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Dysfunction of the NO/sGC/cGMP signaling pathway has been implicated in the pathogenesis of pulmonary hypertension (PH). Therefore, agents stimulating cGMP synthesis via sGC are important therapeutic options for treatment of PH patients. An unwanted effect of this novel class of drugs is their systemic hypotensive effect. We tested the hypothesis that aerosolized intra-tracheal delivery of the sGC stimulator BAY41-8543 could diminish its systemic vasodilating effect.
Pharmacodynamics and -kinetics of BAY41-8543 after single intra-tracheal delivery was tested in healthy rats. Four weeks after a single injection of monocrotaline (MCT, 60 mg/kg s.c.), rats were randomized to a two-week treatment with either placebo, BAY 41-8543 (10 mg/kg per os (PO)) or intra-tracheal (IT) instillation (3 mg/kg or 1 mg/kg).
Circulating concentrations of the drug 10 mg/kg PO and 3 mg/kg IT were comparable. BAY 41-8543 was detected in the lung tissue and broncho-alveolar fluid after IT delivery at higher concentrations than after PO administration. Systemic arterial pressure transiently decreased after oral BAY 41-8543 and was unaffected by intratracheal instillation of the drug. PO 10 mg/kg and IT 3 mg/kg regimens partially reversed pulmonary hypertension and improved heart function in MCT-injected rats. Minor efficacy was noted in rats treated IT with 1 mg/kg. The degree of pulmonary vascular remodeling was largely reversed in all treatment groups.
Intratracheal administration of BAY 41-8543 reverses PAH and vascular structural remodeling in MCT-treated rats. Local lung delivery is not associated with systemic blood pressure lowering and represents thus a further development of PH treatment with sGC stimulators.
T lymphocytes against tumor-specific mutated neoantigens can induce tumor regression. Also, the size of the immunogenic cancer mutanome is supposed to correlate with the clinical efficacy of checkpoint inhibition. Herein, we studied the susceptibility of tumor cell lines from lymph node metastases occurring in a melanoma patient over several years towards blood-derived, neoantigen-specific CD8+ T cells. In contrast to a cell line established during early stage III disease, all cell lines generated at later time points from stage IV metastases exhibited partial or complete loss of HLA class I expression. Whole exome and transcriptome sequencing of the four tumor lines and a germline control were applied to identify expressed somatic single nucleotide substitutions (SNS), insertions and deletions (indels). Candidate peptides encoded by these variants and predicted to bind to the patient’s HLA class I alleles were synthesized and tested for recognition by autologous mixed lymphocyte-tumor cell cultures (MLTCs). Peptides from four mutated proteins, HERPUD1G161S, INSIG1S238F, MMS22LS437F and PRDM10S1050F, were recognized by MLTC responders and MLTC-derived T cell clones restricted by HLA-A*24:02 or HLA-B*15:01. Intracellular peptide processing was verified with transfectants. All four neoantigens could only be targeted on the cell line generated during early stage III disease. HLA loss variants of any kind were uniformly resistant. These findings corroborate that, although neoantigens represent attractive therapeutic targets, they also contribute to the process of cancer immunoediting as a serious limitation to specific T cell immunotherapy.
Despite advances in myocardial reperfusion therapies, acute myocardial ischaemia/reperfusion injury and consequent ischaemic heart failure represent the number one cause of morbidity and mortality in industrialized societies. Although different therapeutic interventions have been shown beneficial in preclinical settings, an effective cardioprotective or regenerative therapy has yet to be successfully introduced in the clinical arena. Given the complex pathophysiology of the ischaemic heart, large scale, unbiased, global approaches capable of identifying multiple branches of the signalling networks activated in the ischaemic/reperfused heart might be more successful in the search for novel diagnostic or therapeutic targets. High-throughput techniques allow high-resolution, genome-wide investigation of genetic variants, epigenetic modifications, and associated gene expression profiles. Platforms such as proteomics and metabolomics (not described here in detail) also offer simultaneous readouts of hundreds of proteins and metabolites. Isolated omics analyses usually provide Big Data requiring large data storage, advanced computational resources and complex bioinformatics tools. The possibility of integrating different omics approaches gives new hope to better understand the molecular circuitry activated by myocardial ischaemia, putting it in the context of the human ‘diseasome’. Since modifications of cardiac gene expression have been consistently linked to pathophysiology of the ischaemic heart, the integration of epigenomic and transcriptomic data seems a promising approach to identify crucial disease networks. Thus, the scope of this Position Paper will be to highlight potentials and limitations of these approaches, and to provide recommendations to optimize the search for novel diagnostic or therapeutic targets for acute ischaemia/reperfusion injury and ischaemic heart failure in the post-genomic era.
The CRISPR/Cas9 prokaryotic adaptive immune system and its swift repurposing for genome editing enables modification of any prespecified genomic sequence with unprecedented accuracy and efficiency, including targeted gene repair. We used the CRISPR/Cas9 system for targeted repair of patient-specific point mutations in the Cytochrome b-245 heavy chain gene (CYBB), whose inactivation causes chronic granulomatous disease (XCGD)—a life-threatening immunodeficiency disorder characterized by the inability of neutrophils and macrophages to produce microbicidal reactive oxygen species (ROS). We show that frameshift mutations can be effectively repaired in hematopoietic cells by non-integrating lentiviral vectors carrying RNA-guided Cas9 endonucleases (RGNs). Because about 25% of most inherited blood disorders are caused by frameshift mutations, our results suggest that up to a quarter of all patients suffering from monogenic blood disorders could benefit from gene therapy employing personalized, donor template-free RGNs.
Purpose: Due to the demographic change morbidity raises the demand for medical hospital services as well as a need for medical specialization, while economic and human resources are diminishing. Unlike other industries hospitals do not have sufficient data and adequate models to relate growing demands and increasing performance to growth in staff capacity and to increase in staff competences.
Method: Based on huge medical data sample covering the years from 2010 to 2014 with more than 150,000 operations of the Department for Anesthesiology at the University Hospital Muenster, Germany, comparisons are drawn between the development of medical services and the development of personnel capacity and expertise.
Results: The numbers of surgical operations increased by 21% and "skin incision to closure" time by 17%. Simultaneously, personnel capacity grew by 16% largely resting upon recruiting first-time employees. Expertise measured as "years of professional experience" dwindled from 10 years to 5.4 years on average and staff turnover accelerated.
Conclusion: Static benchmark data collected at fixed reference dates do not sufficiently reflect the nexus between capacity and competence and do not reflect the dynamic changes in a hospital’s requirements for expertise and specialization, at all. Staff turnover leads to a loss of experience, which jeopardizes patient safety and hampers medical specialization. In consequence of the dramatic shortage of medical specialists, drop-off rates must be reduced and retention rates must be increased. To that end, working conditions need to be fundamentally converted for a multigeneration, multicultural, and increasingly female workforce.
In the later stages of addiction, automatized processes play a prominent role in guiding drug-seeking and drug-taking behavior. However, little is known about the neural correlates of automatized drug-taking skills and drug-related action knowledge in humans. We employed functional magnetic resonance imaging (fMRI) while smokers and non-smokers performed an orientation affordance task, where compatibility between the hand used for a behavioral response and the spatial orientation of a priming stimulus leads to shorter reaction times resulting from activation of the corresponding motor representations. While non-smokers exhibited this behavioral effect only for control objects, smokers showed the affordance effect for both control and smoking-related objects. Furthermore, smokers exhibited reduced fMRI activation for smoking-related as compared to control objects for compatible stimulus-response pairings in a sensorimotor brain network consisting of the right primary motor cortex, supplementary motor area, middle occipital gyrus, left fusiform gyrus and bilateral cingulate gyrus. In the incompatible condition, we found higher fMRI activation in smokers for smoking-related as compared to control objects in the right primary motor cortex, cingulate gyrus, and left fusiform gyrus. This suggests that the activation and performance of deeply embedded, automatized drug-taking schemata employ less brain resources. This might reduce the threshold for relapsing in individuals trying to abstain from smoking. In contrast, the interruption or modification of already triggered automatized action representations require increased neural resources.
Na+/H+ antiporters are located in the cytoplasmic and intracellular membranes and play crucial roles in regulating intracellular pH, Na+, and volume. The NhaA antiporter of Escherichia coli is the best studied member of the Na+/H+ exchanger family and a model system for all related Na+/H+ exchangers, including eukaryotic representatives. Several amino acid residues are important for the transport activity of NhaA, including Lys-300, a residue that has recently been proposed to carry one of the two H+ ions that NhaA exchanges for one Na+ ion during one transport cycle. Here, we sought to characterize the effects of mutating Lys-300 of NhaA to amino acid residues containing side chains of different polarity and length (i.e. Ala, Arg, Cys, His, Glu, and Leu) on transporter stability and function. Salt resistance assays, acridine-orange fluorescence dequenching, solid supported membrane-based electrophysiology, and differential scanning fluorometry were used to characterize Na+ and H+ transport, charge translocation, and thermal stability of the different variants. These studies revealed that NhaA could still perform electrogenic Na+/H+ exchange even in the absence of a protonatable residue at the Lys-300 position. However, all mutants displayed lower thermal stability and reduced ion transport activity compared with the wild-type enzyme, indicating the critical importance of Lys-300 for optimal NhaA structural stability and function. On the basis of these experimental data, we propose a tentative mechanism integrating the functional and structural role of Lys-300.
Objective: Trauma patients (TP) frequently develop an imbalanced immune response that often causes infectious postinjury complications. Monocytes show a diminished capability of both producing proinflammatory cytokines and antigen presentation after trauma. TLR2, TLR4, and TLR9 recognize pathogens and subsequently activate monocytes. While there are conflictive data about TLR2 and TLR4 expression after trauma, no studies about the expression of TLR2, TLR4, TLR9, and HLA-DR on monocytes from TP after their secondary ex vivo-in vitro “hit” have been reported.
Methods/Results: Ex vivo-in vitro lipopolysaccharide- (LPS-) stimulated blood from TP showed diminished interleukin- (IL-) 1β-release in TP for five postinjury days compared to healthy volunteers (HV). The recovery was observed at day 5. In parallel, monocytes from TP showed an impaired capability of TLR2, TLR4, and TLR9 expression after secondary stimulation compared to HV, while the measurement of unstimulated samples showed significant reduction of TLR4 and TLR9 at ED. Furthermore, HLA-DR decreased after trauma and was even more profound by stimulation of monocytes. Ratio of monocytes to leukocytes was significantly increased at days 6 and 7 after trauma compared to HV.
Conclusion: Impaired expression of TLRs and HLA-DR in acute inflammatory conditions may be responsible for the well-described monocyte paralysis after severe trauma.
Sphingolipids are characterized by a broad range of bioactive properties. Particularly, the development of insulin resistance, a major pathophysiological hallmark of Type 2 Diabetes mellitus (T2D), has been linked to ceramide signaling. Since vitamin D supplementation may slow down T2D progression by improving glucose concentrations and insulin sensitivity, we investigated whether vitamin D supplementation impacts on plasma sphingolipid levels in T2D patients. Thus, plasma samples of 59 patients with non-insulin-requiring T2D from a placebo-controlled, randomized, and double-blind study were retrospectively analyzed. Once per week, patients received either 20 drops of Vigantol oil, corresponding to a daily dose of 1904 IU/d vitamin D (verum: n = 31), or a placebo oil consisting of medium chain triglycerides (placebo: n = 28). Blood samples were taken from all of the participants at three different time points: 1) at the beginning of the study (baseline), 2) after 6 months supplementation, and 3) after an additional 6 months of follow-up. Plasma sphingolipids were measured by high-performance liquid chromatography tandem mass spectrometry. At baseline and 6 months follow-up, no significant differences in plasma sphingolipid species were detected between the placebo and verum groups. After 6 months, vitamin D supplementation significantly enhanced plasma C18dihydroceramide (dhCer; N-stearoyl-sphinganine (d18:0/18:0)) and C18ceramide (Cer; N-stearoyl-sphingosine (d18:1/18:0)) levels were observed in the verum group compared to the placebo group. This was accompanied by significantly higher 25-hydroxyvitamin D3 (25(OH)D3) blood levels in patients receiving vitamin D compared to the placebo group. Taken together, vitamin D supplementation induced changes of the C18 chain-length-specific dhCer and Cer plasma levels in patients with T2D. The regulation of sphingolipid signaling by vitamin D may thus unravel a novel mechanism by which vitamin D can influence glucose utilization and insulin action. Whether this acts favorably or unfavorably for the progression of T2D needs to be clarified.
Background: Signal transduction pathways are important cellular processes to maintain the cell’s integrity. Their imbalance can cause severe pathologies. As signal transduction pathways feature complex regulations, they form intertwined networks. Mathematical models aim to capture their regulatory logic and allow an unbiased analysis of robustness and vulnerability of the signaling network. Pathway detection is yet a challenge for the analysis of signaling networks in the field of systems biology. A rigorous mathematical formalism is lacking to identify all possible signal flows in a network model.
Results: In this paper, we introduce the concept of Manatee invariants for the analysis of signal transduction networks. We present an algorithm for the characterization of the combinatorial diversity of signal flows, e.g., from signal reception to cellular response. We demonstrate the concept for a small model of the TNFR1-mediated NF- κB signaling pathway. Manatee invariants reveal all possible signal flows in the network. Further, we show the application of Manatee invariants for in silico knockout experiments. Here, we illustrate the biological relevance of the concept.
Conclusions: The proposed mathematical framework reveals the entire variety of signal flows in models of signaling systems, including cyclic regulations. Thereby, Manatee invariants allow for the analysis of robustness and vulnerability of signaling networks. The application to further analyses such as for in silico knockout was shown. The new framework of Manatee invariants contributes to an advanced examination of signaling systems.
Anticoagulation with warfarin and rivaroxaban ameliorates experimental autoimmune encephalomyelitis
(2017)
Background: In multiple sclerosis, coagulation factors have been shown to modulate inflammation. In this translational study, we investigated whether long-term anticoagulation with warfarin or rivaroxaban has beneficial effects on the course of autoimmune experimental encephalomyelitis (EAE).
Methods: Female SJL/J mice treated with anticoagulants namely warfarin or rivaroxaban were immunized with PLP139–151. Stable anticoagulation was maintained throughout the entire experiment. Mice without anticoagulation treated with the vehicle only were used as controls. The neurological deficit was recorded during the course of EAE, and histopathological analyses of inflammatory lesions were performed.
Results: In preventive settings, both treatment with warfarin and rivaroxaban reduced the maximum EAE score as compared to the control group and led to a reduction of inflammatory lesions in the spinal cord. In contrast, therapeutic treatment with warfarin had no beneficial effects on the clinical course of EAE. Signs of intraparenchymal hemorrhage at the site of the inflammatory lesions were not observed.
Conclusion: We developed long-term anticoagulation models that allowed exploring the course of EAE under warfarin and rivaroxaban treatment. We found a mild preventive effect of both warfarin and rivaroxaban on neurological deficits and local inflammation, indicating a modulation of the disease induction by anticoagulation.
Maintenance therapy after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) is conceptually attractive to prevent relapse, but has been hampered by the limited number of suitable anti-leukemic agents. The deacetylase inhibitor (DACi) panobinostat demonstrated moderate anti-leukemic activity in a small subset of patients with advanced AML and high-risk MDS in phase I/II trials.1, 2 It also displays immunomodulatory activity3 that may enhance leukemia-specific cytotoxicity4 and mitigate graft versus host disease (GvHD), but conversely could impair T- and NK cell function.5, 6 We conducted this open-label, multi-center phase I/II trial (NCT01451268) to assess the feasibility and preliminary efficacy of prolonged prophylactic administration of panobinostat after HSCT for AML or MDS. The study protocol was approved by an independent ethics committee and conducted in compliance with the Declaration of Helsinki. All patients provided written informed consent. ...
BACKGROUND: Ketone bodies are known to substitute for glucose as brain fuel when glucose availability is low. Ketogenic diets have been described as neuroprotective. Similar data have been reported for triheptanoin, a fatty oil and anaplerotic compound. In this study, we monitored the changes of energy metabolites in liver, blood, and brain after transient brain ischemia to test for ketone body formation induced by experimental stroke.
METHODS AND RESULTS: Mice were fed a standard carbohydrate-rich diet or 2 fat-rich diets, 1 enriched in triheptanoin and 1 in soybean oil. Stroke was induced in mice by middle cerebral artery occlusion for 90 minutes, followed by reperfusion. Mice were sacrificed, and blood plasma and liver and brain homogenates were obtained. In 1 experiment, microdialysis was performed. Metabolites (eg glucose, β-hydroxybutyrate, citrate, succinate) were determined by gas chromatography-mass spectrometry. After 90 minutes of brain ischemia, β-hydroxybutyrate levels were dramatically increased in liver, blood, and brain microdialysate and brain homogenate, but only in mice fed fat-rich diets. Glucose levels were changed in the opposite manner in blood and brain. Reperfusion decreased β-hydroxybutyrate and increased glucose within 60 minutes. Stroke-induced ketogenesis was blocked by propranolol, a β-receptor antagonist. Citrate and succinate were moderately increased by fat-rich diets and unchanged after stroke.
CONCLUSIONS: We conclude that brain ischemia induces the formation of β-hydroxybutyrate (ketogenesis) in the liver and the consumption of β-hydroxybutyrate in the brain. This effect seems to be mediated by β-adrenergic receptors.
In the article by Chun et al, "The Impact of Cryoballoon Versus Radiofrequency Ablation for Paroxysmal Atrial Fibrillation on Healthcare Utilization and Costs: An Economic Analysis From the FIRE AND ICE Trial" which published online July 27, 2017, and appeared in the August 2017 issue of the journal (J Am Heart Assoc. 2017;6:e006043. DOI: 10.1161/JAHA.117.006043.), there were errors found in Figure 1. On page 5, Figure 1, "United Kingdom" and "United States" were misspelled.
Background: This study sought to assess payer costs following cryoballoon or radiofrequency current (RFC) catheter ablation of paroxysmal atrial fibrillation in the randomized FIRE AND ICE trial.
Methods and Results: A trial period analysis of healthcare costs evaluated the impact of ablation modality (cryoballoon versus RFC) on differences in resource use and associated payer costs. Analyses were based on repeat interventions, rehospitalizations, and cardioversions during the trial, with unit costs based on 3 national healthcare systems (Germany [€], the United Kingdom [£], and the United States [Embedded Image]). Total payer costs were calculated by applying standard unit costs to hospital stays, using International Classification of Diseases, 10th Revision diagnoses and procedure codes that were mapped to country‐specific diagnosis‐related groups. Patients (N=750) randomized 1:1 to cryoballoon (n=374) or RFC (n=376) ablation were followed for a mean of 1.5 years. Resource use was lower in the cryoballoon than the RFC group (205 hospitalizations and/or interventions in 122 patients versus 268 events in 154 patients). The cost differences per patient in mean total payer costs during follow‐up were €640, £364, and Embedded Image925 in favor of cryoballoon ablation (P=0.012, 0.013, and 0.016, respectively). This resulted in trial period total cost savings of €245 000, £140 000, and Embedded Image355 000.
Conclusions: When compared with RFC ablation, cryoballoon ablation was associated with a reduction in resource use and payer costs. In all 3 national healthcare systems analyzed, this reduction resulted in substantial trial period cost savings, primarily attributable to fewer repeat ablations and a reduction in cardiovascular rehospitalizations with cryoballoon ablation.
Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Identifier: NCT01490814.
Objective: Worldwide, the respiratory syncytial virus (RSV) represents the predominant viral agent causing bronchiolitis and pneumonia in children. To conduct research and tackle existing healthcare disparities, RSV-related research activities around the globe need to be described. Hence, we assessed the associated scientific output (represented by research articles) by geographical, chronological and socioeconomic criteria and analysed the authors publishing in the field by gender. Also, the 15 most cited articles and the most prolific journals were identified for RSV research.
Design: Retrospective, descriptive study.
Setting: The NewQIS (New Quality and Quantity Indices in Science) platform was employed to identify RSV-related articles published in the Web of Science until 2013. We performed a numerical analysis of all articles, and examined citation-based aspects (eg, citation rates); results were visualised by density equalising mapping tools.
Results: We identified 4600 RSV-related articles. The USA led the field; US-American authors published 2139 articles (46.5%% of all identified articles), which have been cited 83 000 times. When output was related to socioeconomic benchmarks such as gross domestic product or Research and Development expenditures, Guinea-Bissau, The Gambia and Chile were ranked in leading positions. A total of 614 articles on RSV (13.34% of all articles) were attributed to scientific collaborations. These were primarily established between high-income countries. The gender analysis indicated that male scientists dominated in all countries except Brazil.
Conclusions: The majority of RSV-related research articles originated from high-income countries whereas developing nations showed only minimal publication productivity and were barely part of any collaborative networks. Hence, research capacity in these nations should be increased in order to assist in addressing inequities in resource allocation and the clinical burden of RSV in these countries.
Background: Imbalances in female career promotion are a key factor of gender disparities at the workplace. They may lead to stress and stress-related diseases including burnout, depression or cardiovascular diseases. Since this problem cannot be generalized and varies between different fields, new approaches are needed to assess and describe the magnitude of the problem in single fields of work.
Methods: To construct a new index, operating figures of female and male medical students were collected for Germany in a period over 15 years and their progression throughout their studies towards specialization and academic chair positions. By the use of different female to male ratios (f:m), we constructed an index that describes the extend by which women can ascent in their academic career by using the field of academic medicine as an example.
Results: A medical student f:m ratio of 1.54 (52,366 female vs. 34,010 male) was found for Germany in 2013. In 1998, this f:m ratio was 0.999. In the same year (2013), the OB/GYN hospital specialists’ f:m ratio was 1.566 (3347 female vs. 2137 male physicians) and 0.577 (516 female vs 894 male physicians) for ENT hospital specialists, respectively. The f:m ratios concerning chairs of OB/GYN and ENT were 0.105 and 0.1, respectively. Then an index was generated that incorporated these operating figures with the student f:m ratio as denominator and the chair f:m ratio as numerator while the hospital specialist f:m ratio served as a corrector in the numerator in order to adjust to the attraction of a given field to female physicians. As a result, the index was 0.044 for OB/GYN and 0.113 for ENT instead of ideally ~1 in a completely gender harmonized situation.
Conclusion: In summary, a new index to describe female career advancement was established for academic medicine. By the use of this index, different academic and medical fields can now be compared to each other and future benchmarks could be proposed. Also, country differences may be examined using the proposed index and the success of specific funding programs.
Zika virus (ZIKV) infection, a public health emergency of international concern, has recently been confirmed in Indonesia. However, to date, there has been no study to assess how prepared healthcare workers in Indonesia are to confront this emerging infectious disease. The aim of this study was to assess the attitudes of medical doctors in Indonesia towards ZIKV infection and its associated explanatory variables. A cross-sectional self-administered online survey was conducted from 3 May to 3 June 2016 in Aceh province, Indonesia. A pre-tested questionnaire was used to collect data on doctors’ attitudes towards ZIKV infection and a range of explanatory variables (basic demographic data, professional characteristics, workplace characteristics and facilities, and medical experience related to ZIKV infection). Associations between attitude and explanatory variables were assessed using multiple-step logistic regression. We received 631 responses, 424 (67.19%) of which were included in the final analysis. Approximately 64% (271) of doctors had a poor attitude towards ZIKV infection. Experience considering ZIKV infection as a differential diagnosis and attendance at a national conference was associated with a good attitude, with odds ratios (OR) of 3.93 (95% confidence interval [CI]: 1.15–13.49) and 1.69 (95% CI: 1.03–2.76), respectively. Unexpectedly, doctors who had attended an international conference and those working at places that had molecular diagnostic (polymerase chain reaction based testing) facilities had lower odds of having a good attitude (OR: 0.35 [95% CI: 0.15–0.84] and 0.42 [95% CI: 0.19–0.95], respectively). In conclusion, the attitude towards ZIKV infection is relatively poor among doctors in Aceh. Therefore, strategies for enhancing their capacity to respond to ZIKV infection are needed. The survey concept and tools were well accepted by the participants of this study, suggesting that this rapid assessment could be rolled out across the Indonesian archipelago and elsewhere to identify and regionally differentiate unmet needs of disease and outbreak preparedness.
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: 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Human brain dynamics and functional connectivity fluctuate over a range of temporal scales in coordination with internal states and environmental demands. However, the neurobiological significance and consequences of functional connectivity dynamics during rest have not yet been established. We show that the coarse-grained clustering of whole-brain dynamic connectivity measured with magnetic resonance imaging reveals discrete patterns (dynamic connectivity states) associated with wakefulness and sleep. We validate this using EEG in healthy subjects and patients with narcolepsy and by matching our results with previous findings in a large collaborative database. We also show that drowsiness may account for previous reports of metastable connectivity states associated with different levels of functional integration. This implies that future studies of transient functional connectivity must independently monitor wakefulness. We conclude that a possible neurobiological significance of dynamic connectivity states, computed at a sufficiently coarse temporal scale, is that of fluctuations in wakefulness.
NEK family kinases are serine/threonine kinases that have been functionally implicated in the regulation of the disjunction of the centrosome, the assembly of the mitotic spindle, the function of the primary cilium and the DNA damage response. NEK1 shows pleiotropic functions and has been found to be mutated in cancer cells, ciliopathies such as the polycystic kidney disease, as well as in the genetic diseases short-rib thoracic dysplasia, Mohr-syndrome and amyotrophic lateral sclerosis. NEK1 is essential for the ionizing radiation DNA damage response and priming of the ATR kinase and of Rad54 through phosphorylation. Here we report on the structure of the kinase domain of human NEK1 in its apo- and ATP-mimetic inhibitor bound forms. The inhibitor bound structure may allow the design of NEK specific chemo-sensitizing agents to act in conjunction with chemo- or radiation therapy of cancer cells. Furthermore, we characterized the dynamic protein interactome of NEK1 after DNA damage challenge with cisplatin. Our data suggest that NEK1 and its interaction partners trigger the DNA damage pathways responsible for correcting DNA crosslinks.
CryoEM structures of membrane pore and prepore complex reveal cytolytic mechanism of Pneumolysin
(2017)
Many pathogenic bacteria produce pore-forming toxins to attack and kill human cells. We have determined the 4.5 Å structure of the ~2.2 MDa pore complex of pneumolysin, the main virulence factor of Streptococcus pneumoniae, by cryoEM. The pneumolysin pore is a 400 Å ring of 42 membrane-inserted monomers. Domain 3 of the soluble toxin refolds into two ~85 Å β-hairpins that traverse the lipid bilayer and assemble into a 168-strand β-barrel. The pore complex is stabilized by salt bridges between β-hairpins of adjacent subunits and an internal α-barrel. The apolar outer barrel surface with large sidechains is immersed in the lipid bilayer, while the inner barrel surface is highly charged. Comparison of the cryoEM pore complex to the prepore structure obtained by electron cryo-tomography and the x-ray structure of the soluble form reveals the detailed mechanisms by which the toxin monomers insert into the lipid bilayer to perforate the target membrane.
Membrane proteins frequently assemble into higher order homo- or hetero-oligomers within their natural lipid environment. This complex formation can modulate their folding, activity as well as substrate selectivity. Non-disruptive methods avoiding critical steps, such as membrane disintegration, transfer into artificial environments or chemical modifications are therefore essential to analyze molecular mechanisms of native membrane protein assemblies. The combination of cell-free synthetic biology, nanodisc-technology and non-covalent mass spectrometry provides excellent synergies for the analysis of membrane protein oligomerization within defined membranes. We exemplify our strategy by oligomeric state characterization of various membrane proteins including ion channels, transporters and membrane-integrated enzymes assembling up to hexameric complexes. We further indicate a lipid-dependent dimer formation of MraY translocase correlating with the enzymatic activity. The detergent-free synthesis of membrane protein/nanodisc samples and the analysis by LILBID mass spectrometry provide a versatile platform for the analysis of membrane proteins in a native environment.
Summary: Persistence with osteoporosis therapy is vital for fracture prevention. This non-interventional study of postmenopausal women receiving denosumab in Germany, Austria, Greece, and Belgium found that persistence with denosumab remains consistently high after 24 months in patients at high risk of fracture.
Purpose: Continued persistence with osteoporosis therapy is vital for fracture prevention. This non-interventional study of clinical practice evaluated medication-taking behavior of postmenopausal women receiving denosumab in Germany, Austria, Greece, and Belgium and factors influencing persistence.
Methods: Subcutaneous denosumab (60 mg every 6 months) was assigned according to prescribing information and local guidelines before and independently of enrollment; outcomes were recorded during routine practice for up to 24 months. Persistence was defined as receiving the subsequent injection within 6 months + 8 weeks of the previous injection and adherence as administration of subsequent injections within 6 months ± 4 weeks of the previous injection. Medication coverage ratio (MCR) was calculated as the proportion of time a patient was covered by denosumab. Associations between pre-specified baseline covariates and 24-month persistence were assessed using multivariable logistic regression.
Results: The 24-month analyses included 1479 women (mean age 66.3–72.5 years) from 140 sites; persistence with denosumab was 75.1–86.0%, adherence 62.9–70.1%, and mean MCR 87.4–92.4%. No covariate had a significant effect on persistence across all four countries. For three countries, a recent fall decreased persistence; patients were generally older with chronic medical conditions. In some countries, other covariates (e.g., older age, comorbidity, immobility, and prescribing reasons) decreased persistence. Adverse drug reactions were reported in 2.3–6.9% patients.
Conclusions: Twenty-four-month persistence with denosumab is consistently high among postmenopausal women in Europe and may be influenced by patient characteristics. Further studies are needed to identify determinants of low persistence.
NMR spectroscopy is a powerful technique to study ribonucleic acids (RNAs) which are key players in a plethora of cellular processes. Although the NMR toolbox for structural studies of RNAs expanded during the last decades, they often remain challenging. Here, we show that solvent paramagnetic relaxation enhancements (sPRE) induced by the soluble, paramagnetic compound Gd(DTPA-BMA) provide a quantitative measure for RNA solvent accessibility and encode distance-to-surface information that correlates well with RNA structure and improves accuracy and convergence of RNA structure determination. Moreover, we show that sPRE data can be easily obtained for RNAs with any isotope labeling scheme and is advantageous regarding sample preparation, stability and recovery. sPRE data show a large dynamic range and reflect the global fold of the RNA suggesting that they are well suited to identify interaction surfaces, to score structural models and as restraints in RNA structure determination.
Background: Correct species identification of blow flies is a crucial step for understanding their biology, which can be used not only for designing fly control programs, but also to determine the minimum time since death. Identification techniques are usually based on morphological and molecular characters. However, the use of classical morphology requires experienced entomologists for correct identification; while molecular techniques rely on a sound laboratory expertise and remain ambiguous for certain taxa. Landmark-based geometric morphometric analysis of insect wings has been extensively applied in species identification. However, few wing morphometric analyses of blow fly species have been published.
Methods: We applied a landmark-based geometric morphometric analysis of wings for species identification of 12 medically and forensically important blow fly species of Thailand. Nineteen landmarks of each right wing of 372 specimens were digitised. Variation in wing size and wing shape was analysed and evaluated for allometric effects. The latter confirmed the influence of size on the shape differences between species and sexes. Wing shape variation among genera and species were analysed using canonical variates analysis followed by a cross-validation test.
Results: Wing size was not suitable for species discrimination, whereas wing shape can be a useful tool to separate taxa on both, genus and species level depending on the analysed taxa. It appeared to be highly reliable, especially for classifying Chrysomya species, but less robust for a species discrimination in the genera Lucilia and Hemipyrellia. Allometry did not affect species separation but had an impact on sexual shape dimorphism.
Conclusions: A landmark-based geometric morphometric analysis of wings is a useful additional method for species discrimination. It is a simple, reliable and inexpensive method, but it can be time-consuming locating the landmarks for a large scale study and requires non-damaged wings for analysis.
A balanced sphingolipid rheostat is indispensable for dendritic cell function and survival and thus initiation of an immune response. Sphingolipid levels are dynamically maintained by the action of sphingolipid enzymes of which sphingosine kinases, S1P phosphatases (SGPP-1/2) and S1P lyase (SGPL-1), are pivotal in the balance of S1P and sphingosine levels. In this study, we present that SGPP-1 and SGPL-1 are regulated in inflammatory dendritic cells and contribute to S1P fate. TLR-dependent activation caused SGPL-1 protein downregulation with subsequent decrease of enzymatic activity by two-thirds. In parallel, confocal fluorescence microscopy revealed that endogenous SGPP-1 was expressed in nuclei of naive dendritic cells and was translocated into the cytoplasmatic compartment upon inflammatory stimulation resulting in dephosphorylation of S1P. Mass spectrometric determination showed that a part of the resulting sphingosine was released from the cell, increasing extracellular levels. Another route of diminishing intracellular S1P was possibly taken by its export via ATP-binding cassette transporter C1 which was upregulated in array analysis, while the S1P transporter, spinster homolog 2, was not relevant in dendritic cells. These investigations newly describe the sequential expression and localization of the endogenous S1P regulators SGPP-1 and SGPL-1 and highlight their contribution to the sphingolipid rheostat in inflammation.
Flightless-I governs cell fate by recruiting the SUMO isopeptidase SENP3 to distinct HOX genes
(2017)
Background: Despite recent studies on the role of ubiquitin-related SUMO modifier in cell fate decisions, our understanding on precise molecular mechanisms of these processes is limited. Previously, we established that the SUMO isopeptidase SENP3 regulates chromatin assembly of the MLL1/2 histone methyltransferase complex at distinct HOX genes, including the osteogenic master regulator DLX3. A comprehensive mechanism that regulates SENP3 transcriptional function was not understood.
Results: Here, we identified flightless-I homolog (FLII), a member of the gelsolin family of actin-remodeling proteins, as a novel regulator of SENP3. We demonstrate that FLII is associated with SENP3 and the MLL1/2 complex. We further show that FLII determines SENP3 recruitment and MLL1/2 complex assembly on the DLX3 gene. Consequently, FLII is indispensible for H3K4 methylation and proper loading of active RNA polymerase II at this gene locus. Most importantly, FLII-mediated SENP3 regulation governs osteogenic differentiation of human mesenchymal stem cells.
Conclusion: Altogether, these data reveal a crucial functional interconnection of FLII with the sumoylation machinery that converges on epigenetic regulation and cell fate determination.
Background: Aside from the fully licensed herbal medicines there are products on the European pharmaceutical market which are registered by virtue of their longstanding traditional use. The normal registration procedure does not apply to them because presently they do not meet the legal requirements for a full license as set out in the relevant European Union Directive. One of these requirements, “proof of tradition”, has so far been dealt with in different ways and fails to meet the criteria of good practice.
Method: This analysis is based on a selective literature search in PubMed and in databases of medical and pharmaceutical history, interviews with licensing experts, a consensus meeting attended by researchers with a background in general medicine, phytotherapy, medical and pharmaceutical history, biometry, ethnopharmacology, pharmacognosy and the pharmaceutical industry.
Results and discussion: The 2004 EU Directive, which governs the registration of Traditional Herbal Medicinal Products and demands proof of tradition, is a regulatory construct and, above all, the outcome of a political process that has ended in a pragmatic compromise. The concept of tradition applied in the Directive does not sufficiently reflect the semantic breadth of the term. The only condition defined is that a specific commercial preparation needs to have been on the market for 30 years (15 of them inside the EU). Such an approach does not make full scientific use of the evidence available because the information excerpted from historical sources, if adequately processed, may yield valuable insights. This applies to indications, modes of application, efficacy and product safety (innocuousness). Such criteria should enter in full into the benefit-risk-analysis of applied preparations, in the registration process as well as in the therapeutic practice.
Conclusion: When registering Traditional Herbal Medicinal Products the criterion of evidence-based medicine will only be met if all the facts available are assessed and evaluated, over and above the formally stipulated regulatory provisions (30 years, product reference). To this end, the scientific methods (from among the natural, life or cultural sciences), which are recognized as authoritative in each case, must be applied.
The comprehensive assessment of pain-related human phenotypes requires combinations of nociceptive measures that produce complex high-dimensional data, posing challenges to bioinformatic analysis. In this study, we assessed established experimental models of heat hyperalgesia of the skin, consisting of local ultraviolet-B (UV-B) irradiation or capsaicin application, in 82 healthy subjects using a variety of noxious stimuli. We extended the original heat stimulation by applying cold and mechanical stimuli and assessing the hypersensitization effects with a clinically established quantitative sensory testing (QST) battery (German Research Network on Neuropathic Pain). This study provided a 246 × 10-sized data matrix (82 subjects assessed at baseline, following UV-B application, and following capsaicin application) with respect to 10 QST parameters, which we analyzed using machine-learning techniques. We observed statistically significant effects of the hypersensitization treatments in 9 different QST parameters. Supervised machine-learned analysis implemented as random forests followed by ABC analysis pointed to heat pain thresholds as the most relevantly affected QST parameter. However, decision tree analysis indicated that UV-B additionally modulated sensitivity to cold. Unsupervised machine-learning techniques, implemented as emergent self-organizing maps, hinted at subgroups responding to topical application of capsaicin. The distinction among subgroups was based on sensitivity to pressure pain, which could be attributed to sex differences, with women being more sensitive than men. Thus, while UV-B and capsaicin share a major component of heat pain sensitization, they differ in their effects on QST parameter patterns in healthy subjects, suggesting a lack of redundancy between these models.
Structural and functional dissection of the DH and PH domains of oncogenic Bcr-Abl tyrosine kinase
(2017)
The two isoforms of the Bcr-Abl tyrosine kinase, p210 and p190, are associated with different leukemias and have a dramatically different signaling network, despite similar kinase activity. To provide a molecular rationale for these observations, we study the Dbl-homology (DH) and Pleckstrin-homology (PH) domains of Bcr-Abl p210, which constitute the only structural differences to p190. Here we report high-resolution structures of the DH and PH domains and characterize conformations of the DH–PH unit in solution. Our structural and functional analyses show no evidence that the DH domain acts as a guanine nucleotide exchange factor, whereas the PH domain binds to various phosphatidylinositol-phosphates. PH-domain mutants alter subcellular localization and result in decreased interactions with p210-selective interaction partners. Hence, the PH domain, but not the DH domain, plays an important role in the formation of the differential p210 and p190 Bcr-Abl signaling networks.
β-barrel proteins mediate nutrient uptake in bacteria and serve vital functions in cell signaling and adhesion. For the 14-strand outer membrane protein G of Escherichia coli, opening and closing is pH-dependent. Different roles of the extracellular loops in this process were proposed, and X-ray and solution NMR studies were divergent. Here, we report the structure of outer membrane protein G investigated in bilayers of E. coli lipid extracts by magic-angle-spinning NMR. In total, 1847 inter-residue 1H–1H and 13C–13C distance restraints, 256 torsion angles, but no hydrogen bond restraints are used to calculate the structure. The length of β-strands is found to vary beyond the membrane boundary, with strands 6–8 being the longest and the extracellular loops 3 and 4 well ordered. The site of barrel closure at strands 1 and 14 is more disordered than most remaining strands, with the flexibility decreasing toward loops 3 and 4. Loop 4 presents a well-defined helix.
Midkine is a pleiotropic factor, which is involved in angiogenesis. However, its mode of action in this process is still ill defined. The function of midkine in arteriogenesis, the growth of natural bypasses from pre-existing collateral arteries, compensating for the loss of an occluded artery has never been investigated. Arteriogenesis is an inflammatory process, which relies on the proliferation of endothelial cells and smooth muscle cells. We show that midkine deficiency strikingly interferes with the proliferation of endothelial cells in arteriogenesis, thereby interfering with the process of collateral artery growth. We identified midkine to be responsible for increased plasma levels of vascular endothelial growth factor A (VEGFA), necessary and sufficient to promote endothelial cell proliferation in growing collaterals. Mechanistically, we demonstrate that leukocyte domiciled midkine mediates increased plasma levels of VEGFA relevant for upregulation of endothelial nitric oxide synthase 1 and 3, necessary for proper endothelial cell proliferation, and that non-leukocyte domiciled midkine additionally improves vasodilation.
The data provided on the role of midkine in endothelial proliferation are likely to be relevant for both, the process of arteriogenesis and angiogenesis. Moreover, our data might help to estimate the therapeutic effect of clinically applied VEGFA in patients with vascular occlusive diseases.
Dysregulation of lysophosphatidic acids in multiple sclerosis and autoimmune encephalomyelitis
(2017)
Bioactive lipids contribute to the pathophysiology of multiple sclerosis. Here, we show that lysophosphatidic acids (LPAs) are dysregulated in multiple sclerosis (MS) and are functionally relevant in this disease. LPAs and autotaxin, the major enzyme producing extracellular LPAs, were analyzed in serum and cerebrospinal fluid in a cross-sectional population of MS patients and were compared with respective data from mice in the experimental autoimmune encephalomyelitis (EAE) model, spontaneous EAE in TCR1640 mice, and EAE in Lpar2 -/- mice. Serum LPAs were reduced in MS and EAE whereas spinal cord LPAs in TCR1640 mice increased during the ‘symptom-free’ intervals, i.e. on resolution of inflammation during recovery hence possibly pointing to positive effects of brain LPAs during remyelination as suggested in previous studies. Peripheral LPAs mildly re-raised during relapses but further dropped in refractory relapses. The peripheral loss led to a redistribution of immune cells from the spleen to the spinal cord, suggesting defects of lymphocyte homing. In support, LPAR2 positive T-cells were reduced in EAE and the disease was intensified in Lpar2 deficient mice. Further, treatment with an LPAR2 agonist reduced clinical signs of relapsing-remitting EAE suggesting that the LPAR2 agonist partially compensated the endogenous loss of LPAs and implicating LPA signaling as a novel treatment approach.
Regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking in response to neuronal activity is critical for synaptic function and plasticity. Here, we show that neuronal activity induces the binding of ephrinB2 and ApoER2 receptors at the postsynapse to regulate de novo insertion of AMPA receptors. Mechanistically, the multi-PDZ adaptor glutamate-receptor-interacting protein 1 (GRIP1) binds ApoER2 and bridges a complex including ApoER2, ephrinB2, and AMPA receptors. Phosphorylation of ephrinB2 in a serine residue (Ser-9) is essential for the stability of such a complex. In vivo, a mutation on ephrinB2 Ser-9 in mice results in a complete disruption of the complex, absence of ApoER2 downstream signaling, and impaired activity-induced and ApoER2-mediated AMPA receptor insertion. Using compound genetics, we show the requirement of this complex for long-term potentiation (LTP). Together, our findings uncover a cooperative ephrinB2 and ApoER2 signaling at the synapse, which serves to modulate activity-dependent AMPA receptor dynamic changes during synaptic plasticity.
Checkpoint kinase inhibitor AZD7762 strongly sensitises urothelial carcinoma cells to gemcitabine
(2017)
Background: More effective chemotherapies are urgently needed for bladder cancer, a major cause of morbidity and mortality worldwide. We therefore explored the efficacy of the combination of gemcitabine and AZD7762, a checkpoint kinase 1/2 (CHK1/2) inhibitor, for bladder cancer.
Methods: Viability, clonogenicity, cell cycle distribution and apoptosis were assessed in urothelial cancer cell lines and various non-malignant urothelial cells treated with gemcitabine and AZD7762. DNA damage was assessed by γH2A.X and 53-BP1 staining and checkpoint activation was followed by Western blotting. Pharmacological inhibition of CHK1 and CHK2 was compared to downregulation of either CHK1 or CHK2 using siRNAs.
Results: Combined use of gemcitabine and AZD7762 synergistically reduced urothelial carcinoma cell viability and colony formation relative to either single treatment. Non-malignant urothelial cells were substantially less sensitive to this drug combination. Gemcitabine plus AZD7762 inhibited cell cycle progression causing cell accumulation in S-phase. Moreover, the combination induced pronounced levels of apoptosis as indicated by an increase in the fraction of sub-G1 cells, in the levels of cleaved PARP, and in caspase 3/7 activity. Mechanistic investigations showed that AZD7762 treatment inhibited the repair of gemcitabine-induced double strand breaks by interference with CHK1, since siRNA-mediated depletion of CHK1 but not of CHK2 mimicked the effects of AZD7762.
Conclusions: AZD7762 enhanced sensitivity of urothelial carcinoma cells to gemcitabine by inhibiting DNA repair and disturbing checkpoints. Combining gemcitabine with CHK1 inhibition holds promise for urothelial cancer therapy.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a condition of abnormal heart rhythm (arrhythmia), induced by physical activity or stress. Mutations in ryanodine receptor 2 (RyR2), a Ca2+ release channel located in the sarcoplasmic reticulum (SR), or calsequestrin 2 (CASQ2), a SR Ca2+ binding protein, are linked to CPVT. For specific drug development and to study distinct arrhythmias, simple models are required to implement and analyze such mutations. Here, we introduced CPVT inducing mutations into the pharynx of Caenorhabditis elegans, which we previously established as an optogenetically paced heart model. By electrophysiology and video-microscopy, we characterized mutations in csq-1 (CASQ2 homologue) and unc-68 (RyR2 homologue). csq-1 deletion impaired pharynx function and caused missed pumps during 3.7 Hz pacing. Deletion mutants of unc-68, and in particular the point mutant UNC-68(R4743C), analogous to the established human CPVT mutant RyR2(R4497C), were unable to follow 3.7 Hz pacing, with progressive defects during long stimulus trains. The pharynx either locked in pumping at half the pacing frequency or stopped pumping altogether, possibly due to UNC-68 leakiness and/or malfunctional SR Ca2+ homeostasis. Last, we could reverse this ‘worm arrhythmia’ by the benzothiazepine S107, establishing the nematode pharynx for studying specific CPVT mutations and for drug screening.
Background: Malaria remains one of the most serious infections for travellers to tropical countries. Due to the lack of harmonized guidelines a large variety of treatment regimens is used in Europe to treat severe malaria.
Methods: The European Network for Tropical Medicine and Travel Health (TropNet) conducted an 8-year, multicentre, observational study to analyse epidemiology, treatment practices and outcomes of severe malaria in its member sites across Europe. Physicians at participating TropNet centres were asked to report pseudonymized retrospective data from all patients treated at their centre for microscopically confirmed severe Plasmodium falciparum malaria according to the 2006 WHO criteria.
Results: From 2006 to 2014 a total of 185 patients with severe malaria treated in 12 European countries were included. Three patients died, resulting in a 28-day survival rate of 98.4%. The majority of infections were acquired in West Africa (109/185, 59%). The proportion of patients treated with intravenous artesunate increased from 27% in 2006 to 60% in 2013. Altogether, 56 different combinations of intravenous and oral drugs were used across 28 study centres. The risk of acute renal failure (36 vs 17% p = 0.04) or cerebral malaria (54 vs 20%, p = 0.001) was significantly higher in patients ≥60 years than in younger patients. Respiratory distress with the need for mechanical ventilation was significantly associated with the risk of death in the study population (13 vs 0%, p = 0.001). Post-artemisinin delayed haemolysis was reported in 19/70 (27%) patients treated with intravenous artesunate.
Conclusion: The majority of patients with severe malaria in this study were tourists or migrants acquiring the infection in West Africa. Intravenous artesunate is increasingly used for treatment of severe malaria in many European treatment centres and can be given safely to European patients with severe malaria. Patients treated with intravenous artesunate should be followed up to detect and manage late haemolytic events.
Progressive neurodegenerative diseases plague millions of individuals both in the United States and across the world. The current pathology of progressive neurodegenerative tauopathies, such as Alzheimer’s disease (AD), Pick’s disease, frontotemporal dementia (FTD), and progressive supranuclear palsy, primarily revolves around phosphorylation and hyperphosphorylation of the tau protein. However, more recent evidence suggests acetylation of tau protein at lysine 280 may be a critical step in molecular pathology of these neurodegenerative diseases prior to the tau hyperphosphorylation. Secondary injury cascades such as oxidative stress, endoplasmic reticulum stress, and neuroinflammation contribute to lasting damage within the brain and can be induced by a number of different risk factors. These injury cascades funnel into a common pathway of early tau acetylation, which may serve as the catalyst for progressive degeneration. The post translational modification of tau can result in production of toxic oligomers, contributing to reduced solubility as well as aggregation and formation of neurofibrillary tangles, the hallmark of AD pathology. Chronic Traumatic Encephalopathy (CTE), caused by repetitive brain trauma is also associated with a hyperphosphorylation of tau. We postulated acetylation of tau at lysine 280 in CTE disease could be present prior to the hyperphosphorylation and tested this hypothesis in CTE pathologic specimens. We also tested for ac-tau 280 in early stage Alzheimer’s disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first "triggering" event leading to neuronal loss. To the best of our knowledge, this is the first study to identify acetylation of the tau protein in CTE. Prevention of tau acetylation could possibly serve as a novel target for stopping neurodegeneration before it fully begins. In this study, we highlight what is known about tau acetylation and neurodegeneration.
Online reading behavior can be regarded as a "new" form of cultural capital in today’s digital world. However, it is unclear whether "traditional" mechanisms of cultural and social reproduction are also found in this domain, and whether they manifest uniformly across countries at different stages of development. This article analyzes whether the early home literacy environment has an impact on informational online reading behavior among adolescents and whether this association varies between countries with different levels of digitalization and educational expansion. Data from the 2009 Programme for International Student Assessment (PISA) were used for the empirical analyses. The results of regression models with country-fixed effects indicate a positive association between literacy activities in early childhood and informational online reading at age 15. This association was quite stable across countries. These findings are discussed in light of cultural and social reproduction theory and digital divide research.
The toolbox for imaging molecules is well-equipped today. Some techniques visualize the geometrical structure, others the electron density or electron orbitals. Molecules are many-body systems for which the correlation between the constituents is decisive and the spatial and the momentum distribution of one electron depends on those of the other electrons and the nuclei. Such correlations have escaped direct observation by imaging techniques so far. Here, we implement an imaging scheme which visualizes correlations between electrons by coincident detection of the reaction fragments after high energy photofragmentation. With this technique, we examine the H2 two-electron wave function in which electron–electron correlation beyond the mean-field level is prominent. We visualize the dependence of the wave function on the internuclear distance. High energy photoelectrons are shown to be a powerful tool for molecular imaging. Our study paves the way for future time resolved correlation imaging at FELs and laser based X-ray sources.
Secretins form multimeric channels across the outer membrane of Gram-negative bacteria that mediate the import or export of substrates and/or extrusion of type IV pili. The secretin complex of Thermus thermophilus is an oligomer of the 757-residue PilQ protein, essential for DNA uptake and pilus extrusion. Here, we present the cryo-EM structure of this bifunctional complex at a resolution of ~7 Å using a new reconstruction protocol. Thirteen protomers form a large periplasmic domain of six stacked rings and a secretin domain in the outer membrane. A homology model of the PilQ protein was fitted into the cryo-EM map. A crown-like structure outside the outer membrane capping the secretin was found not to be part of PilQ. Mutations in the secretin domain disrupted the crown and abolished DNA uptake, suggesting a central role of the crown in natural transformation.
Patients who undergo endovascular repair of aortic aneurysms (EVAR) require life-long surveillance because complications including, in particular, endoleaks, aneurysm rupture, and graft dislocation are diagnosed in a certain share of the patient population and may occur at any time after the original procedure. Radiation exposure in patients undergoing EVAR and post-EVAR surveillance has been investigated by previous authors. Arriving at realistic exposure data is essential because radiation doses resulting from CT were shown to be not irrelevant. Efforts directed at identification of factors impacting the level of radiation exposure in both the course of the EVAR procedure and post-EVAR endovascular interventions and CTAs are warranted as potentially modifiable factors may offer opportunities to reduce the radiation. In the light of the risks found to be associated with radiation exposure and considering the findings above, those involved in EVAR and post-EVAR surveillance should aim at optimal dose management.
We have determined the crystal structures of two decachlorocyclopentasilanes, namely bis(tetra-n-butylammonium) dichloride decachlorocyclopentasilane dichloromethane disolvate, 2C16H36N+·2Cl−·Si5Cl10·2CH2Cl2, (I), and bis(tetraethylammonium) dichloride decachlorocyclopentasilane dichloromethane disolvate, 2C8H20N+·2Cl−·Si5Cl10·2CH2Cl2, (II), both of which crystallize with discrete cations, anions, and solvent molecules. In (I), the complete decachlorocyclopentasilane ring is generated by a crystallographic twofold rotation axis. In (II), one cation is located on a general position and the other two are disordered about centres of inversion. These are the first structures featuring the structural motif of a five-membered cyclopentasilane ring coordinated from both sides by a chloride ion. The extended structures of (I) and (II) feature numerous C—H⋯Cl interactions. In (II), the N atoms are located on centres of inversion and as a result, the ethylene chains are disordered over equally occupied orientations.
Status and restoration potential of heathlands and sand grasslands in the southwest of Luxembourg
(2017)
In Europe, semi-natural nutrient-poor ecosystems such as sand grasslands and heathlands have shown extreme declines in surface area and species richness within the last century. The remaining sites are hence of high conservation value. This study analysed the vascular plant species inventory of established and recently restored heathlands and sand grasslands in the southwest of Luxembourg. Analyses to explain differences in vegetation composition between “old” (remnant sites or sites restored a long time ago) and “new” (recently restored) sites in relation to environmental variables were carried out with DCAs and ANOVA/Mann-Whitney-U tests, respectively. The vegetation of old heathlands had few character species of typical heathland communities (Calluno-Ulicetea, Nardetalia), whereas new heathland sites were preponderantly marked by taxa of meso- or eutrophic grasslands and ruderal communities. New heathland sites mainly differed from old sites by higher soil phosphorus contents. Sand grassland vegetation was species-rich and composed by species of the Sedo-Scleranthetea and Festuco-Brometea. With increasing age of the sites, vegetation composition shifted to grass dominance with species of the Molinio-Arrhenateretea. New sand grasslands differed from old sand grasslands by higher soil pH, higher soil potassium content and lower graminoid cover. The differences between new and old sites of both habitat types could mainly be explained by successional processes or were a result of topsoil removal. In some cases, former anthropogenic impact at or in close proximity of restored sites resulted in unsuitable conditions, such as alkaline soil on former landfill sites or highly eutrophic soil due to intensive agriculture. Future management options for the study sites are discussed.
This study describes the vascular flora and community structure of grasslands occurring on heaps of waste rock left by former Zn-Pb mining in relation to the metal content in the soil and other environmental factors. The study was performed on 65 heaps scattered in agricultural land in southern Poland. The sites were described in terms of plant community characteristics, soil physicochemical properties, distance from woodland, altitude and local climate. The number of plant species and proportion of species of the Festuco-Brometea class decreased with increasing heavy metal (Cd, Pb, Zn) content in the soil, and increased with Ca content and pH of the soil. There was a negative relationship between the proportion of the later successional species and heavy metal content in the soil and a positive relationship between plants connected with the earlier stages of succession and metals. Floristic composition was also affected by distance from woodland and height above sea level. The investigated heaps were primarily colonised by native species dispersed by wind, characterised as competitive stresstolerant, ruderal and competitive strategy species. Three types of Carlino acaulis-Brometum erecti (CB) communities were distinguished: CB typicum – dominated by Brachypodium pinnatum, with the highest proportion of calcareous grassland species, CB festucetosum ovinae subass. nova – loose grassland with abundant facultative metallophytes, and the CB rubietosum caesi subass. nova with nutrientdemanding ruderal and woody plants invading from the nearby forest communities. The three subassociations represent different successional stages of Carlino acaulis-Brometum erecti, strongly dependent on both the substrate and spatial relations. The proportions of species traits, especially a high occurrence of endangered species and a very low proportion of alien species show that the post-mining habitats studied have a similar degree of ‘naturalness’ as valuable xerothermic grasslands on nonmetalliferous habitats. They thus may be considered as valuable objects for the protection of plant diversity.
This paper provides a comprehensive survey of the results of phytocoenological research into Alnus incana forests from the alliance Alnion incanae in the Dinarides. Stands from the south-eastern Dinarides (Alnetum incanae = Oxali-Alnetum incanae) were analyzed and compared with those from the north-western Dinarides (Lamio orvalae-Alnetum incanae). The comparison reveals significant differences in the floristic composition and in the degree of differentiation – and particularly in the presence of the species of the Illyrian floristic geoelement. Focus was placed on the area of western Croatia where a geographic variant of Helleborus dumetorum had previously been defined within the association Lamio orvalae-Alnetum incanae. Two of its subtypes, Salix alba and Alnus glutinosa, were determined in our research. The former subtype thrives on occasionally flooded, moist sites, where the floristic composition is dominated by hygrophytes. The latter subtype grows on elevated and drier terraces and is richer in mesophilous species from the surrounding zonal forests. A floristic-sociological comparison of the Lamio orvalae-Alnetum incanae with the related syntaxa indicates the presence of about fourty diagnostic species which accentuate its independence and the need to assess it at the level of an independent, regional association within the alliance Alnion incanae.
The aim of our study was to reveal the differences in the species composition and soil properties of open sandy grasslands dominated by different Festuca species, Festuca vaginata and F. pseudovaginata. Due to the arid conditions, sandy grasslands are generally covered by xerothermic vegetation in which F. vaginata is a typical dominant species. Festuca pseudovaginata, a species newly described by the authors, can also gain dominance in sandy grasslands. However, species composition and soil properties of grasslands dominated by this recently discovered species are still undiscovered. Based on previous coenological studies, we hypothesised that the grasslands characterised by the endemic F. vaginata are more species-rich than those with F.pseudovaginata.
Coenological sampling was carried out in May 2009 at two study sites using the Braun-Blanquet method in quadrats of 2 m × 2 m. Five relevés were sampled in stands dominated by F. vaginata and F. pseudovaginata respectively at two study sites in Central Hungary, resulting in a total of twenty relevés. Analyses were based on the cover scores of vascular plant species and cryptogam crust and values of seven soil properties (pH [KCl], pH [H2O], humus, total N, Ca, P2O5 and K2O) measured in the 0–15 and 15–30 cm soil layers. Soil properties of the grasslands dominated by F. pseudovaginata and F. vaginata (dependent variables) were compared by linear mixed models, where ‘grassland type’ was the fixed factor and ‘site nested in grassland type’ was considered as random factor. Data were analysed by cluster analysis, fusion algorithm was a combinatorial method (minimising increase of variance), and the correlation was used as comparative function. We compared the cover of subordinate species by Mann-Whitney U test. We found that F. pseudovaginata and F. vaginata samples were well separated, and grasslands dominated by F. pseudovaginata had nearly two times more species than those dominated by F. vaginata. Based on the cluster analyses using plant cover and upper 0–15 cm soil layer data, F. pseudovaginata and F. vaginata groups could be well separated. Linear mixed models revealed that F. vaginata grasslands were typical on soils with higher pH, nitrogen, phosphorous and potassium contents compared to F. pseudovaginata grasslands, which indicates a tight connection between the properties of the upper soil layer and the vegetation in sandy grasslands.
Bromus racemosus L. is a rather rare grass species of moist meadows. It has strongly decreased in the course of the 20th century due to intensification of agricultural grassland management, and is therefore included in Red Lists of several European countries. Its winter annual life-cycle is remarkable for a species of permanent grasslands.
The aim of this study is to determine the habitat preference and optimal management of B. racemosus in the Netherlands and surrounding countries. Vegetation, soil and hydrological data from 28 sites in the Netherlands have been compared with B. racemosus cover, and with vegetation data from surrounding countries. The results indicate that B. racemosus is characteristic of Molinio-Arrhenatheretea meadows with good mineralisation and aftermath grazing. The optimum lies in grasslands of the alliance Alopecurion pratensis (Deschampsion cespitosae), but the species ranges from wetter Calthion palustris meadows to drier Arrhenatherion elatioris and Cynosurion cristati grasslands. It prefers intermediate nutrient levels and hydrological conditions (mesic sites), but within this range the highest cover is found in relatively nutrient rich and dry sites. Because of the absence of a seedbank and a low dispersal capability, B. racemosus is vulnerable to changes in grassland management. A management of mowing after 15 June and aftermath grazing is most suitable, since it enables fruit ripening and the maintenance of an open sward, needed for germination and development. The risk of extinction is likely to be higher in flat polders than in floodplain sites with natural relief, where the species may shift between belts in different years.
Vegetation patterns of floodplain forests are highly variable across different habitats in European regions. Their plant communities have been well described from the phytosociological point of view, but plant species richness and composition patterns and their underlying environmental factors are still insufficiently known. Sixty-one vegetation plots of black alder-dominated floodplain forests were sampled in central Slovakia in order to find main environmental predictors affecting floristic diversity of their vegetation. For each vegetation plot with a constant size (400m2), vascular plant species and a set of topographic, climatic, soil physical and chemical characteristics were recorded. A generalized linear model was applied to explain relevance of environmental factors on changes of species richness, whereas the relationship between species composition and explanatory variables was tested using ordination methods. Main gradients of species compositional variation were soil moisture, light, elevation and soil chemistry-related variables. Vascular species richness of plots varied between 19 and 59 (mean 38). Herb-layer species richness was positively related to the soil pH, stream power index and negatively to the concentration of soil iron. These linear trends were accompanied by a hump-shaped response to sand content and a U-shaped response to elevation.
Background: Isolated transient vertigo can be the only symptom of posterior circulation ischemia. Thus, it is important to differentiate isolated vertigo of a cerebrovascular origin from that of more benign origins, as patients with cerebral ischemia have a much higher risk for future stroke than do those with "peripheral" vertigo. The current study aims to identify risk factors for cerebrovascular origin of isolated transient vertigo, and for future cerebrovascular events.
Methods: From the files of 339 outpatients with isolated transient vertigo we extracted history, clinical and technical findings, diagnosis, and follow-up information on subsequent stroke or transient ischemic attack (TIA). Risk factors were analyzed using multivariate regression models (logistic or Cox) and reconfirmed in univariate analyses.
Results: On first presentation, 48 (14.2%) patients received the diagnosis "probable or definite cerebrovascular vertigo". During follow-up, 41 patients suffered stroke or TIA (event rate 7.9 per 100 person years, 95% confidence interval (CI) 5.5–10.4), 26 in the posterior circulation (event rate 4.8 per 100 person years, 95% CI 3.0–6.7). The diagnosis was not associated with follow-up cerebrovascular events. In multivariate models testing multiple potential determinants, only the presentation mode was consistently associated with the diagnosis and stroke risk: patients who presented because of vertigo (rather than reporting vertigo when they presented for other reasons) had a significantly higher risk for future stroke or TIA (p = 0.028, event rate 13.4 vs. 5.4 per 100 person years) and for future posterior circulation stroke or TIA (p = 0.044, event rate 7.8 vs. 3.5 per 100 person years).
Conclusions: We here report for the first time follow-up stroke rates in patients with transient isolated vertigo. In such patients, the identification of those with cerebrovascular origin remains difficult, and presentation mode was found to be the only consistent risk factor. Confirmation in an independent prospective sample is needed.
Functional imaging studies using BOLD contrasts have consistently reported activation of the supplementary motor area (SMA) both during motor and internal timing tasks. Opposing findings, however, have been shown for the modulation of beta oscillations in the SMA. While movement suppresses beta oscillations in the SMA, motor and non-motor tasks that rely on internal timing increase the amplitude of beta oscillations in the SMA. These independent observations suggest that the relationship between beta oscillations and BOLD activation is more complex than previously thought. Here we set out to investigate this rapport by examining beta oscillations in the SMA during movement with varying degrees of internal timing demands. In a simultaneous EEG-fMRI experiment, 20 healthy right-handed subjects performed an auditory-paced finger-tapping task. Internal timing was operationalized by including conditions with taps on every fourth auditory beat, which necessitates generation of a slow internal rhythm, while tapping to every auditory beat reflected simple auditory-motor synchronization. In the SMA, BOLD activity increased and power in both the low and the high beta band decreased expectedly during each condition compared to baseline. Internal timing was associated with a reduced desynchronization of low beta oscillations compared to conditions without internal timing demands. In parallel with this relative beta power increase, internal timing activated the SMA more strongly in terms of BOLD. This documents a task-dependent non-linear relationship between BOLD and beta-oscillations in the SMA. We discuss different roles of beta synchronization and desynchronization in active processing within the same cortical region.
Reactive oxygen species are produced transiently in response to cell stimuli, and function as second messengers that oxidize target proteins. Protein-tyrosine phosphatases are important reactive oxygen species targets, whose oxidation results in rapid, reversible, catalytic inactivation. Despite increasing evidence for the importance of protein-tyrosine phosphatase oxidation in signal transduction, the cell biological details of reactive oxygen species-catalyzed protein-tyrosine phosphatase inactivation have remained largely unclear, due to our inability to visualize protein-tyrosine phosphatase oxidation in cells. By combining proximity ligation assay with chemical labeling of cysteine residues in the sulfenic acid state, we visualize oxidized Src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2). We find that platelet-derived growth factor evokes transient oxidation on or close to RAB5+/ early endosome antigen 1− endosomes. SHP2 oxidation requires NADPH oxidases (NOXs), and oxidized SHP2 co-localizes with platelet-derived growth factor receptor and NOX1/4. Our data demonstrate spatially and temporally limited protein oxidation within cells, and suggest that platelet-derived growth factor-dependent “redoxosomes,” contribute to proper signal transduction.
Steilhänge der Mittelgebirge weisen eine kleinräumige standörtliche Vielfalt auf und wurden aufgrund ihrer exponierten Lage bereits frühzeitig durch den Menschen u. a. als Befestigungsanlage genutzt. Daraus resultierte häufig eine hohe floristische und vegetationskundliche Diversität mit hohem Naturschutzwert. Durch Umwelt- und Nutzungsveränderungen hat sich aber auch an diesen Standorten in den letzten Jahrzehnten ein starker Wandel vollzogen. Durch Auswertung alter Florenlisten und Vegetationsaufnahmen und durch aktuelle Erhebungen wollen wir die Vegetationszusammensetzung der Lengder Burg, eines Steilhangs auf Unterem Muschelkalk im südlichen Göttinger Wald (Süd-Niedersachsen, Deutschland), und ihre Veränderung aufzeigen und Rückschlüsse für die zukünftige Behandlung ziehen. Dazu wurden Angaben zur Gefäßpflanzenflora aus dem Zeitraum 1950 bis 1995 mit einer aktuellen floristischen Kartierung des Gesamtgebiets von 2016 verglichen. Die Vegetationszusammensetzung wurde anhand von 37 Vegetationsaufnahmen aus dem früheren Zeitraum harakterisiert. 29 dieser Flächen wurden 2009 bis 2016 erneut aufgenommen. Räumliche und zeitliche Unterschiede in der Diversität und Artenzusammensetzung wurden hinsichtlich verschiedener standörtlicher Parameter und ökologischer Artengruppen analysiert.
Die Vegetation lässt sich zwei Gruppen zuordnen: 1. Das Carici-Fagetum und seine Kontaktgesellschaften an südlich und westlich exponierten Steilhängen. 2. Das Hordelymo-Fagetum mit verschiedenen Ausbildungen auf dem Plateau und an flacheren Süd- und Nordhangbereichen. Im Carici-Fagetum ist ein deutlicher Diversitätsverlust und eine Zunahme in der Dominanzstruktur der Krautschicht zu erkennen, der im Vergleich der Aufnahmezeiträume auf eine zunehmende Homogenisierung der Vegetation hinweist. Zurückgegangen sind dabei besonders die typischen Kenn- und Trennarten dieser Waldgesellschaft bei gleichzeitiger Zunahme der Buche in der Verjüngung. Im Hordelymo-Fagetum bewirkt neben Gehölzen in der Strauch- und Krautschicht vor allem die Zunahme von Allium ursinum eine homogenere Artenzusammensetzung, jedoch ohne Diversitätsverlust. Neben Stickstoffeinträgen, dem Klimawandel sowie einem reduzierten Rehwild-Verbiss bedingt besonders der Nutzungswandel diese Veränderungen. Vor allem im Carici-Fagetum wirkte sich der Übergang zwischen früherer Nieder- und Mittelwald-Nutzung mit Waldweide über eine fast 100jährige Hochwald-Nutzung bis zum jetzigen Schutzwald stark aus. Gleichwohl weisen die steilen Hänge weiterhin einen hohen Anteil an Rote-Liste-Arten auf und tragen wesentlich zur hohen Biodiversität des Gebiets bei. Veränderungen in der Vegetation der Lengder Burg spiegeln die Veränderungen im Göttinger Wald insgesamt wider. Kleinflächige Offenhaltungsmaßnahmen zur Erhaltung wertvoller floristischer Elemente sind teilweise erfolgreich. Kleinwüchsige, lichtbedürftige Magerkeitszeiger verschwinden jedoch zunehmend aus den sich entwickelnden, hochwüchsigen Stauden-Säumen. In den benachbarten, unbewirtschafteten Hangbuchenwäldern sorgt die fehlende Nutzung nach Jahrhunderten der Auflichtung und Aushagerung für eine Sukzession in Richtung mesophilen Kalkbuchenwalds.
In Borstgrasrasen (Nardetalia) des Werra-Meißner-Gebietes (Nordhessen, Südniedersachsen) wurden 2012 nach 25 Jahren auf möglichst gleichen Untersuchungsflächen (quasi-Dauerflächen) Wiederholungsaufnahmen angefertigt, um den gegenwärtigen Zustand bzw. Veränderungen in diesem prioritären FFH-Lebensraumtyp zu erfassen. Es wurden insgesamt 61 Flächen untersucht. Neben der Artenzusammensetzung wurden auch Bodenparameter (pH, C/N-Verhältnis, Mächtigkeit der organischen Auflage) und die Nutzung erfasst.
Bei der Wiederholungsaufnahme 2012 waren, abgesehen von einer Aufforstungsfläche, noch auf allen Flächen Arten der Borstgrasrasen vorhanden. Die Flächen wurden 2012 überwiegend genutzt oder gepflegt, während 1986/87 Brachflächen noch bei weitem dominierten. Eine Düngung der Flächen erfolgte nicht. Trotz dieser generell günstigen Nutzungssituation lässt sich ein genereller Trend zur Eutrophierung feststellen, der sich hinsichtlich Artenzahl und Deckung in einer Zunahme von Arten des Wirtschaftsgrünlandes (Molinio-Arrhenatheretea) bei gleichzeitiger Abnahme der Borstgrasrasen-Kennarten äußert. Auch die Artenzahlen der übrigen Magerkeitszeiger nahmen im Mittel ab, während Verbrachungszeiger im Allgemeinen zunahmen. Eine Veränderung der Gesamtartenzahl war nicht festzustellen. Die mittleren Zeigerwerte spiegeln die Verschiebungen im Arteninventar durch erhöhte mittlere Reaktions- und Stickstoffzahlen wider. Strukturell hat in den vergangenen 25 Jahren vor allem eine generelle Zunahme der Moosschichtdeckung und eine Ausbreitung der Sträucher auf Brachflächen stattgefunden. Bei den Bodenparametern waren 2012 eine signifikante Erhöhung der pH-Werte, eine Einengung der C/N-Verhältnisse und eine Abnahme der Mächtigkeit der organischen Auflage (Of) feststellbar. Regressionsmodelle zeigen, dass dabei die Zunahme von Arten des Wirtschaftsgrünlandes direkt mit den ansteigenden pH-Werten zusammen hing, während die Veränderungen bei den Kennarten eher vom Ausgangs-C/N-Verhältnis, teilweise auch von der Entwicklung der organischen Auflage und der Nutzung abhängig waren. Die vorgefundenen Veränderungen werden vor dem Hintergrund möglicher Gefährdungsszenarien (Brache, Eutrophierung, Bodenversauerung, Klimawandel) diskutiert. Angesichts des unerwarteten Befundes einer Eutrophierung bei gleichzeitig nachlassender Bodenversauerung, wird die Hypothese aufgestellt, dass der seit den 1990er-Jahren erfolgte Rückgang der Schwefeldepositionen mit nachfolgender Erholung der Boden-pH-Werte und nachlassender Stressbelastung, z. B. durch Ammonium-Toxizität, die Veränderungen ausgelöst haben könnte. Außerdem deuten die Ergebnisse auf eine zumindest teilweise zu geringe Nutzungs- bzw. Pflegeintensität bzw. zu späte Nutzungstermine. Möglicherweise führt der erhöhte Eutrophierungsdruck hier auch zu verstärkten Anforderungen an das Management der Flächen. Eindeutige Indizien für klimabedingte Veränderungen im Arteninventar ließen sich nicht finden. Indirekte Effekte über eine erwärmungsbedingte Förderung der Mineralisationsraten oder ein ursächlicher Zusammenhang zwischen höheren Wintertemperaturen und der Zunahme der Moosdeckung lassen sich jedoch nicht ausschließen.
Transitional between the Pannonian Basin and the Eastern Carpathians the Transcarpathian Ukraine (Transcarpathia) has a diverse geology including Quaternary sediments, volcanites, limestones and flysch, and its climate at low altitudes is relatively warm and humid. We conducted a field survey in June 2016 focusing on mesophilous forest vegetation along a transect covering almost the whole lowaltitudinal part of Transcarpathia. We recorded 54 relevés in the field and further digitized 22 relevés from literature. Using classification analysis, we distinguished three clusters of oak-hornbeam forests (alliance Carpinion betuli; 1–3) and three clusters of scree and ravine forests (alliance Tilio platyphylli-Acerion; 4–6): (1) Slightly wet Pannonian oak-hornbeam forests occurring in the lowland part of the region (Circaeo-Carpinetum); (2) Mesophilous oak-hornbeam forests (Carici pilosae-Carpinetum); (3) Xero-mesophilous oak-hornbeam forests (a drier subtype of the Carici pilosae-Carpinetum and the association Primulo veris-Carpinetum); (4) Mesophilous scree forests (Phyllitido-Aceretum); (5) Forests of steep slopes (Aceri-Tilietum) and transitions to mesophilous oak-hornbeam forests (Carici pilosae-Carpinetum); (6) Cool and wet scree and ravine forests (Arunco dioici-Aceretum pseudoplatani). Using indirect ordination analysis, three environmental variables (altitude, heat load index and slope) were identified as factors of significant influence on the species composition. These factors well distinguish oak-hornbeam forests from scree and ravine forests.
Understanding plant-plant interactions is essential in planning and implementing effective grassland management strategies. Positive and negative interactions generally co-occur in plant communities and the net effect of these interactions may depend on the disturbance regime, including grazing. Shrubs can act as biotic refuges by physically protecting neighbouring plants from herbivores. As a result, we would expect that in pastures the diversity and flowering success of plants is higher in the close vicinity of shrubs compared to the open vegetation. Nevertheless, we can also assume a competitive trade-off cost for plants that grow together with shrubs. In this study, we assessed the small-scale effects of dwarf shrubs (30–40 cm in diameter) on species density and flowering success. Specifically, we considered three types of microsites: (i) shrub interior, (ii) edge of shrub, and (iii) open pasture (more than 2 meters away from the shrub). We surveyed these three types of microsites using 10 × 10 cm sized plots both in grazed and ungrazed meadow steppe, in central Hungary. The highest species density was found at the edge of shrubs, both in grazed and ungrazed vegetation. Meanwhile, species density did not differ significantly between shrub interiors and the open pasture. However, in grazed vegetation, species flowering success was significantly higher in shrub interiors and edges than in the open pasture; no significant trend was observed for this measure in ungrazed vegetation. In contrast to previous studies, we did not detect a competitive effect of small-sized shrubs on plants in ungrazed vegetation. Our results indicate that small-sized shrubs protect other plants from herbivores and that the edge effect plays an important role for the maintenance of small-scale species diversity in pastures. Overall, our results underline the beneficial effect of biotic refuges in pastures and we suggest that retaining a sparse population of small-sized native shrubs is advantageous from a conservation point of view.
The influence of the Eastern migration route on the Slovak flora – a comparison after 40 years
(2017)
Transport is an important source of introduction and spread of alien plants into new areas and countries. This study provides comprehensive research of selected railway localities in South-Eastern Slovakia to determine the influence of the Eastern Migration Route on the Slovak flora. Railway transshipment yards in Čierna nad Tisou, Dobrá, Velké Kapušany and Matovce were studied from 1964 to 2013; with historic data sampled 1964–1998 and recent data sampled 2012–2013. These data sets were compared to determine differences in species structure following the decreased use of the transshipment yards.
A total of 657 vascular plant taxa were recorded in all localities (566 taxa in the historic and 431 taxa in the recent data set). Native species prevailed over aliens and archaeophytes over neophytes in both time periods. The most frequent aliens were naturalised taxa, where Asiatic and European species prevailed. The most frequent families were Poaceae, Asteraceae and Brassicaceae, and while many species introduced with Russian wheat were recorded only in the past, several taxa are also recorded only recently. Hemicryptophytes were the most abundant life form. Most recorded species were competitors, reproducing by seed and pollinated by insects. Zoochory and hemerochory were the most frequent dispersal types. The proportion of species traits has not changed over time. We identified 49 threatened taxa (38 in the historic and 27 in the recent data set). The Eastern migration route significantly increases the species number of alien vascular plants in the Slovak flora. Although this route had much greater importance in the past, when the role of the Eastern Slovak trans-shipment railway yards was much higher, the studied yards remain an important gateway to Eastern Central Europe and they continue to support agestochory migration of adventive plants.
Wet grasslands once covered a large area in the lowlands of northern Germany, but have declined since several decades as a result of land use intensification. Permanent plot data from such grasslands in the region that would allow to assess the extent of changes in species composition and richness are still rare. Here, we present a re-visitation study of 52 quasi-permanent plots from the Stedinger Land area in the basin of the river Weser near Bremen, comparing quadrat data between 1948 and 2015. In 1948, the grasslands were characterized by species typical of wet, moderately fertile grasslands belonging to the Bromo-Senecionetum aquatici (Bromion racemosi), including 15 species currently classified as threatened. Until 2015, the vegetation had changed strongly: almost all indicators of wet grasslands had either declined or completely vanished, whereas more nutrient-demanding species of less wet soils had increased, especially grasses. The cumulative number of species had declined by 50%, while mean plot species richness had decreased by 64.6%, mainly resulting from the pronounced loss of many herbs. A comparison of mean Ellenberg indicator values suggested that the plots had become drier, but also more base- and nutrient-rich, most likely triggered by the intensification of land use with drainage and fertilization as well as more frequent and earlier cutting. Our study reflects the dramatic loss of plant species diversity in wet grasslands over the past 60−70 years in areas not preserved and properly managed, and it documents the need for protecting remnants of these grasslands and for restoring wet grassland areas by re-wetting, nutrient removal and the transition to a less intensive land use.
Marginal associations, i.e. floristically impoverished associations at the margin of the distribution area of a higher syntaxon, form a problem in vegetation classification, because true character species are lacking. We propose a new approach for the classification of such marginal associations, making use of the notion of 'chorological tension zones'. In the absence of true character species, the species from other syntaxa of the same formation can be used as such. Our proposal is to use the species group from every formation-true class only once within every marginal alliance, to limit the number of possible marginal associations. This approach is illustrated in a classification of the retamoid thickets in the Netherlands. On the basis of a numerical-subjective classification of the relevant species in the scrub layer and the evaluation of relevant literature, we conclude that the broom and gorse thickets in the Netherlands can be assigned to the Cytisetea scopario-striati Rivas-Mart. 1974, which is represented by four associations, each of which is characterised by the species of other scrub classes. The Ulici europaei-Sarothamnion scoparii Doing ex Weber 1997 is represented by the Rubo plicati-Sarothamnetum scoparii Weber 1987 and the Crataego monogynae-Cytisetum scoparii R. Haveman, I. de Ronde & J.H.J. Schaminée ass. nov., the Ulici europaei-Cytision striati Rivas-Mart., Báscones, Díaz, Fern. Gonz. & Loidi 1991 by the Frangulo alni-Ulicetum europaei De Foucault 1988 and the Rubo ulmifolii-Ulicetum europaei J.-M. Géhu ex R. Haveman, I. de Ronde & J.H.J. Schaminée ass. nov. This classification is based on a restricted dataset though, and a revision, based on a larger dataset from a wider region has to prove the tenability of the classification.
Extensively managed pastures harbour rare and endangered species and have a decisive role in maintaining grassland biodiversity. Traditional herding of local robust cattle breeds is considered as a feasible tool for preserving these habitats. We studied the scale-dependent effects of grazing on the species richness and composition of three dry grassland types in the Great Hungarian Plain: Achilleo setaceae-Festucetum pseudovinae and Artemisio santonici-Festucetum pseudovinae alkaline grasslands, and Potentillo arenariae-Festucetum pseudovinae sand grassland. We asked the following questions: (1) Does extensive grazing have a scale-dependent effect on plant species richness of alkaline and sand grasslands? (2) How does grazing affect the proportion of specialists, generalists and weeds in the three grassland types? We sampled ten sites of each grassland type, including five extensively grazed and five non-grazed sites (altogether we had 30 sites). We used a series of nested plots each consisting of 10 plots from the size of 0.01 m² to 16 m². We revealed that grazing has contrasting effects in the three grassland types, and had a considerable effect on their species richness even at small scales. In both alkaline grassland types, total species richness was overall higher in grazed plots but it increased in a similar manner for both ungrazed and grazed habitats across plot sizes. Small-scale heterogeneity likely due to the uneven distribution of grazing, trampling and defecation together with mitigated rate of competition allowed more species to co-exist even at small scales in grazed alkaline grasslands. Grazing increased the richness of specialists, but likely due to the salt stress, establishment of weeds was hampered. Open gaps formed by trampling likely supported the establishment of several specialist species such as Plantago tenuiflora and Puccinellia limosa which are typical to open alkali grasslands. Contrary, in sand grasslands, we did not detect any effect of grazing on total species richness, likely due to the adverse effect of grazing on the species richness of specialists and weeds. In contrast with the former findings we detected significantly higher species richness in 0.01 m² and 0.0625 m² plots in the grazed sand grasslands, but found no differences at larger scales. Whilst species richness of specialists was significantly decreased, richness of weeds was increased by grazing. Decrease in the specialist species richness was likely due to the lack of their evolutionary adaptation to grazing. Degradation caused by grazing and trampling together with the propagule pressure from the neighbouring anthropogenic habitats resulted in an increased richness of weeds in the grazed sites.
The vast majority of European grasslands strongly depend on the regular removal of aboveground biomass by agricultural land use, mostly grazing or mowing or a combination of both. These specific management schemes have strong influence on plant diversity and vegetation composition, depending on their particular characteristics and their intensity. For example, the presence or absence of fertilization will favour some species over others, changing plant communities accordingly. Additionally, the farmer’s choice of a specific management scheme will also depend on the abiotic site conditions. This leads to a complex set of associated factors potentially affecting the structure and diversity of grasslands.
In this study, we compiled a unique dataset of 169 differently managed grasslands (in total 202 plots), which were sampled in five regions across Germany. For each plot, we documented management characteristics, measured plant diversity and functional group composition, recorded endangered species according to red lists, and calculated Ellenberg indicator values. We assessed patterns in vegetation composition and diversity in relation to the particular management scheme, which was categorized as meadow, meadow with autumn or winter grazing (with mowing as predominant management), mown pasture (where mowing and grazing are used at roughly equal intensity), seasonal pasture (with grazing as predominant management) and year-round pasture.
Our study showed that grasslands of different management schemes significantly differed in diversity, structure and functional composition. However, it also became obvious that vegetation composition was not strictly distinguished by management alone. Local and regional characteristics such as soil conditions, size of the grassland species pool or land-use history, often played a more prominent role than land use alone. Assumingly, the interplay of those local and regional characteristics with the proportion of grazing and mowing at a particular site inhibit clear differences among our predefined management schemes. Nevertheless, species richness was the lowest in year-round pastures, moderate in meadows and highest in seasonal pastures. In contrast, year-round pastures harboured the highest mean numbers of endangered species. The dependency of a certain management scheme on site-specific environmental factors such as soil fertility, further complicated the clear separation of management effects from those of the environmental background. In summary, modern grassland management strongly shaped grassland vegetation, but today’s combination of different management practices complicated the assessment of specific land-use effects on plant diversity. Thus, neither mowing nor grazing turned out to be “the one and only” management for nature conservation. Although our results challenge long-term prognoses for future vegetation development under modern grassland management, we clearly showed that low-intensity management and the absence of fertilization promoted plant diversity, with higher values in pastures compared to meadows and mown pastures.
Die in Amerika heimische Kolumbianische Zwergwasserlinse (Wolffia columbiana) tritt neuerdings in Europa als Neophyt auf und konnte in Niedersachsen zum ersten Mal im Jahr 2016 nachgewiesen werden. Im Hintergrund stehen die für den Naturschutz relevanten Fragen, wie viele vermeintliche Vorkommen von Wolffia arrhiza in Wirklichkeit Wolffia columbiana repräsentieren und ob dieser Neophyt die heimische und gefährdete Art Wolffia arrhiza verdrängen kann.
Die Floristisch-soziologische Arbeitsgemeinschaft wurde am 13. August 1927 in Göttingen gegründet und besteht nun, mit einer Unterbrechung zwischen 1941 und 1948, seit 90 Jahren. In diesem Rückblick wird vor allem die Entwicklung nach dem 2. Weltkrieg näher dargestellt. Hauptkapitel sind Verein, Satzung und Vorstände, Mitgliederentwicklung, Jahrestagungen, Arbeitskurse und Workshops, die Publikation der Mitteilungen und von Tuexenia mit ihren Beiheften sowie der Synopsis der Pflanzengesellschaften Deutschlands. Insgesamt wird eine sehr erfolgreiche Entwicklung mit Konstanz wesentlicher, schon zu Beginn formulierter Ziele und dynamischen Anpassungen an neue Gegebenheiten festgestellt.
GrassVeg.DE – die neue kollaborative Vegetationsdatenbank für alle Offenlandhabitate Deutschlands
(2017)
Der Bericht stellt die neue kollaborative Vegetationsdatenbank GrassVeg.DE (EU-DE-020; http://bit.ly/2qgX208) vor, die Vegetationsaufnahmen von Grasländern und anderen nicht-aquatischen Offenlandhabitaten Deutschlands sammelt, um sie national und international für die vegetationsökologische Forschung zur Verfügung zu stellen. GrassVeg.DE trägt die Daten zum European Vegetation Archive (EVA) und künftig auch zur globalen Vegetationsdatenbank „sPlot“ bei. Datenlieferanten von GrassVeg.DE behalten volle Verfügungsgewalt über ihre Daten und werden Mitglied des GrassVeg.DE-Konsortiums. Dadurch profitieren sie durch Co-Autorenschaften und Zitate von ihren Beiträgen und erlangen zugleich die Möglichkeit, selbst Projekte zu beantragen, die GrassVeg.DE- oder EVA-Daten nutzen. Die schnell wachsende GrassVeg.DE-Datenbank umfasste im Juli 2017 3.181 Vegetationsaufnahmen aus acht deutschen Bundesländern. Perspektivisch kann GrassVeg.DE dazu beitragen, eine konsistente Neuklassifikation der Graslandvegetationstypen Deutschlands im Rahmen der Synopsis der Pflanzengesellschaften Deutschlands zu ermöglichen. Wir schließen den Beitrag mit einem Aufruf, eigene und aus der Literatur digitalisierte Vegetationsaufnahmen zu GrassVeg.DE beizutragen.
Seit 12 Jahren werden von Mitgliedern der Eurasian Dry Grassland Group (EDGG) und deren Vorgängerorganisationen Grasland-Sonderteile in Tuexenia herausgegeben. Der diesjährige Sonderteil enthält fünf Artikel, die das Grasland verschiedener mitteleuropäischer Länder mit unterschiedlichen Zielen untersuchen. Der erste Artikel untersucht Auswirkungen von Weide und Mahd auf die Diversität des Graslands in Deutschland in Abhängigkeit von verschiedenen Umweltfaktoren, der zweite die Auswirkung kleiner Büsche auf den Artenreichtum von Gefäßpflanzen in beweideten Wiesensteppen in Ungarn. Der dritte Artikel fragt, ob sich ungarische Sandtrockenrasen mit Festuca vaginata von solchen mit F. pseudovaginata in ihrer Vegetation und ihren Standortsbedingungen unterscheiden; die letztere war erst kürzlich beschrieben worden. Der vierte Artikel modelliert Auswirkungen des Klimawandels auf geschützte Graslandbestände in Serbien und deren Arten während schließlich der fünfte Artikel die Initiative einer neuen Datenbank des deutschen Graslands (GrassVeg.DE) vorstellt und dazu aufruft, sich daran zu beteiligen. Insgesamt haben zu diesem 12. Grasland-Sonderteil 41 Autoren aus fünf Ländern (Dänemark, Deutschland, Italien, Schweiz, Serbien und Ungarn) beigetragen.
Ants were shown to be significant pollinators of two orchid species in the alpine zone of the Alps. Repeated observations from several localities confirm the ant Formica lemani as pollinator of Chamorchis alpina whereas Formica exsecta is reported here for the first time as pollinator of Dactylorhiza viridis. These findings appear of great interest, as significant ant pollination of orchids is unknown so far from any other region or habitat type in the Holarctic. This raises the question if there are specific adaptations. The observations do not provide suggestions to adaptations of the Formica ants for pollinating orchids – they simply followed their normal foraging behavior shown in any type of habitat. Yet, special adaptations are given by the two orchid species in developing pollination mechanisms more strongly involving ground-moving insects which are not inactivated by increased wind velocity and lower temperatures in the alpine zone. These are mainly beetles and ants. The pollination mechanisms and interactions with ants of both orchid species are described. Dactylorhiza viridis is outstanding among orchids in needing 20 to 30 minutes for the 90-degree forward bending of the pollinium after attachment to the insect’s forehead whereas the same process takes place between 15 seconds and 3 to 5 minutes in other orchids. Forward bending of pollinia is required for precise placement of the pollen at the stigmatic surface of another flower. The very long bending time is an adaptation to the longer presence time of ground-moving insects at the same plant and aims to reduce the frequency of geitonogamy (self-fertilization). The high frequency of ant pollination in these orchids is a consequence of the high activity density of aggressive, predatory worker ants leading to a displacement of other pollinators. Attempts of ants to remove the fresh, strongly adhesive pollinia from their foreheads failed and a single ant head could carry up to eight pollinia.
Intense direct and indirect human pressure has been imposed on grasslands throughout their range. Mostly due to the constant need for more food production or due to changes in environmental conditions, grasslands as habitats are expected to become highly endangered. The aim of this study was to estimate the grasslands’ ecological response to future climate and environmental changes. The study took place in three ecologically different grassland communities in three protected natural areas of Serbia (Southeastern Europe), following the same methodology. The study sites were: 1) Peštersko polje Special Nature Reserve (SNR), 2) Deliblato sands SNR (its southern part: Labudovo okno) and 3) Zasavica SNR.
Climate change was simulated for mean temperatures and precipitations using the Eta Belgrade University-Princeton Ocean Model (EBU-POM) climate model, for the A1B Intergovernmental Panel on Climate Change (IPCC) emission scenario covering the 1951–2100 period and insolation and volumetric soil moisture content for the 1979–2100 period. Grassland vegetation was analysed at all three sites. One representative plant community per site was selected for further analysis and simulation of ecological changes. One plot was positioned inside each of the above-mentioned communities, all vascular plant species inside the plot were recorded, and soil samples were taken. Ecological Optima (EO) for moisture and temperature were calculated from modified Ellenberg’s plant indicator values of recorded species. The plants’ response to climate and environmental changes was simulated using the VSD+ model for the 2010–2100 period. The data obtained from the model were further analysed with Canonical Correspondence Analysis (CCA).
Overall results show that the temperature rise, along with the irregular precipitation at all three sites, will lead to a drop of the relative abundance of many native species in the period between 2040 and 2060. The low obtained Habitat Suitability Index for the future means that there will be either unfavourable environmental conditions for the development of grasslands, or the species we analysed were untypical. Cosmopolitans and xerothermic species will be more accustomed to the new conditions. Grasses will be the most resilient functional group according to our study. It may be concluded that the functional group of grasses will also play the leading role in future
grasslands at the studied sites.
Central European temperate forests are – with the exception of floodplain forests – relatively little invaded by alien plants. However, despite substantial recent progress, there is still a lack of using vege-tation plot data for analyzing spatio-temporal patterns of alien tree species invasions.
We calculated relevé-based metrics of tree species’ ecological preferences using 19,413 phytosociological forest relevés of the Austrian vegetation database. We focused on the five most widely distributed alien trees, i.e. two archaeophytes (Castanea sativa, Juglans regia) and three neophytes (Acer negundo, Ailanthus altissima, Robinia pseudoacacia). For each of these species we analyzed the mean cover in the tree layer and the occurrence in the herb and shrub layers in relevés colonized by adult trees as a measure for persistence. Further, we evaluated the intergenerational ecological plasticity (= the ability of young trees to grow under different site conditions than adults) for the tree species, and the mean relevé indicator values for light, nutrients, moisture and hemeroby. We then compared these alien and native tree species metrics.
We found that A. altissima and R. pseudoacacia build up high mean cover values in invaded forests, but this was not the case for the other alien trees. Thus, both species strongly affected forest communities of invaded sites. Similarly, the two species were common in the lower vegetation layers indicating recruitment under the canopy of adult conspecifics; this was facilitated by their ability to produce root suckers. Highest values of inter-generational ecological plasticity occurred in native pioneer trees and species of softwood floodplain forests, while alien trees had moderately high (A. negundo, A. altissima, J. regia) to low values (C. sativa, R. pseudoacacia). With the exception of C. sativa, all alien species showed high mean Ellenberg indicator values for light and nutrients, and were more common in sites with high hemeroby and high mean Ellenberg indicator values for temperature. Distinct from the ecological preferences of alien trees, and thus rarely invaded, were montane beech forests, coniferous mountain forests and forests at extremely dry sites, as well as swamp and bog forests dominated by willows and ash.
We conclude that relevé-based metrics of the behavior of alien tree species allow new insights into the spatio-temporal dynamics of invasion of woody species in forests. Future work should expand this approach, e.g., by considering the role of life history traits and actual site conditions.
The flora in the Caucasus Ecoregion is rich in economically important plants. While its value in terms of food crops and medicinal plants has recently been subject to scientific research, the ornamental value of many Caucasian plant species has not yet been fully recognized. In order to assess the ornamental value of the Caucasian flora, vegetation data from two mountainous study regions in Georgia (n = 958 species, mostly grassland vegetation) was compared with the product range of ornamental plants in Germany using an online plant shopping guide. Characterization of the 150 plant species listed in both databases revealed that 121 species are present in central Europe and 117 species are natives or archaeophytes in Germany. Thus, only few species are Caucasian endemics. Furthermore, a list of 79 potential ornamentals endemic to the Caucasus was compiled from the literature. In order to place them in context of the horticultural market, the species characteristics were examined. Following this, a critical discussion of the potentials and risks arising from trade with ornamental plants was carried out with regard to nature conservation, biological invasion control, genetic resource maintenance and socioeconomic significance.
Der Zwerg-Rohrkolben (Typha minima Funck ex Hoppe) ist eine charakteristische Pionierpflanze von alpinen Wildflusslandschaften. Seit den siebziger Jahren ist diese Kennart jedoch in Deutschland vollständig und in Österreich nahezu ausgestorben. Die anhaltenden Populationsrückgänge der Art sind wahrscheinlich das Ergebnis der weitverbreiteten Flussregulierung und des Kraftwerksbaus in Kombination mit den sehr speziellen Standortsansprüchen der Art. Dank den Anstrengungen von Wiederansiedlungsprogrammen befindet sich T. minima wieder an der Oberen Drau in Österreich. In dieser Publikation wird über die Keimung, das Wachstum, die Reproduktion und die Umweltpräferenzen von T. minima berichtet.
Die Keimungsexperimente von 2014 zeigten eine sehr niedrige mittlere Keimungsrate von 15,6% bei einem Schwankungsbereich von 0–90 %. Die Keimungsraten stiegen mit höheren Temperaturen, erhöhter Saatgutreife und kürzeren Saatgutlagerungszeiten. Nach der Saatgutlagerung von 480 Stunden wurde keine Keimung mehr beobachtet.
Beim FFH-Monitoring 2014 an der Oberen Drau wurden Zwerg-Rohrkolben-Keimlinge (Höhe < 5 cm) generell nur selten gefunden. Die vegetative Jungphase (Höhe > 15 cm, ausschließlich sterile Triebe) wies zumeist den höchsten Flächenanteil im Mittel von 62% auf. Typha minima bildete bis zu einem Alter von ca. 3 Jahren ausschließlich sterile Triebe aus. Ab einem Alter von ca. 9 Jahren wurden auch fertile Triebe mit Blütenständen ausgebildet, wobei deren Anzahl mit zunehmendem Alter sich tendenziell erhöhte. Die Analyse der Standortsfaktoren zeigte, dass T. minima auf eine hohe Bodenfeuchte im Mittel von 39 Vol-% angewiesen ist. Darüber hinaus war der Faktor Beschattung entscheidend. Erst ab einem Beschattungsgrad von 50% durch Weidengebüsche war eine Abnahme der Triebdichte von T. minima zu verzeichnen. Wir schließen daraus, dass T. minima-Populationen während der Keimungsphase extrem empfindlich sind und dass massive Habitatverluste überwiegend das Ergebnis der Flussregulation und der reduzierten Morphodynamik sind, die normalerweise geeignete offene Siedlungsräume für die Keimung des Zwerg-Rohrkolbens schaffen würde.
The view that tumors consist of a homogenous mass of clonal derived cells has dramatically changed in recent years. Tumors harbor an enormous heterogeneity of cells with distinct capabilities and functions. The heterogeneity originates from a differentiation hierarchy of tumor cells, similar to normal tissue organization of stem-cell driven organs, but also from clonal succession of subpopulations by randomly acquired genetic mutations and epigenetic changes. Both scenarios are certainly not mutually exclusive, and also stem and progenitor cells underlie mutational selection. Intratumoral heterogeneity is a major challenge for cancer treatment and disease monitoring. Functional studies revealed that not all tumor cells have the same ability to initiate tumor growth upon transplantation in receptive animal models. The tumorinitiating cells (TICs) were called cancer stem cells due to their similarities to normal tissue stem cells in their molecular and functional properties. They can renew themselves long-term and give rise to tumor cells lacking cancer stem cell properties. However, it is worth stressing here that TICs do not necessarily originate from stem cells, but may have regained stem cell properties. TICs caught major attention since they may provide important steps in the progression of malignant diseases, such as epithelial-to-mesenchymal transition, dissemination, long-term persistence, therapy resistance, and relapse of the disease. The prospective identification of TICs using distinct surface markers would allow their molecular and functional characterization, the design of detection methods for diagnosis and prognosis, and the development of targeted therapies against these detrimental cells. While functional evidence for the existence of TICs were provided for many tumor entities, their marker profile still remains largely undefined and controversial. ...
Purpose: To evaluate long-term outcome of three years and treatment patterns of patients suffering from severely drug-refractory epilepsy (SDRE).
Methods: This analysis was population-based and retrospective, with data collected from four million individuals insured by statutory German health insurance. ICD-10 codes for epilepsy (G40*) and intake of anticonvulsants were used to identify prevalent cases, which were then compared with a matched cohort drawn from the population at large. Insurance data were available from 2008 to 2013. Any patient who had been prescribed with at least four different antiepileptic drugs (AEDs) in an 18-month period was defined as an SDRE case.
Results: A total of 769 patients with SDRE were identified. Of these, 19% were children and adolescents; the overall mean age was 42.3 years, 45.4% were female and 54.6% male. An average of 2.7 AEDs per patient was prescribed during the first follow-up year. The AEDs most commonly prescribed were: levetiracetam (53.5%), lamotrigine (41.4%), valproate (41.3%), lacosamide (20.4%), and topiramate (17.8%). During 3-year follow-up, there was an annual rate of hospitalization in the range 42.7 to 55%, which was significantly higher than the 11.6–12.8% (p < 0.001) for the matched controls. Admissions to hospital because of epilepsy ranged between 1.7 and 1.9 per year, with an average duration for each epilepsy-caused hospitalization of 10–11.1 days. The number of comorbidities for SDRE patients was significantly increased compared with the matched controls: depression (28% against 10%), vascular disorders (22% against 5%), and injury rates were also higher (head 16% against 3%, trunk and limbs 16% against 8%). The 3-year mortality rate for SDRE patients was 14% against 2.1% in the matched cohort.
Conclusion: SDRE patients are treated with AED polytherapy for all of the 3-year follow-up period. They are hospitalized more frequently than the general population and show increased morbidity levels and a sevenfold increase in mortality rate over 3 years. Further examination is required of ways in which new approaches to treatment could lead to better outcomes in severely affected patients.
Background: CML presenting with a variant Philadelphia translocation, atypical BCR-ABL transcript, additional chromosomal aberrations, and evolving MDS is uncommon and therapeutically challenging. The prognostic significance of these genetic findings is uncertain, even as singular aberrations, with nearly no data on management and outcome when they coexist. MDS evolving during the course of CML may be either treatment-associated or an independently coexisting disease, and is generally considered to have an inferior prognosis. Tyrosine kinase inhibitors (TKI) directed against BCR-ABL are the mainstay of treatment for CML, whereas treatment modalities that may be utilized for MDS and CML include allogeneic stem cell transplant and – at least conceptually – hypomethylating agents.
Case report: Here, we describe the clinical course of such a patient, demonstrating that long-term combined treatment with dasatinib and azacitidine for coexisting CML and MDS is feasible and well tolerated, and may be capable of slowing disease progression. This combination therapy had no deleterious effect on subsequent potentially curative haploidentical bone marrow transplantation.
Conclusions: The different prognostic implications of this unusual case and new therapeutic options in CML are discussed, together with a review of the current literature on CML presenting with different types of genomic aberrations and the coincident development of MDS. Additionally, this case gives an example of long-term combined treatment of tyrosine kinase inhibitors and hypomethylating agents, which could be pioneering in CML treatment.
Cellular attachment plays a vital role in the differentiation of pheochromocytoma (PC12) cells. PC12 cells are noradrenergic clonal cells isolated from the adrenal medulla of Rattus norvegicus and studied extensively as they have the ability to differentiate into sympathetic neuron-like cells. The effect of several experimental parameters including (i) the concentration of nerve growth factor (NGF); (ii) substratum coatings, such as poly-L-lysine (PLL), fibronectin (Fn), and laminin (Lam); and (iii) double coatings composed of PLL/Lam and PLL/Fn on the differentiation process of PC12 cells were studied. Cell morphology was visualised using brightfield phase contrast microscopy, cellular metabolism and proliferation were quantified using a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, and the neurite outgrowth and axonal generation of the PC12 cells were evaluated using wide field fluorescence microscopy. It was found that double coatings of PLL/Lam and PLL/Fn supported robust adhesion and a two-fold enhanced neurite outgrowth of PC12 cells when treated with 100 ng/mL of NGF while exhibiting stable metabolic activity, leading to the accelerated generation of axons.
We present a dataset of free-viewing eye-movement recordings that contains more than 2.7 million fixation locations from 949 observers on more than 1000 images from different categories. This dataset aggregates and harmonizes data from 23 different studies conducted at the Institute of Cognitive Science at Osnabrück University and the University Medical Center in Hamburg-Eppendorf. Trained personnel recorded all studies under standard conditions with homogeneous equipment and parameter settings. All studies allowed for free eye-movements, and differed in the age range of participants (~7–80 years), stimulus sizes, stimulus modifications (phase scrambled, spatial filtering, mirrored), and stimuli categories (natural and urban scenes, web sites, fractal, pink-noise, and ambiguous artistic figures). The size and variability of viewing behavior within this dataset presents a strong opportunity for evaluating and comparing computational models of overt attention, and furthermore, for thoroughly quantifying strategies of viewing behavior. This also makes the dataset a good starting point for investigating whether viewing strategies change in patient groups.
Background: The Aedes (Stegomyia) albopictus subgroup includes 11 cryptic species of which Ae. albopictus is the most widely distributed. Its global expansion associated with a documented vector competence for several emerging arboviruses raise obvious concerns in the recently colonized regions. While several studies have provided important insights regarding medical importance of Ae. albopicus, the investigations of the other sibling species are scarce. In Asia, indigenous populations within the Ae. albopictus subgroup can be found in sympatry. In the present study, we aimed to describe and compare molecular, morphological and bacterial symbionts composition among sympatric individuals from the Ae. albopictus subgroup inhabiting a Vietnamese protected area.
Results: Based on morphological structure of the cibarial armarture, we identified a cryptic species in the forest park at Bù Gia Mập in the south-eastern region of Vietnam. Analysis of nuclear (ITS1-5.8S-ITS2) and mitochondrial (cox1, nad5) markers confirmed the divergence between the cryptic species and Ae. albopictus. Analysis of midgut bacterial microbiota revealed a strong similarity among the two species with a notable difference; contrary to Ae. albopictus, the cryptic species did not harbour any Wolbachia infection.
Conclusions: These results could reflect either a recent invasion of Wolbachia in Ae. albopictus or alternatively a loss of this symbiont in the cryptic species. We argue that neglected species of the Ae. albopictus subgroup are of main importance in order to estimate variation of host-symbionts interactions across evolution.
Ion channel gating is essential for cellular homeostasis and is tightly controlled. In some eukaryotic and most bacterial ligand-gated K+ channels, RCK domains regulate ion fluxes. Until now, a single regulatory mechanism has been proposed for all RCK-regulated channels, involving signal transduction from the RCK domain to the gating area. Here, we present an inactive ADP-bound structure of KtrAB from Vibrio alginolyticus, determined by cryo-electron microscopy, which, combined with EPR spectroscopy and molecular dynamics simulations, uncovers a novel regulatory mechanism for ligand-induced action at a distance. Exchange of activating ATP to inactivating ADP triggers short helical segments in the K+-translocating KtrB dimer to organize into two long helices that penetrate deeply into the regulatory RCK domains, thus connecting nucleotide-binding sites and ion gates. As KtrAB and its homolog TrkAH have been implicated as bacterial pathogenicity factors, the discovery of this functionally relevant inactive conformation may advance structure-guided drug development.
SR proteins function in nuclear pre-mRNA processing, mRNA export, and translation. To investigate their cellular dynamics, we developed a quantitative assay, which detects differences in nucleocytoplasmic shuttling among seven canonical SR protein family members. As expected, SRSF2 and SRSF5 shuttle poorly in HeLa cells but surprisingly display considerable shuttling in pluripotent murine P19 cells. Combining individual-resolution cross-linking and immunoprecipitation (iCLIP) and mass spectrometry, we show that elevated arginine methylation of SRSF5 and lower phosphorylation levels of cobound SRSF2 enhance shuttling of SRSF5 in P19 cells by modulating protein-protein and protein-RNA interactions. Moreover, SRSF5 is bound to pluripotency-specific transcripts such as Lin28a and Pou5f1/Oct4 in the cytoplasm. SRSF5 depletion reduces and overexpression increases their cytoplasmic mRNA levels, suggesting that enhanced mRNA export by SRSF5 is required for the expression of pluripotency factors. Remarkably, neural differentiation of P19 cells leads to dramatically reduced SRSF5 shuttling. Our findings indicate that posttranslational modification of SR proteins underlies the regulation of their mRNA export activities and distinguishes pluripotent from differentiated cells.