm posture, to control the potential influence of arm movements on the performance: The participants walked with their arms stretched out perpendicularly in the frontal plane, spontaneously, i.e., without restrictions to the arm movements, and with their hands on their thighs. After applying an inverse-dynamics analysis to the measured joint kinematics, we investigated the contribution of upper and lower body joints to balance regulation in terms of torque amplitude and variation. On the condition with the hands on the thighs, the contribution of the upper body remains significantly lower than the contribution of the lower body irrespective of beam widths. For spontaneous arm movements and for outstretched arms we find that the upper body (including the arms) contributes to the balancing to a similar extent as the lower body. Moreover, when the task becomes more difficult, i.e., for narrower beam widths, the contribution of the upper body increases, while the contribution of the lower body remains nearly constant. These findings lend further support to the hypothetical existence of an "upper body strategy" complementing the ankle and hip strategies especially during challenging dynamic balance tasks.
Background: Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. Growing evidence indicates that tumor-initiating cells (TICs) are responsible for tumor growth and progression. Conventional chemotherapeutics do not sufficiently eliminate TICs, leading to tumor relapse. We aimed to gain insight into TIC biology by comparing the transcriptome of primary TIC cultures and their normal stem cell counterparts to uncover expression differences.
Methods: We established colonosphere cultures derived from the resection of paired specimens of primary tumor and normal mucosa in patients with CRC. These colonospheres, enriched for TICs, were used for differential transcriptome analyses to detect new targets for a TIC-directed therapy. Effects of target inhibition on CRC cells were studied in vitro and in vivo.
Results: Pathway analysis of the regulated genes showed enrichment of genes central to PI3K/AKT and Wnt-signaling. We identified CD133 as a marker for a more aggressive CRC subpopulation enriched with TICs in SW480 CRC cells in an in vivo cancer model. Treatment of CRC cells with the selective AKT inhibitor MK-2206 caused a decrease in cell proliferation, particularly in the TIC fraction, resulting in a significant reduction of the stemness capacity to form colonospheres in vitro and to initiate tumor formation in vivo. Consequently, MK-2206 treatment of mice with established xenograft tumors exhibited a significant deceleration of tumor progression. Primary patient-derived tumorsphere growth was significantly inhibited by MK-2206.
Conclusion: This study reveals that AKT signaling is critical for TIC proliferation and can be efficiently targeted by MK-2206 representing a preclinical therapeutic strategy to repress colorectal TICs.
Chromosomal translocations - leading to the expression of fusion genes - are well-studied genetic abberrations associated with the development of leukemias. Most of them represent altered transcription factors that affect transcription or epigenetics, while others - like BCR-ABL - are enhancing signaling. BCR-ABL has become the prototype for rational drug design, and drugs like Imatinib and subsequently improved drugs have a great impact on cancer treatments. By contrast, MLL-translocations in acute leukemia patients are hard to treat, display a high relapse rate and the overall survival rate is still very poor. Therefore, new treatment modalities are urgently needed. Based on the molecular insights of the most frequent MLL rearrangements, BET-, DOT1L-, SET- and MEN1/LEDGF-inhibitors have been developed and first clinical studies were initiated. Not all results of these studies have are yet available, however, a first paper reports a failure in the DOT1L-inhibitor study although it was the most promising drug based on literature data. One possible explanation is that all of the above mentioned drugs also target the cognate wildtype proteins. Here, we want to strengthen the fact that efforts should be made to develop drugs or strategies to selectively inhibit only the fusion proteins. Some examples will be given that follow exactly this guideline, and proof-of-concept experiments have already demonstrated their feasibility and effectiveness. Some of the mentioned approaches were using drugs that are already on the market, indicating that there are existing opportunities for the future which should be implemented in future therapy strategies.
Schleppen und Schleifen
(2015)
Schleppen und Schleifen sind einander etymologisch verwandt. Seit dem 13. Jahrhundert soll die Ähnlichkeit von Schleppen und Schleifen bereits in der Deutschordensdichtung belegt sein; das Grimm'sche 'Wörterbuch' notiert, dass "die identität von schleppen und schleifen" um 1430 erkannt und erstmals in Wörterbüchern erfasst wurde. Nun sind Schleppen und Schleifen nicht nur Verben für den mehr oder weniger identischen Vorgang, etwas unter Mühe langsam, schwerfällig und mit großem Kraftaufwand am Boden entlang zu ziehen, sondern auch Pluralformen von Substantiven. Die Schleppe und die Schleife bezeichnen dabei geradezu das Gegenteil der verbalen Bedeutung: Anders als die Verben 'schleppen' und 'schleifen' sind sie nicht mit Mühe, Last und Erschöpfung konnotiert, sondern stehen vielmehr für Luxus und Verschwendung - für die unendliche Leichtigkeit des Seins.
Die Rüsche am Rock der Revolutionärin markiert eine diskrete Dissonanz, die es in sich hat. Der Revolutionärin wie dem Mikrologen ist die Rüsche nicht nur ästhetisch keine 'quantité négligeable', sondern genauso epistemologisch und geschichtsphilosophisch - die Revolution steckt hier definitiv im Detail.
So wie alle anderen Ebenen der Inszenierung wird auch die Kleidung zum Mittel im Kampf um die Aufmerksamkeit der Zuschauer - schließlich gilt es, im Wettstreit mit etwa 25 Konkurrenten zu beeindrucken und in Erinnerung zu bleiben. Die Auftritte bestehen daher zumeist aus Performances, die bis auf Sekundenbruchteile präzise durchchoreografiert sind, in denen nicht nur das Geschehen auf der Bühne, sondern auch die Vermittlung an den Fernsehzuschauer - jede Kameraeinstellung, jeder Schnitt - exakt vorgeplant ist. Dabei darf jeder Auftritt nach aktuellem Regelwerk maximal drei Minuten dauern. Kein Wunder, dass Trickkleider unter diesen Bedingungen relativ häufig zum Einsatz kommen. Schließlich bilden sie eine Möglichkeit, in dieser kurzen Dauer der Performance durch eine überraschende Veränderung im Aussehen der Künstler für einen besonderen Effekt zu sorgen.
Future Fashion
(2015)
Neue Materialien und neue Technologien stehen für Zukunftsmode. Davon schrieben Science-Fiction-Autoren, noch bevor Modemacher diese Kombination alltagstauglich machten. Prinz Vladimir Odoevskij, bekannt für seinen exzentrischen Kleidungsstil, entwarf in der Zukunftsnovelle 'Das Jahr 4338' (1835) schillernde Gewänder à la 'comète', gefertigt aus synthetischen Materialen wie "elastischem Kristall" mit eingewebten "metallischen Kristallisationen". Amerikanische Designer, die hundert Jahre später in dem British-Pathé-Clip 'Eve, Ad 2000!' (1939) mit eigenen Entwürfen die Zukunftsmode im Jahr 2000 ›voraussagen‹, kommen in Hinblick auf Material und Effekte auch der romantischen Vorstellung Odoevskijs erstaunlich nahe. Odoevskijs elegant-romantische Zukunftsästhetik, die synthetische Textilproduktion und spezifische Leuchteffekte dekorativer Glasfaserprodukte vorwegnimmt, erinnert an die LED-Technologie von heute. Denn dieser Tage sorgen nicht selten LED-Lämpchen, ob als falsche Wimpern oder am Gala-Kleid, für strahlende Auftritte: Future Fashion.
Gagarins Raumanzug
(2015)
Raumanzüge gehören zu Astronauten und Kosmonauten wie der Feuerwehranzug zum 'Firefighter' und der Tauchanzug zum Taucher - sie sind Funktionskleidung, ohne die die Retter in der Not, Entdecker der Tiefsee und Pioniere des Weltraums ihre Heldentaten nicht vollbringen könnten. In der populären Ikonographie der bemannten Raumfahrt sind die meist monochromen, häufig amorph wirkenden Ganzkörperkleidungsstücke mit dem runden, überproportional großen Helm, die die Menschen in etwas schwerfällig sich bewegende, leicht roboterartige Wesen verwandeln, untrennbar verbunden mit dem sogenannten 'Space Race', mit 'Star Wars' und mit '2001: A Space Odyssey'. Nur der erste Mensch im Weltraum, Juri Gagarin, hatte keinen.
Siebenmeilenstiefel gab es einmal in zwei Welten: zum einen im Märchen, wo sie Wunderdinge sind, die übernatürliche Fähigkeiten verleihen; zum anderen wurden die Reitstiefel der Postreiter so genannt, "die nur alle sieben Meilen den Boden berührten, wenn Postreiter oder Gespanne an Stationen die Pferde wechselten". Als literarisches Motiv haben die Siebenmeilenstiefel eine lange Geschichte, die mindestens bis in den griechischen Mythos zurückreicht, wo Perseus von den Nymphen Flügelsandalen erhält - zum Dank dafür, dass er die übelriechenden Graien ins Meer wirft. In der Science-Fiction des 20. Jahrhunderts kehrt das Motiv auf - zeitgemäß - abstrakterer Ebene wieder, in der Figur der Teleportation, also des Reisens durch den Raum ohne zeitliche Verzögerung - und ohne ein bestimmtes Schuhwerk.
Walter Benjamin schlug vor, den Pessimismus in der geschichtlichen Welt zu organisieren, indem man im Hohlraum unseres "politischen Handelns" selbst einen "Bildraum" entdeckt. Diese Vorstellung betrifft die unreine Zeitlichkeit unseres geschichtlichen Lebens, die weder vollendete Zerstörung noch beginnende Erlösung umfasst. In diesem Sinne ist auch das Nachleben der Bilder zu verstehen, seine fundamentale Immanenz: weder als Nichtigkeit noch als Fülle, weder als jedem Gedächtnis vorausgehende Quelle noch als jeder Katastrophe nachfolgender Horizont, sondern als ihnen eignende Ressource, Ressource des Begehrens und der Erfahrung im Hohlraum selbst unserer unmittelbarsten Entscheidungen, unseres alltäglichsten Lebens.
Tissue size regulation is critical for the normal functioning of the organ as well as to prevent unwanted pathogenesis such as cancer. The Hippo signaling pathway is well known for its robust regulation of tissue growth by the negative regulation of its nuclear effectors YAP1 and WWTR1. In this study, I have described the role of Yap1/Wwtr1 in zebrafish development, with a primary emphasis on the cardiovascular system.
I have generated zebrafish yap1 and wwtr1 mutants by CRISPR/CAS9. The mutant alleles are likely to be nonfunctional due to a premature stop codon and they show evidence of nonsense-mediated decay. Given that Yap1 and Wwtr1 are closely related proteins and have overlapping functions, I am given the opportunity to perform combinatorial analysis of the mutations on zebrafish development. Together with molecular probing tools, high-throughput sequencing and high-resolution imaging, I showed that
1. Double yap1;wwtr1 mutants exhibit severe posterior elongation phenotype, but somitogenesis appears to proceed as usual.
2. Yap1 and Wwtr1 may play an important role in PCV development and secondary angiogenic sprouting. However, key experiments will be needed to elucidate the direct role of Yap1 and Wwtr1 on these processes.
3. wwtr1-/- larvae hearts have a reduction in trabeculation, but in mosaic WT hearts, mutant cardiomyocytes prefer to populate the trabecular layer. My studies revealed that the mutant compact wall could not support trabeculation, which explains the hypotrabeculation phenotype of wwtr1-/- hearts. Additionally, Wwtr1 is required for myocardial Notch activity and can inhibit compact wall cardiomyocytes from entering the trabecular layer.
In summary, the Hippo signaling pathway, through Yap1/Wwtr1 has important regulatory functions in growth control. My work has revealed a surprising role for Yap1/Wwtr1 in tissue morphogenesis such as posterior tail morphogenesis and specific developmental processes of the cardiovascular system. It will be of interest to elucidate the regulation of Yap1/Wwtr1 in individual cells that translates into the complex cellular behaviors that drives morphogenesis.
The new edition of the 2016 World Health Organization (WHO) classification system for tumors of the hematopoietic and lymphoid tissues was published in September 2017. Under the category of myeloproliferative neoplasms (MPNs), the revised document includes seven subcategories: chronic myeloid leukemia, chronic neutrophilic leukemia, polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET), chronic eosinophilic leukemia-not otherwise specified and MPN, unclassifiable (MPN-U); of note, mastocytosis is no longer classified under the MPN category. In the current review, we focus on the diagnostic criteria for JAK2/CALR/MPL mutation-related MPNs: PV, ET, and PMF. In this regard, the 2016 changes were aimed at facilitating the distinction between masked PV and JAK2-mutated ET and between prefibrotic/early and overtly fibrotic PMF. In the current communication, we (i) provide practically useful resource tables and graphs on the new diagnostic criteria including outcome, (ii) elaborate on the rationale for the 2016 changes, (iii) discuss the complementary role of mutation screening, (iv) address ongoing controversies and propose solutions, (v) attend to the challenges of applying WHO criteria in routine clinical practice, and (vi) outline future directions from the perspectives of the clinical pathologist.
Background: Rare diseases are, by definition, very serious and chronic diseases with a high negative impact on quality of life. Approximately 350 million people worldwide live with rare diseases. The resulting high disease burden triggers health information search, but helpful, high-quality, and up-to-date information is often hard to find. Therefore, the improvement of health information provision has been integrated in many national plans for rare diseases, discussing the telephone as one access option. In this context, this study examines the need for a telephone service offering information for people affected by rare diseases, their relatives, and physicians.
Methods: In total, 107 individuals participated in a qualitative interview study conducted in Germany. Sixty-eight individuals suffering from a rare disease or related to somebody with rare diseases and 39 health care professionals took part. Individual interviews were conducted using a standardized semi-structured questionnaire. Interviews were analysed using the qualitative content analysis, triangulating patients, relatives, and health care professionals. The fulfilment of qualitative data processing standards has been controlled for.
Results: Out of 68 patients and relatives and 39 physicians, 52 and 18, respectively, advocated for the establishment of a rare diseases telephone service. Interviewees expected a helpline to include expert staffing, personal contact, good availability, low technical barriers, medical and psychosocial topics of counselling, guidance in reducing information chaos, and referrals. Health care professionals highlighted the importance of medical topics of counselling—in particular, differential diagnostics—and referrals.
Conclusions: Therefore, the need for a national rare diseases helpline was confirmed in this study. Due to limited financial resources, existing offers should be adapted in a stepwise procedure in accordance with the identified attributes.
Background: The Catechol-O-methyltransferase (COMT) represents the key enzyme in catecholamine degradation. Recent studies suggest that the COMT rs4680 polymorphism is associated with the response to endogenous and exogenous catecholamines. There are, however, conflicting data regarding the COMT Met/Met phenotype being associated with an increased risk of acute kidney injury (AKI) after cardiac surgery. The aim of the current study is to prospectively investigate the impact of the COMT rs4680 polymorphism on the incidence of AKI in patients undergoing cardiac surgery.
Methods: In this prospective single center cohort study consecutive patients hospitalized for elective cardiac surgery including cardiopulmonary-bypass (CPB) were screened for participation. Demographic clinical data, blood, urine and tissue samples were collected at predefined time points throughout the clinical stay. AKI was defined according to recent recommendations of the Kidney Disease Improving Global Outcome (KDIGO) group. Genetic analysis was performed after patient enrolment was completed.
Results: Between April and December 2014, 150 patients were recruited. The COMT genotypes were distributed as follows: Val/Met 48.7%, Met/Met 29.3%, Val/Val 21.3%. No significant differences were found for demography, comorbidities, or operative strategy according to the underlying COMT genotype. AKI occurred in 35 patients (23.5%) of the total cohort, and no differences were evident between the COMT genotypes (20.5% Met/Met, 24.7% Val/Met, 25.0% Val/Val, p = 0.66). There were also no differences in the post-operative period, including ICU or in-hospital stay.
Conclusions: We did not find statistically significant variations in the risk for postoperative AKI, length of ICU or in-hospital stay according to the underlying COMT genotype.
Galunisertib, a Transforming growth factor-βRI (TGF-βRI) kinase inhibitor, blocks TGF-β-mediated tumor growth in glioblastoma. In a three-arm study of galunisertib (300 mg/day) monotherapy (intermittent dosing; each cycle =14 days on/14 days off), lomustine monotherapy, and galunisertib plus lomustine therapy, baseline tumor tissue was evaluated to identify markers associated with tumor stage (e.g., histopathology, Ki67, glial fibrillary acidic protein) and TGF-β-related signaling (e.g., pSMAD2). Other pharmacodynamic assessments included chemokine, cytokine, and T cell subsets alterations. 158 patients were randomized to galunisertib plus lomustine (n = 79), galunisertib (n = 39) and placebo+lomustine (n = 40). In 127 of these patients, tissue was adequate for central pathology review and biomarker work. Isocitrate dehydrogenase (IDH1) negative glioblastoma patients with baseline pSMAD2+ in cytoplasm had median overall survival (OS) 9.5 months vs. 6.9 months for patients with no tumor pSMAD2 expression (p = 0.4574). Eight patients were IDH1 R132H+ and had a median OS of 10.4 months compared to 6.9 months for patients with negative IDH1 R132H (p = 0.5452). IDH1 status was associated with numerically higher plasma macrophage-derived chemokine (MDC/CCL22), higher whole blood FOXP3, and reduced tumor CD3+ T cell counts. Compared to the baseline, treatment with galunisertib monotherapy preserved CD4+ T cell counts, eosinophils, lymphocytes, and the CD4/CD8 ratio. The T-regulatory cell compartment was associated with better OS with MDC/CCL22 as a prominent prognostic marker.
Monitoring of minimal residual disease (MRD) or chimerism may help guide pre-emptive immunotherapy (IT) with a view to preventing relapse in childhood acute lymphoblastic leukemia (ALL) after transplantation. Patients with ALL who consecutively underwent transplantation in Frankfurt/Main, Germany between January 1, 2005 and July 1, 2014 were included in this retrospective study. Chimerism monitoring was performed in all, and MRD assessment was performed in 58 of 89 patients. IT was guided in 19 of 24 patients with mixed chimerism (MC) and MRD and by MRD only in another 4 patients with complete chimerism (CC). The 3-year probabilities of event-free survival (EFS) were .69 ± .06 for the cohort without IT and .69 ± .10 for IT patients. Incidences of relapse (CIR) and treatment-related mortality (CITRM) were equally distributed between both cohorts (without IT: 3-year CIR, .21 ± .05, 3-year CITRM, .10 ± .04; IT patients: 3-year CIR, .18 ± .09, 3-year CITRM .13 ± .07). Accordingly, 3-year EFS and 3-year CIR were similar in CC and MC patients with IT, whereas MC patients without IT experienced relapse. IT was neither associated with an enhanced immune recovery nor an increased risk for acute graft-versus-host disease. Relapse prevention by IT in patients at risk may lead to the same favorable outcome as found in CC and MRD-negative-patients. This underlines the importance of excellent MRD and chimerism monitoring after transplantation as the basis for IT to improve survival in childhood ALL.
apl. Prof. Dr. Jörg W. Busch (Goethe Uni Frankfurt) hat bisher 2 Vorträge in Trebur gehalten. Der erste am 14. Oktober 2004 mit dem Titel "Trebur ein Königshof am Mittelrhein" und am 6. Oktober 2005 mit dem Titel "Die Pfalz Trebur unter Heinrich IV. vom Schauplatz großer Politik zum gemiedenen Ort" ...
Wir freuen uns, dass Sie sich für einen Aufenthalt an der Goethe-Universität entschieden haben. Frankfurt ist eine der internationalsten Städte Deutschlands, eine Stadt der Begegnungen und interkulturellen Befruchtung. Seit jeher war dieser beeindruckende und überaus historische akademische, logistische, kommerzielle und finanzielle Knotenpunkt auf den regen Austausch mit anderen Kulturen und Völkern angewiesen. ...
This thesis primarily covers a systematic assessment of quantum chemical methods to predict accurate 19F NMR shifts for fluoroarenes and magnetic exchange coupling constant (J) in organic spin dimers which are basic building blocks for rational designing of organic magnetic materials.
One of the most important goals in chemistry is to design and synthesize molecules with optimum properties. This thesis is divided into two parts: the first part comprises of a systematic effort to find an inexpensive quantum chemical method to predict accurate 19F NMR chemical shifts (within an accuracy of 2 ppm) for perfluoraromatics. Essentially, these strenuous efforts have been devoted to find best DFT functional and basis set combination to predict accurate 19F shifts. In addition,the influence of geometrical parameters, solvents, chemical environment was also analyzed. Various correction approaches were tested to correct the calculated shifts. The influence of various functionals and basis sets was also analyzed on the correction efficiency of an individual scheme. All the NMR calculation methods already being used and correction approaches were verified to predict shifts of three different fluorine-substituted molecular sets. These structure sets include fluorobenzenes, substituted benzenes and fluorine substituted aromatic fused rings (e.g. fluorine substituted anthracene).
In the second part of this thesis, we investigated the accurate prediction of magnetic exchange couplings (J) for organic spin dimers using quantum chemical methods. We analyzed the performance of various DFT methods and various post-HF methods, such as the CASSCF, CASPT2, MSTDISD, DDCI1, DDCI2, DDCI3, and FCI to predict magnetic exchange couplings (J).
Overview of the Chapters:
Chapter 1, presents a brief theoretical introduction to the Schrödinger equation and its application in quantum mechanical calculations, the Hartree-Fock approximation, basis sets, electron correlation energy, and density functional theory (using pure and hybrid functionals).
In chapters 2 and 3, an introduction is given for quantum chemical approaches used to calculate NMR parameters and magnetic exchange coupling constants. We discuss an effective spin Hamiltonian, the Breit-Pauli Hamiltonian (BPH), chemical shielding tensor and total energy relationship, measuring of the NMR spectra, and different techniques to deal with gauge origin problem. In addition, the theoretical background of magnetic exchange coupling constant calculation for spin dimers, the Heisenberg-Dirac-van-Vleck Hamiltonian (HDVV) and the Noodelman's broken-symmetry approach for calculating J values are briefly discussed.
Chapter 4, presents a benchmark study of various DFT functionals and basis sets to calculate accurate C-F bond lengths and 19F chemical shifts. High-resolution NMR spectral data of complex molecules are often difficult to interpret. Great scientific efforts have been devoted to search for a computational approach to interpret experimental NMR data. Quantum chemical methods such as the CCSD(T) method offer high accuracy in calculation of NMR parameters but being computationally too demanding they cannot be applied to large chemical systems. On the other hand, density functional theory (DFT) is achieving a steady progress among diversity of computational techniques. An accuracy within 2 ppm deviation from the experimental values in 19F chemical shifts can be achieved if the NMR calculation is performed using accurate equilibrium geometries, GIAO is used to tackle gauge origin problem and electron correlation is properly treated by employing a high level of theory (e.g. CCSD (T)/cc-pVQZ). We found that the calculation of 19F shielding tensors with the density-functional theory does not provide any noticeable improvement over the HF method. Post-HF theory demands too much computational resources that makes them impossible to use for large systems [35] .
We found that a quantitative prediction of NMR shifts can be made as the errors introduced by theoretical methods are cancelled out while calculating shifts. Various benchmark studies in this thesis show that 19F chemical shifts calculated for perfluoraromatics with the M06-L, BHandH, BHandHLYP in combination with the 6-311+G (2d,p) basis set are within 4 ppm deviation from the experiments. Furthermore, we noted that NMR calculations on accurate
C-F (e.g. PBE/6-311G (d, p)) bond lengths does not show any improvement if the NMR calculation and optimization are performed at the same level of theory. A significant improvement can be achieved on calculated 19F NMR shifts, if some correction schemes are used.
In chapter 4 we discuss various correction schemes applied to correct the calculated 19F chemical shifts. A multi-standard approach (MSTD) was used to minimize the error that may occur due to the difference in the nature of the reference compound and test molecules [122]. We propose another approach to correct shielding constants which is the reference corrected approach. This approach makes a correction similar to the MSTD. We also tested a Linear Regression Correction Approach and we noted that this is the best approach amongst all. This is found to be less dependent on the theoretical method. We use conformation averaging corrections to correct the calculated shifts[126].
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Infant acute leukemia still has a poor prognosis, and allogeneic hematopoietic stem cell transplantation is indicated in selected patients. Umbilical cord blood (UCB) is an attractive cell source for this population because of the low risk of chronic graft-versus-host disease (GVHD), the strong graft-versus-leukemia effect, and prompt donor availability. This retrospective, registry-based study reported UCB transplantation (UCBT) outcomes in 252 children with acute lymphoblastic leukemia (ALL; n = 157) or acute myelogenous leukemia (AML; n = 95) diagnosed before 1 year of age who received a single-unit UCBT after myeloablative conditioning between 1996 and 2012 in European Society for Blood and Marrow Transplantation centers. Median age at UCBT was 1.1 years, and median follow-up was 42 months. Most patients (57%) received a graft with 1 HLA disparity and were transplanted in first complete remission (CR; 55%). Cumulative incidence function (CIF) of day 100 acute GVHD (grades II to IV) was 40% ± 3% and of 4-year chronic GVHD was 13% ± 2%. CIF of 1-year transplant-related mortality was 23% ± 3% and of 4-year relapse was 27% ± 3%. Leukemia-free-survival (LFS) at 4 years was 50% ± 3%; it was 40% and 66% for those transplanted for ALL and AML, respectively (P = .001). LFS was better for patients transplanted in first CR, regardless of diagnosis. In multivariate model, diagnosis of ALL (P = .001), advanced disease status at UCBT (<.001), age at diagnosis younger than 3 months (P = .012), and date of transplant before 2004 were independently associated with worse LFS. UCBT is a suitable option for patients diagnosed with infant acute leukemia who achieve CR. In this cohort, patients with AML had better survival than those with ALL.
Natural Killer (NK) cells are active against Aspergillus fumigatus, which in turn is able to impair the host defense. Unfortunately, little is known on the mutual interaction of NK cells and A. fumigatus. We coincubated human NK cells with A. fumigatus hyphae and assessed the gene expression and protein concentration of selected molecules. We found that A. fumigatus up-regulates the gene expression of pro-inflammatory molecules in NK cells, but inhibited the release of these molecules resulting in intracellular accumulation and limited extracellular availability. A. fumigatus down-regulatedmRNA levels of perforin in NK cells, but increased its intra- and extracellular protein concentration. The gene expression of stress related molecules of A. fumigatus such as heat shock protein hsp90 was up-regulated by human NK cells. Our data characterize for the first time the immunosuppressive effect of A. fumigatus on NK cells and may help to develop new therapeutic antifungal strategies.
This paper presents three acceptability experiments investigating German verb-final clauses in order to explore possible sources of sentence complexity during human parsing. The point of departure was De Vries et al.'s (2011) generalization that sentences with three or more crossed or nested dependencies are too complex for being processed by the human parsing mechanism without difficulties. This generalization is partially based on findings from Bach et al. (1986) concerning the acceptability of complex verb clusters in German and Dutch. The first experiment tests this generalization by comparing two sentence types: (i) sentences with three nested dependencies within a single clause that contains three verbs in a complex verb cluster; (ii) sentences with four nested dependencies distributed across two embedded clauses, one center-embedded within the other, each containing a two-verb cluster. The results show that sentences with four nested dependencies are judged as acceptable as control sentences with only two nested dependencies, whereas sentences with three nested dependencies are judged as only marginally acceptable. This argues against De Vries et al.'s (2011) claim that the human parser can process no more than two nested dependencies. The results are used to refine the Verb-Cluster Complexity Hypothesis of Bader and Schmid (2009a). The second and the third experiment investigate sentences with four nested dependencies in more detail in order to explore alternative sources of sentence complexity: the number of predicted heads to be held in working memory (storage cost in terms of the Dependency Locality Theory [DLT], Gibson, 2000) and the length of the involved dependencies (integration cost in terms of the DLT). Experiment 2 investigates sentences for which storage cost and integration cost make conflicting predictions. The results show that storage cost outweighs integration cost. Experiment 3 shows that increasing integration cost in sentences with two degrees of center embedding leads to decreased acceptability. Taken together, the results argue in favor of a multifactorial account of the limitations on center embedding in natural languages.
The UDP-glucose ceramide glycosyltransferase (UGCG) is a key enzyme in the sphingolipid metabolism by generating glucosylceramide (GlcCer), the precursor for all glycosphingolipids (GSL), which are essential for proper cell function. Interestingly, the UGCG is also overexpressed in several cancer types and correlates with multidrug resistance protein 1 (MDR1) gene expression. This membrane protein is responsible for efflux of toxic substances and protects cancer cells from cell damage through chemotherapeutic agents. Studies showed a connection between UGCG and MDR1 overexpression and multidrug resistance development, but the precise underlying mechanisms are unknown. Here, we give an overview about the UGCG and its connection to MDR1 in multidrug resistant cells. Furthermore, we focus on UGCG transcriptional regulation, the impact of UGCG on cellular signaling pathways and the effect of UGCG and MDR1 on the lipid composition of membranes and how this could influence multidrug resistance development. To our knowledge, this is the first review presenting an overview about UGCG with focus on the relationship to MDR1 in the process of multidrug resistance development.
The 900th anniversary of the death of Emperor Henry IV (7 August 2006) occasioned several special colloquia (in Cologne, Speyer, Goslar) and publications in celebration of the so-called "Year of the Salians" . While several scholarly publications and exhibits also appeared with specific focus on Henry IV himself, the present volume contains the papers given at a colloquium held at the University of Cologne (26–30 September 2006), which accordingly focused on the Salian dynasty’s history in the lower Rhine region. Prof. Dr. Tilman Struve (emeritus professor at the University of Cologne), who has spent much of his career studying the Salian house during the Investiture Struggle, lends his considerable expertise to framing this collection of disparate essays. ...
Background: Worldwide, the number of recorded human hantavirus infections as well as the number of affected countries is on the rise. In Europe, most human hantavirus infections are caused by the Puumala virus (PUUV), with bank voles (Myodes glareolus) as reservoir hosts. Generally, infection outbreaks have been related to environmental conditions, particularly climatic conditions, food supply for the reservoir species and land use. However, although attempts have been made, the insufficient availability of environmental data is often hampering accurate temporal and spatially explicit models of human hantavirus infections.
Methods: In the present study, dynamics of human PUUV infections between 2001 and 2015 were explored using ArcGIS in order to identify spatio-temporal patterns.
Results: Percentage cover of forest area was identified as an important factor for the spatial pattern, whereas beech mast was found explaining temporal patterns of human PUUV infections in Germany. High numbers of infections were recorded in 2007, 2010 and 2012 and areas with highest records were located in Baden-Wuerttemberg (southwest Germany) and North Rhine-Westphalia (western Germany).
Conclusion: More reliable data on reservoir host distribution, pathogen verification as well as an increased awareness of physicians are some of the factors that should improve future human infection risk assessments in Germany.
Background: As ectothermic animals, temperature influences insects in almost every aspect. The potential disease spreading Asian bush mosquito (Aedes japonicus japonicus) is native to temperate East Asia but invasive in several parts of the world. We report on the previously poorly understood temperature-dependence of its life history under laboratory conditions to understand invasion processes and to model temperature niches.
Results: To evaluate winter survival, eggs were exposed between 1 day and 14 days to low temperatures (5 °C, 0 °C, -5 °C and -9 °C). Hatching success was drastically decreased after exposure to 0 °C and -5 °C, and the minimal hatching success of 0% was reached at -9 °C after two days. We then exposed larvae to 14 temperatures and assessed their life trait parameters. Larval survival to adulthood was only possible between 10 °C and 31 °C. Based on this, we modelled the optimal (25 °C), minimal (7 °C) and maximal (31 °C) temperature for cumulative female survival. The time to adult emergence ranges from 12 days to 58 days depending on temperature. We used an age-at-emergence-temperature model to calculate the number of potential generations per year for the Asian bush mosquito in Germany with an average of 4.72 potential generations. At lower temperatures, individuals grew larger than at higher temperatures with female R1 length ranging from 3.04 ± 0.1 mm at 31 °C to 4.26 ± 0.2 mm at 15 °C.
Conclusions: Reduced egg hatch after exposure to sub-zero temperatures prohibits the establishment of the Asian bush mosquito in large parts of Germany. Larval overwintering is not possible at temperature ≤ 5 °C. The many potential generations displayed per year may contribute to the species’ invasion success. This study on the thermal ecology of the Asian bush mosquito adds to our knowledge on the temperature dependence of the species and data could be incorporated in epidemiological and population dynamic modelling.
Die Erfassung von subjektiven Theorien von bildungsfernen Personen gestaltet sich schwierig, wenn die Personen nicht in der Lage sind, ihre Theorien formal zu abstrahieren. In dieser Publikation wird ein Verfahren beschrieben, mit welchen Schritten dennoch subjektive Theorien zur aufgestellten Forschungsfrage extrahiert werden können. Das Verfahren basiert auf einer systematischen Auswertung von transkribierten Interviews.