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Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3-chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases. The compound displayed a potent antiproliferative activity in an array of cultured cancer cell lines. The X-ray structure analyses of three members of the new compound class co-crystallized with CLK proteins corroborated a molecular binding mode predicted by docking studies.
Understanding the spatial and temporal dynamics of species assemblages is a main challenge in ecology. The mechanisms that shape species assemblages and their temporal fluctuations along tropical elevational gradients are particularly poorly understood. Here, we examined the spatio-temporal dynamics of bird assemblages along an elevational gradient in Ecuador. We conducted bird point counts at three elevations (1000, 2000 and 3000 m) on 18 1-ha plots and repeated the sampling eight times over two years (216 hours in total). For each plot, we obtained data of monthly temperatures and precipitation and recorded the overall resource availability (i.e., the sum of flower, fruit, and invertebrate resources). As expected, bird richness decreased from low to high elevations. Moreover, we found a significant decrease in bird abundance and richness and an increase in evenness between the most and least humid season at each of the three elevations. Climatic factors were more closely related to these temporal fluctuations than local resource availability. While temperature had significant positive effects on the abundance of birds at mid and high elevations, precipitation negatively affected bird abundance at low and mid elevations. Our study highlights that bird assemblages along tropical elevational gradients can show pronounced seasonal fluctuations. In particular, low temperatures and high precipitation seem to impose important constraints on birds. We conclude that potential changes in climate, due to global warming, are likely to affect the spatio-temporal dynamics of bird assemblages along tropical elevational gradients.
Background: Glaucoma is a neurodegenerative disease, leading to thinning of the retinal nerve fibre layer (RNFL). The exact influence of ocular, cardiovascular, morphometric, lifestyle and cognitive factors on RNFL thickness (RNFLT) is unknown and was analysed in a subgroup of the Gutenberg Health Study (GHS).
Methods: Global peripapillary RNFLT was measured in 3224 eyes of 1973 subjects (49% female) using spectral-domain optical coherence tomography (SD-OCT). The association of age, sex, ocular, cardiovascular, morphometric, lifestyle and cognitive factors on RNFLT was analysed using Pearson correlation coefficient and fitting a linear mixed model.
Results: In the univariable analysis highest correlations were found for axial length (r = -0.27), spherical equivalent (r = 0.24), and glaucoma (r = -0.15) (p<0.0001, respectively). Other significant correlations with RNFLT were found for age, sex, intraocular pressure, systemic hypertension and systolic blood pressure, previous eye surgery, cholesterol, homocysteine, history of coronary artery disease, history of myocardial infarction, apnoea, diabetes and alcohol intake, p<0.05, respectively. Body length, body weight, BMI, diastolic blood pressure, blood glucose, HbA1c, history of apoplexy, cognitive function, peripheral artery disease, tinnitus, migraine, nicotine intake, central corneal thickness, and pseudophakia were not significantly correlated with RNFLT. The regression model revealed a significant relationship between RNFLT and age in decades (p<0.02), spherical equivalent (p<0.0001), axial length (p<0.0001), glaucoma (p<0.0001), tinnitus (p = 0.04), apnoea (p = 0.047), homocysteine (p = 0.05) and alcohol intake >10g/d for women and >20g/d for men (p = 0.02). Glaucoma, apnoea, higher homocysteine, higher alcohol intake and higher axial length as well as age were related to decreased RNFLT while higher spherical equivalent or history for tinnitus were related to thicker RNFL.
Conclusion: RNFLT is related to age, ocular parameters and lifestyle factors. Considering these parameters in normative databases could improve the evaluation of peripapillary RNFLT. It is necessary to evaluate if a reduction of alcohol intake as well as the therapy of apnea or high homocysteine levels could positively influence RNFLT.
Respiratory syncytial virus (RSV) is a leading cause of severe lower respiratory tract infection in early childhood. Underlying pathomechanisms of elevated pulmonary morbidity in later infancy are largely unknown. We found that RSV‐infected H441 cells showed increased mRNA expression of connective tissue growth factor (CTGF), a key factor in airway remodeling. Additional dexamethasone treatment led to further elevated mRNA levels, indicating additive effects. Caffeine treatment prevented RSV‐mediated increase in CTGF mRNA. RSV may be involved in airway remodeling processes by increasing CTGF mRNA expression. Caffeine might abrogate these negative effects and thereby help to restore lung homeostasis.
Extracellular vesicles (EVs) are increasingly recognized as important mediators of intercellular communication. In this study, we aimed to further characterize the role of macrophage-derived EVs in immune responses against hepatitis C virus (HCV) and the potential of polyunsaturated fatty acids (PUFAs) to modulate this modality of innate immunity. To this end, EVs were isolated from interferon-stimulated macrophage cultures or from serum of patients with acute or chronic hepatitis C. EVs were characterized by electron microscopy, flow cytometry, RNA-sequencing, and Western blot analysis. The effect of EVs on replication of HCV was assessed in coculture models. Functional analyses were performed to assess the impact of PUFAs on EV-mediated antiviral immunity. We found that macrophages secreted various cytokines shortly after stimulation with type I and II IFN, which orchestrated a fast but short-lasting antiviral state. This rapid innate immune answer was followed by the production of macrophage-derived EVs, which induced a late, but long-lasting inhibitory effect on HCV replication. Of note, exposure of macrophages to PUFAs, which are important regulators of immune responses, dampened EV-mediated antiviral immune responses. Finally, EVs from patients with hepatitis C exhibited long-lasting antiviral activities during IFN therapy as well. The antiviral effect of EVs from Caucasian and Japanese patients differed, which may be explained by different nutritional uptake of PUFAs. In conclusion, our data indicate that macrophage-derived EVs mediate long-lasting inhibitory effects on HCV replication, which may bridge the time until efficient adaptive immune responses are established, and which can be blunted by PUFAs.
Background/Aims: Signaling of Gs protein-coupled receptors (GsPCRs) is accomplished by stimulation of adenylyl cyclase, causing an increase of the intracellular cAMP concentration, activation of the intracellular cAMP effectors protein kinase A (PKA) and Epac, and an efflux of cAMP, the function of which is still unclear.
Methods: Activation of adenylyl cyclase by GsPCR agonists or cholera toxin was monitored by measurement of the intracellular cAMP concentration by ELISA, anti-phospho-PKA substrate motif phosphorylation by immunoblotting, and an Epac-FRET assay in the presence and absence of adenosine receptor antagonists or ecto-nucleotide phosphodiesterase/pyrophosphatase2 (eNPP2) inhibitors. The production of AMP from cAMP by recombinant eNPP2 was measured by HPLC. Extracellular adenosine was determined by LC-MS/MS, extracellular ATP by luciferase and LC-MS/MS. The expression of eNPP isoenzymes 1-3 was examined by RT-PCR. The expression of multidrug resistance protein 4 was suppressed by siRNA.
Results: Here we show that the activation of GsPCRs and the GsPCRs-independent activation of Gs proteins and adenylyl cyclase by cholera toxin induce stimulation of cell surface adenosine receptors (A2A or A2B adenosine receptors). In PC12 cells stimulation of adenylyl cyclase by GsPCR or cholera toxin caused activation of A2A adenosine receptors by an autocrine signaling pathway involving cAMP efflux through multidrug resistance protein 4 and hydrolysis of released cAMP to AMP by eNPP2. In contrast, in PC3 cells cholera toxin- and GsPCR-induced stimulation of adenylyl cyclase resulted in the activation of A2B adenosine receptors.
Conclusion: Our findings show that stimulation of adenylyl cyclase causes a remarkable activation of cell surface adenosine receptors.
Endangered species of hosts are coupled with endangered species of parasites, which share the risk of co-extinction. Conservation efforts sometimes include breeding of rare species in captivity. Data on parasites of captive populations of endangered species is scarce and the ability of small numbers of captive host individuals to support the biodiversity of native parasites is limited. Examination of ectosymbionts of the critically endangered Philippine eagles and the endangered Mindanao Hawk-Eagle kept at the Philippine Eagle Center, Philippines, revealed three feather mite species despite regular treatment with insecticide powder. No other ectosymbiont taxa were detected. Studies in morphology and molecular phylogeny of these feather mites based on mitochondrial and nuclear DNA markers indicate that species found were typical for Accipitridae. Three new pterolichoid feather mite species (Acari: Pterolichoidea) were described from two species of eagles (Accipitriformes: Accipitridae) endemic to the Philippines: Hieracolichus philippinensis sp. n. (Gabuciniidae) and Pseudalloptinus pithecophagae sp. n. (Pterolichidae) from the Great Philippine Eagle Pithecophaga jefferyi Ogilvie-Grant, 1896, and Pseudogabucinia nisaeti sp. n. (Kramerellidae) from the Mindanao Hawk-Eagle Nisaetus pinskeri Gould, 1863. The presence of H. philippinensis on P. jefferyi supports the recent finding that the Great Philippine Eagle belongs to the lineage of serpent eagles (Circaetinae) rather than to the Harpy and other eagles.
Background: Molecular hydrogen (H2) is an attractive future energy carrier to replace fossil fuels. Biologically and sustainably produced H2 could contribute significantly to the future energy mix. However, biological H2 production methods are faced with multiple barriers including substrate cost, low production rates, and low yields. The C1 compound formate is a promising substrate for biological H2 production, as it can be produced itself from various sources including electrochemical reduction of CO2 or from synthesis gas. Many microbes that can produce H2 from formate have been isolated; however, in most cases H2 production rates cannot compete with other H2 production methods.
Results: We established a formate-based H2 production method utilizing the acetogenic bacterium Acetobacterium woodii. This organism can use formate as sole energy and carbon source and possesses a novel enzyme complex, the hydrogen-dependent CO2 reductase that catalyzes oxidation of formate to H2 and CO2. Cell suspensions reached specific formate-dependent H2 production rates of 71 mmol g protein −1 h−1 (30.5 mmol g CDW −1 h−1) and maximum volumetric H2 evolution rates of 79 mmol L−1 h−1. Using growing cells in a two-step closed batch fermentation, specific H2 production rates reached 66 mmol g CDW −1 h−1 with a volumetric H2 evolution rate of 7.9 mmol L−1 h−1. Acetate was the major side product that decreased the H2 yield. We demonstrate that inhibition of the energy metabolism by addition of a sodium ionophore is suitable to completely abolish acetate formation. Under these conditions, yields up to 1 mol H2 per mol formate were achieved. The same ionophore can be used in cultures utilizing formate as specific switch from a growing phase to a H2 production phase.
Conclusions: Acetobacterium woodii reached one of the highest formate-dependent specific H2 productivity rates at ambient temperatures reported so far for an organism without genetic modification and converted the substrate exclusively to H2. This makes this organism a very promising candidate for sustainable H2 production and, because of the reversibility of the A. woodii enzyme, also a candidate for reversible H2 storage.
Stress-induced cell surface expression of MHC class I-related glycoproteins of the MIC and ULBP families allows for immune recognition of dangerous “self cells” by human cytotoxic lymphocytes via the NKG2D receptor. With two MIC molecules (MICA and MICB) and six ULBP molecules (ULBP1–6), there are a total of eight human NKG2D ligands (NKG2DL). Since the discovery of the NKG2D–NKG2DL system, the cause for both redundancy and diversity of NKG2DL has been a major and ongoing matter of debate. NKG2DL diversity has been attributed, among others, to the selective pressure by viral immunoevasins, to diverse regulation of expression, to differential tissue expression as well as to variations in receptor interactions. Here, we critically review the current state of knowledge on the poorly studied human NKG2DL ULBP4. Summarizing available facts and previous studies, we picture ULBP4 as a peculiar ULBP family member distinct from other ULBP family members by various aspects. In addition, we provide novel experimental evidence suggesting that cellular processing gives rise to mature ULBP4 glycoproteins different to previous reports. Finally, we report on the proteolytic release of soluble ULBP4 and discuss these results in the light of known mechanisms for generation of soluble NKG2DL.
This article advances the argument that quality of democracy depends not only on the performance of democratic institutions but also on the dispositions of citizens. We make three contributions to the study of democratic quality. First, we develop a fine-grained, structured conceptualization of the three core dispositions (democratic commitments, political capacities, and political participation) that make up the citizen component of democratic quality. Second, we provide a more precise account of the notion of inter-component congruence or "fit" between the institutional and citizen components of democratic quality, distinguishing between static and dynamic forms of congruence. Third, drawing on cross-national data, we show the importance of taking levels of inter-dispositional consistency into account when measuring democratic quality.
Despite multidisciplinary local and systemic therapeutic approaches, the prognosis for most patients with brain metastases is still dismal. The role of adaptive and innate anti-tumor response including the Human Leukocyte Antigen (HLA) machinery of antigen presentation is still unclear. We present data on the HLA class II-chaperone molecule CD74 in brain metastases and its impact on the HLA peptidome complexity.
We analyzed CD74 and HLA class II expression on tumor cells in a subset of 236 human brain metastases, primary tumors and peripheral metastases of different entities in association with clinical data including overall survival. Additionally, we assessed whole DNA methylome profiles including CD74 promoter methylation and differential methylation in 21 brain metastases. We analyzed the effects of a siRNA mediated CD74 knockdown on HLA-expression and HLA peptidome composition in a brain metastatic melanoma cell line.
We observed that CD74 expression on tumor cells is a strong positive prognostic marker in brain metastasis patients and positively associated with tumor-infiltrating T-lymphocytes (TILs). Whole DNA methylome analysis suggested that CD74 tumor cell expression might be regulated epigenetically via CD74 promoter methylation. CD74high and TILhigh tumors displayed a differential DNA methylation pattern with highest enrichment scores for antigen processing and presentation. Furthermore, CD74 knockdown in vitro lead to a reduction of HLA class II peptidome complexity, while HLA class I peptidome remained unaffected.
In summary, our results demonstrate that a functional HLA class II processing machinery in brain metastatic tumor cells, reflected by a high expression of CD74 and a complex tumor cell HLA peptidome, seems to be crucial for better patient prognosis.
Rationale: With advances in contemporary radiotherapy techniques, and as cancer survival improves, severe isolated coronary ostial disease may develop many years following mediastinal radiotherapy, even in the absence of classical cardiovascular risk factors.
Patient concerns: We describe the case of a 73-year-old woman with previous chest radiotherapy for breast cancer who underwent coronary artery bypass graft surgery for severe bilateral coronary ostial lesions.
Diagnoses: Coronary angiography demonstrated severe, isolated bilateral coronary ostial lesions.
Interventions: The patient underwent urgent coronary artery bypass graft surgery to treat her critical coronary artery disease.
Outcomes: Intra-operatively, internal mammary arteries were not amenable to harvesting due to very dense mediastinal adhesions. Therefore, saphenous vein grafts were performed to the left anterior descending, distal left circumflex, obtuse marginal and distal right coronary arteries. The patient made a satisfactory in-hospital recovery, and was subsequently discharged back to her local hospital for rehabilitation.
Lessons: Patients successfully treated with mediastinal radiotherapy require careful long-term follow-up for the assessment of radiation-induced coronary artery disease. Importantly, mediastinal irradiation may preclude internal mammary artery utilization, and thus alter the strategy for surgical myocardial revascularization.
During the Holocene, North American ice sheet collapse and rapid sea-level rise reconnected the Black Sea with the global ocean. Rapid meltwater releases into the North Atlantic and associated climate change arguably slowed the pace of Neolithisation across southeastern Europe, originally hypothesized as a catastrophic flooding that fueled culturally-widespread deluge myths. However, we currently lack an independent record linking the timing of meltwater events, sea-level rise and environmental change with the timing of Neolithisation in southeastern Europe. Here, we present a sea surface salinity record from the Northern Aegean Sea indicative of two meltwater events at ~8.4 and ~7.6 kiloyears that can be directly linked to rapid declines in the establishment of Neolithic sites in southeast Europe. The meltwater events point to an increased outflow of low salinity water from the Black Sea driven by rapid sea level rise >1.4 m following freshwater outbursts from Lake Agassiz and the final decay of the Laurentide ice sheet. Our results shed new light on the link between catastrophic sea-level rise and the Neolithisation of southeastern Europe, and present a historical example of how coastal populations could have been impacted by future rapid sea-level rise.
We investigate whether and how the shift from discretionary forward-looking provisioning to the restrictive incurred loss approach under International Financial Reporting Standards (IFRS) in the European Union (EU) affects the cross-country comparability and predictive ability of loan loss allowances. Given bank supervisors’ keen interest in comparable and adequate loan loss allowances, we also examine the role of supervisors in determining financial statement effects around IFRS adoption. We find that the application of the incurred loss approach has led to more comparable loan loss allowances. However, some differences persist in countries where supervisors were reluctant to enforce the incurred loss approach. Our results also suggest that the predictive ability of loan loss allowances improved following IFRS adoption. Finally, in supplemental analyses we document that increased comparability of loan loss allowances is associated with the cross-country convergence of the risk sensitivity of bank leverage indicating an improvement in the effectiveness of market discipline in the EU.
Background: The Indonesian region of Aceh was the area most severely affected by the earthquake and tsunami of 26 December 2004. Department of Health data reveal an upward trend of dengue cases in Aceh since the events of the tsunami. Despite the increasing incidence of dengue in the region, there is limited understanding of dengue among the general population of Aceh. The aim of this study was to assess the knowledge, attitude, and practice (KAP) regarding dengue among the people of Aceh, Indonesia in order to design intervention strategies for an effective dengue prevention program.
Methods: A community-based cross-sectional study was conducted in Aceh between November 2014 and March 2015 with a total of 609 participants living in seven regencies and two municipalities. Information on the socio-demographic characteristics of participants and their KAP regarding dengue was collected using a pre-tested structured questionnaire. The KAP status (good vs. poor) of participants with different socio-demographic characteristics was compared using Chi Square-test, ANOVA or Fisher’s exact test as appropriate. Logistic regression analysis was used to determine the predictors of each KAP domain.
Results: We found that 45% of participants had good knowledge regarding dengue and only 32% had good attitudes and good dengue preventive practices. There was a significant positive correlation between knowledge and attitudes, knowledge and practice, and attitudes and practice. In addition, people who had good knowledge were 2.7 times more likely to have good attitudes, and people who had good attitudes were 2.2 times more likely to have good practices regarding dengue. The level of education, occupation, marital status, monthly income, socioeconomic status (SES) and living in the city were associated with the knowledge level. Occupation, SES, and having experienced dengue fever were associated with attitudes. Education, occupation, SES and type of residence were associated with preventive practices.
Conclusion: Our study suggests that dengue prevention programs are required to increase KAP levels regarding dengue in the communities of Aceh.
Genetic heterogeneity of primary lesion and metastasis in small intestine neuroendocrine tumors
(2018)
Data on intratumoral heterogeneity of small intestine neuroendocrine tumors (SI-NETs) and related liver metastasis are limited. The aim of this study was to characterize genetic heterogeneity of 5 patients with SI-NETs. Therefore, formalin-fixed, paraffin-embedded tissue samples of primary and metastatic lesions as well as benign liver of five patients with synchronously metastasized, well differentiated SI-NETs were analyzed with whole exome sequencing. For one patient, chip based 850k whole DNA methylome analysis was performed of primary and metastatic tumor tissue as well as control tissue. Thereby, 156 single nucleotide variants (SNVs) in 150 genes were identified and amount of mutations per sample ranged from 9–34 (mean 22). The degree of common (0–94%) and private mutations per sample was strongly varying (6–100%). In all patients, copy number variations (CNV) were found and the degree of intratumoral heterogeneity of CNVs corresponded to SNV analysis. DNA methylation analysis of a patient without common SNVs revealed a large overlap of common methylated CpG sites. In conclusion, SI-NET primary and metastatic lesions show a highly varying degree of intratumoral heterogeneity. Driver events might not be detectable with exome analysis only, and further comprehensive studies including whole genome and epigenetic analyses are warranted.
A recent CLOUD (Cosmics Leaving OUtdoor Droplets) chamber study showed that sulfuric acid and dimethylamine produce new aerosols very efficiently and yield particle formation rates that are compatible with boundary layer observations. These previously published new particle formation (NPF) rates are reanalyzed in the present study with an advanced method. The results show that the NPF rates at 1.7 nm are more than a factor of 10 faster than previously published due to earlier approximations in correcting particle measurements made at a larger detection threshold. The revised NPF rates agree almost perfectly with calculated rates from a kinetic aerosol model at different sizes (1.7 and 4.3 nm mobility diameter). In addition, modeled and measured size distributions show good agreement over a wide range of sizes (up to ca. 30 nm). Furthermore, the aerosol model is modified such that evaporation rates for some clusters can be taken into account; these evaporation rates were previously published from a flow tube study. Using this model, the findings from the present study and the flow tube experiment can be brought into good agreement for the high base-to-acid ratios (∼ 100) relevant for this study. This confirms that nucleation proceeds at rates that are compatible with collision-controlled (a.k.a. kinetically controlled) NPF for the conditions during the CLOUD7 experiment (278 K, 38 % relative humidity, sulfuric acid concentration between 1 × 106 and 3 × 107 cm−3, and dimethylamine mixing ratio of ∼ 40 pptv, i.e., 1 × 109 cm−3).
Mannitol is the major compatible solute, next to glutamate, synthesized by the opportunistic human pathogen Acinetobacter baumannii under low water activities. The key enzyme for mannitol biosynthesis, MtlD, was identified. MtlD is highly similar to the bifunctional mannitol‐1‐phosphate dehydrogenase/phosphatase from Acinetobacter baylyi. After deletion of the mtlD gene from A. baumannii ATCC 19606T cells no longer accumulated mannitol and growth was completely impaired at high salt. Addition of glycine betaine restored growth, demonstrating that mannitol is an important compatible solute in the human pathogen. MtlD was heterologously produced and purified. Enzyme activity was strictly salt dependent. Highest stimulation was reached at 600 mmol/L NaCl. Addition of different sodium as well as potassium salts restored activity, with highest stimulations up to 41 U/mg protein by sodium glutamate. In contrast, an increase in osmolarity by addition of sugars did not restore activity. Regulation of mannitol synthesis was also assayed at the transcriptional level. Reporter gene assays revealed that expression of mtlD is strongly dependent on high osmolarity, not discriminating between different salts or sugars. The presence of glycine betaine or its precursor choline repressed promoter activation. These data indicate a dual regulation of mannitol production in A. baumannii, at the transcriptional and the enzymatic level, depending on high osmolarity.
Spatial modelling of malaria cases associated with environmental factors in South Sumatra, Indonesia
(2018)
Background: Malaria, a parasitic infection, is a life-threatening disease in South Sumatra Province, Indonesia. This study aimed to investigate the spatial association between malaria occurrence and environmental risk factors.
Methods: The number of confirmed malaria cases was analysed for the year 2013 from the routine reporting of the Provincial Health Office of South Sumatra. The cases were spread over 436 out of 1613 villages. Six potential ecological predictors of malaria cases were analysed in the different regions using ordinary least square (OLS) and geographically weighted regression (GWR). The global pattern and spatial variability of associations between malaria cases and the selected potential ecological predictors was explored.
Results: The importance of different environmental and geographic parameters for malaria was shown at global and village-level in South Sumatra, Indonesia. The independent variables altitude, distance from forest, and rainfall in global OLS were significantly associated with malaria cases. However, as shown by GWR model and in line with recent reviews, the relationship between malaria and environmental factors in South Sumatra strongly varied spatially in different regions.
Conclusions: A more in-depth understanding of local ecological factors influencing malaria disease as shown in present study may not only be useful for developing sustainable regional malaria control programmes, but can also benefit malaria elimination efforts at village level.
The emerging relapsing fever spirochete Borrelia (B.) miyamotoi is transmitted by ixodid ticks and causes the so-called hard tick-borne relapsing fever or B. miyamotoi disease (BMD). More recently, we identified a surface-exposed molecule, CbiA exhibiting complement binding and inhibitory capacity and rendering spirochetes resistant to complement-mediated lysis. To gain deeper insight into the molecular principles of B. miyamotoi-host interaction, we examined CbiA as a plasmin(ogen) receptor that enables B. miyamotoi to interact with the serine protease plasmin(ogen). Recombinant CbiA was able to bind plasminogen in a dose-dependent fashion. Moreover, lysine residues appear to play a crucial role in the protein-protein interaction as binding of plasminogen was inhibited by the lysine analog tranexamic acid as well as increasing ionic strength. Of relevance, plasminogen bound to CbiA can be converted by urokinase-type plasminogen activator (uPa) to active plasmin which cleaved both, the chromogenic substrate S-2251 and its physiologic substrate fibrinogen. Concerning the involvement of specific amino acids in the interaction with plasminogen, lysine residues located at the C-terminus are frequently involved in the binding as reported for various other plasminogen-interacting proteins of Lyme disease spirochetes. Lysine residues located within the C-terminal domain were substituted with alanine to generate single, double, triple, and quadruple point mutants. However, binding of plasminogen to the mutated CbiA proteins was not affected, suggesting that lysine residues distant from the C-terminus might be involved in the interaction.
The quasi-two-dimensional organic charge-transfer salt κ -(BEDT-TTF) 2 Cu 2 (CN) 3 is one of the prime candidates for a quantum spin-liquid due the strong spin frustration of its anisotropic triangular lattice in combination with its proximity to the Mott transition. Despite intensive investigations of the material’s low-temperature properties, several important questions remain to be answered. Particularly puzzling are the 6 K anomaly and the enigmatic effects observed in magnetic fields. Here we report on low-temperature measurements of lattice effects which were shown to be particularly strongly pronounced in this material (R. S. Manna et al., Phys. Rev. Lett. 2010, 104, 016403)). A special focus of our study lies on sample-to-sample variations of these effects and their implications on the interpretation of experimental data. By investigating overall nine single crystals from two different batches, we can state that there are considerable differences in the size of the second-order phase transition anomaly around 6 K, varying within a factor of 3. In addition, we find field-induced anomalies giving rise to pronounced features in the sample length for two out of these nine crystals for temperatures T< 9 K. We tentatively assign the latter effects to B-induced magnetic clusters suspected to nucleate around crystal imperfections. These B-induced effects are absent for the crystals where the 6 K anomaly is most strongly pronounced. The large lattice effects observed at 6 K are consistent with proposed pairing instabilities of fermionic excitations breaking the lattice symmetry. The strong sample-to-sample variation in the size of the phase transition anomaly suggests that the conversion of the fermions to bosons at the instability is only partial and to some extent influenced by not yet identified sample-specific parameters.
Compact objects - black holes and neutron stars - are fascinating objects, not only for the astrophysicists, but for a wide range of researchers, including astronomers, theoretical physicists, particle and nuclear physicists, condensed matter physicists and arguably for the layman as well.
First theorized in the first part of the twentieth century, for a long time these objects have been considered just exotic ideas or mathematical curiosities. Pulsar were however detected in the late 1960s and readily identified as rotating, radiating neutron stars, while the first candidate black hole, Cygnus X-1, was observed in 1972. Since then the interest in these objects has steadily grown.
The reasons behind this interest are easily understood considering that compact object dwell at the intersection of many different areas of physics, and are ideal laboratories to explore the interplay between these areas.
Black holes, which are purely gravitational objects, are perfectly suited to study the nature of gravity, its manifestations such as gravitational waves, and the differences between various theories of gravity in the regime where they are expected to be most relevant, i.e. the strong field regime. However, just like any massive astrophysical object, black holes are interested by accretion phenomena, which are thought to be the power source of some very bright astrophysical emitters of electromagnetic signals, such as active galactic nuclei or X-ray binaries.
At the same time, black holes exist in a variety of different mass scales, from stellar mass to supermassive black holes billions of times heavier. The latter play a very important and yet not fully understood role in the formation and evolution of galaxies, as well as in shaping the large scale structure of the universe, making them relevant to cosmology as well.
Neutron stars share with black holes the characteristic of being gravitationally dominated systems; but because they are composed of baryon matter, they display a much richer behaviour. It has been realized early on that the matter in neutron star cores reaches extreme densities, exceeding the one in atomic nuclei. This means that neutron stars could provide invaluable information on the behaviour of matter in such extreme conditions (which are impossible to achieve in laboratory experiments), such as details of the nucleonic interaction, the properties of hyperons or of quark-gluon plasmas.
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Diploid transgenic organisms are either hemi- or homozygous. Genetic assays are, therefore, required to identify the genotype. Our AGameOfClones vector concept uses two clearly distinguishable transformation markers embedded in interweaved, but incompatible Lox site pairs. Cre-mediated recombination leads to hemizygous individuals that carry only one marker. In the following generation, heterozygous descendants are identified by the presence of both markers and produce homozygous progeny that are selected by the lack of one marker. We prove our concept in Tribolium castaneum by systematically creating multiple functional homozygous transgenic lines suitable for long-term fluorescence live imaging. Our approach saves resources and simplifies transgenic organism handling. Since the concept relies on the universal Cre-Lox system, it is expected to work in all diploid model organisms, for example, insects, zebrafish, rodents and plants. With appropriate adaptions, it can be used in knock-out assays to preselect homozygous individuals and thus minimize the number of wasted animals.
The mission of the Compressed Baryonic Matter (CBM) experiment is to investigate the phase diagram of strongly interacting matter in the region of high net-baryon densities and moderate temperatures. According to various transport models, matter densities of more than 5 times saturation density can be reached in collisions between gold nuclei at beam energies between 5 and 11 GeV per nucleon, which will be available at FAIR. The core detector of the CBM experiment is the Silicon Tracking System (STS), which is used to measure the tracks of up to 700 particles per collision with high efficiency (>95%) and good momentum resolution (<1.5%). The technological and experimental challenge is to realize a detector system with very low material budget, in order to reduce multiple scattering of the particles, and a free-streaming data readout chain, in order to achieve reaction rates up to 10 MHz together with an online event reconstruction and selection.
The STS comprises 8 tracking stations positioned between 30 cm and 100 cm downstream the target inside a magnetic field, covering polar emission angles up to 25 degrees. A station consists of vertical structures with increasing number (between 8 and 16, depending on station number), each structure carrying between 2 and 10 double-sided microstrip silicon sensors, which are connected through low-mass microcables to the readout electronics placed at the detector periphery outside the active detector area.
The work presented in this thesis focuses on the detector performance simulation and local hit pattern reconstruction in the STS. For efficient detector design and reconstruction performance, a reliable detector response model is of utmost importance. Within this work, a realistic detector response model was designed and implemented in the CBM software framework. The model includes non-uniform energy loss of an incident particle within a sensor, electric field of a planar p-n junction, Lorentz shift of the charge carriers, their diffusion, and the influence of parasitic capacitances. The developed model has been verified with experimental data from detector tests in a relativistic proton beam. Cluster size distributions at different beam incident angles are sensitive to charge sharing effects and were chosen as an observable for the verification. Taking into account parasitic capacitances further improves the agreement with measured data.
Using the developed detector response model, the cluster position finding algorithm was improved. For two-strip clusters, a new, unbiased algorithm has been developed, which gives smaller residuals than the Centre-Of-Gravity algorithm. For larger clusters, the head-tail algorithm is used as the default one. For an estimate of the track parameters, the Kalman Filter based track fit requires not only hit positions but their uncertainties as an input. A new analytic method to estimate the hit position errors has been designed in this work. It requires as input neither measured spatial resolution nor information about an incident particle track. The method includes all the sources of uncertainties independently, namely: the cluster position finding algorithm itself, the non-uniform energy loss of incident particles, the electronics noise, and the discretisation of charge in the readout chip.
The verification with simulations shows improvements in hit and track pull distributions as well as x²-distributions in comparison to the previous simple approach. The analytic method improves the track parameters reconstruction by 5-10%.
Several STS module prototypes have been tested in a relativistic proton beam. A signal to-noise ratio was obtained at the level of 10-15 for modules made of 30 cm long microcable and of either one or two 6.2 x 6.2 cm² CiS sensors.
First simulations have shown that this signal-to-noise ratio is sufficient to reach the required efficiency and momentum resolution. The high-radiation environment of CBM operation will deteriorate the sensor performance. Radiation hardness of sensors has been studied in the beam with sensors irradiated to 2 x 10[hoch 14] 1MeV [neq/cm²], twice the lifetime dose expected for CBM operation. Charge collection efficiency drops by 17-25%, and simultaneously noise levels increase 1.5-1.75 times. The simulations show that if all sensors in the STS setup are exposed to such a fluence uniformly, the track reconstruction efficiency drops from 95.5% to 93.2% and the momentum resolution degrades from 1.6% to 1.7%.
Rationale: Classic histology is the gold standard for vascular network imaging and analysis. The method however is laborious and prone to artefacts. Here, the suitability of ultramicroscopy (UM) and micro-computed tomography (CT) was studied to establish potential alternatives to histology.
Methods: The vasculature of murine organs (kidney, heart and atherosclerotic carotid arteries) was visualized using conventional 2D microscopy, 3D light sheet ultramicroscopy (UM) and micro-CT. Moreover, spheroid-based human endothelial cell vessel formation in mice was quantified. Fluorescently labeled Isolectin GS-IB4 A647 was used for in vivo labeling of vasculature for UM analysis, and analyses were performed ex vivo after sample preparation. For CT imaging, animals were perfused postmortem with radiopaque contrast agent.
Results: Using UM imaging, 3D vascular network information could be obtained in samples of animals receiving in vivo injection of the fluorescently labeled Isolectin GS-IB4. Resolution was sufficient to measure single endothelial cell integration into capillaries in the spheroid-based matrigel plug assay. Because of the selective staining of the endothelium, imaging of larger vessels yielded less favorable results. Using micro-CT or even nano-CT, imaging of capillaries was impossible due to insufficient X-ray absorption and thus insufficient signal-to-noise ratio. Identification of lumen in murine arteries using micro-CT was in contrast superior to UM.
Conclusion: UM and micro-CT are two complementary techniques. Whereas UM is ideal for imaging and especially quantifying capillary networks and arterioles, larger vascular structures are easier and faster to quantify and visualize using micro-CT. 3D information of both techniques is superior to 2D histology. UM and micro-CT together may open a new field of clinical pathology diagnosis.
Three fungi associated with living leaves of plants are new records for Panama: Annellophora phoenicis causing leaf spots of Cocos nucifera (Arecaceae), Cercospora corniculatae (C. apii s. lat.) on living leaves of Oxalis barrelieri (Oxalidaceae) with and without discoloration, and Sclerotium coffeicola on zonate leaf spots of Annona montana (Annonaceae) and Dioscorea alata (Dioscoreaceae). Some records of A. phoenicis and S. coffeicola relevant for known geographical distribution and available by literature are critically revised.
Background: The Asian tiger mosquito Aedes albopictus is an extremely invasive, globally distributed and medically important vector of various human and veterinary pathogens. In Germany, where this species was recently introduced, its establishment may become modulated by interspecific competition from autochthonous mosquito species, especially Culex pipiens (s.l.). While competitive superiority of Ae. albopictus to Cx. pipiens (s.l.) has been described elsewhere, it has not been assessed in the epidemiological conditions of Germany. The present study aimed to determine if such superiority exists under the physicochemical and microclimatic conditions typical for container habitats in Germany.
Methods: In a replacement series experiment, the larval and pupal responses of Ae. albopictus and Cx. pipiens (s.l.) (mortality, development time, growth) to interspecific interaction (five larval ratios) at (sub-)optimal temperatures (15, 20 and 25 °C) and differing food supply (3 and 6 mg animal-based food larva-1) were investigated using a randomized split-plot design. In addition to physicochemical measurements of the test media, natural physicochemical conditions were determined for comparative analyses in mosquito breeding sites across the Rhine-Main metropolitan region of Germany.
Results: Under the physicochemical and microclimatic conditions similar to the breeding sites of the Rhine-Main region, competitive superiority of Cx. pipiens (s.l.) to Ae. albopictus in terms of larval survival was more frequently observed than balanced coexistence. Food regime and multifactorial interactions, but not temperature alone, were controlling factors for interspecific competition. Larval food regime and the larval ratio of Ae. albopictus influenced the physicochemistry and algal growth at 15 °C, with increased Ae. albopictus mortality linked to a decreasing number of Scenedesmus, Oocystis and Anabaena algae.
Conclusions: Under the present environmental conditions, the spread of Ae. albopictus from isolated foci in Germany may generally be slowed by biotic interactions with the ubiquitous Cx. pipiens (s.l.) (and potentially other container-breeding mosquito species) and by limnic microalgae in microhabitats with high resource levels. Detailed knowledge of the context dependency in temperate mosquito ecology, and interrelations of physicochemistry and phycology may help to achieve a better understanding of the upcoming Ae. albopictus colonization processes in central and northern Europe.
Adipose-derived mesenchymal stem cells (ASCs) have crucial functions, but their roles in obesity are not well defined. We show here that ASCs from obese individuals have defective primary cilia, which are shortened and unable to properly respond to stimuli. Impaired cilia compromise ASC functionalities. Exposure to obesity-related hypoxia and cytokines shortens cilia of lean ASCs. Like obese ASCs, lean ASCs treated with interleukin-6 are deficient in the Hedgehog pathway, and their differentiation capability is associated with increased ciliary disassembly genes like AURKA. Interestingly, inhibition of Aurora A or its downstream target the histone deacetylase 6 rescues the cilium length and function of obese ASCs. This work highlights a mechanism whereby defective cilia render ASCs dysfunctional, resulting in diseased adipose tissue. Impaired cilia in ASCs may be a key event in the pathogenesis of obesity, and its correction might provide an alternative strategy for combating obesity and its associated diseases.
Chlorine and bromine atoms lead to catalytic depletion of ozone in the stratosphere. Therefore the use and production of ozone-depleting substances (ODSs) containing chlorine and bromine is regulated by the Montreal Protocol to protect the ozone layer. Equivalent effective stratospheric chlorine (EESC) has been adopted as an appropriate metric to describe the combined effects of chlorine and bromine released from halocarbons on stratospheric ozone. Here we revisit the concept of calculating EESC. We derive a refined formulation of EESC based on an advanced concept of ODS propagation into the stratosphere and reactive halogen release. A new transit time distribution is introduced in which the age spectrum for an inert tracer is weighted with the release function for inorganic halogen from the source gases. This distribution is termed the release time distribution. We show that a much better agreement with inorganic halogen loading from the chemistry transport model TOMCAT is achieved compared with using the current formulation. The refined formulation shows EESC levels in the year 1980 for the mid-latitude lower stratosphere, which are significantly lower than previously calculated. The year 1980 is commonly used as a benchmark to which EESC must return in order to reach significant progress towards halogen and ozone recovery. Assuming that – under otherwise unchanged conditions – the EESC value must return to the same level in order for ozone to fully recover, we show that it will take more than 10 years longer than estimated in this region of the stratosphere with the current method for calculation of EESC. We also present a range of sensitivity studies to investigate the effect of changes and uncertainties in the fractional release factors and in the assumptions on the shape of the release time distributions. We further discuss the value of EESC as a proxy for future evolution of inorganic halogen loading under changing atmospheric dynamics using simulations from the EMAC model. We show that while the expected changes in stratospheric transport lead to significant differences between EESC and modelled inorganic halogen loading at constant mean age, EESC is a reasonable proxy for modelled inorganic halogen on a constant pressure level.
Background: The risk for major depression and obesity is increased in adolescents and adults with attention-deficit / hyperactivity disorder (ADHD) and adolescent ADHD predicts adult depression and obesity. Non-pharmacological interventions to treat and prevent these co-morbidities are urgently needed. Bright light therapy (BLT) improves day–night rhythm and is an emerging therapy for major depression. Exercise intervention (EI) reduces obesity and improves depressive symptoms. To date, no randomized controlled trial (RCT) has been performed to establish feasibility and efficacy of these interventions targeting the prevention of co-morbid depression and obesity in ADHD. We hypothesize that the two manualized interventions in combination with mobile health-based monitoring and reinforcement will result in less depressive symptoms and obesity compared to treatment as usual in adolescents and young adults with ADHD.
Methods: This trial is a prospective, pilot phase-IIa, parallel-group RCT with three arms (two add-on treatment groups [BLT, EI] and one treatment as usual [TAU] control group). The primary outcome variable is change in the Inventory of Depressive Symptomatology total score (observer-blinded assessment) between baseline and ten weeks of intervention. This variable is analyzed with a mixed model for repeated measures approach investigating the treatment effect with respect to all three groups. A total of 330 participants with ADHD, aged 14 – < 30 years, will be screened at the four study centers. To establish effect sizes, the sample size was planned at the liberal significance level of α = 0.10 (two-sided) and the power of 1-β = 80% in order to find medium effects. Secondary outcomes measures including change in obesity, ADHD symptoms, general psychopathology, health-related quality of life, neurocognitive function, chronotype, and physical fitness are explored after the end of the intervention and at the 12-week follow-up.
Discussion: This is the first pilot RCT on the use of BLT and EI in combination with mobile health-based monitoring and reinforcement targeting the prevention of co-morbid depression and obesity in adolescents and young adults with ADHD. If at least medium effects can be established with regard to the prevention of depressive symptoms and obesity, a larger scale confirmatory phase-III trial may be warranted.
Trial registration: German Clinical Trials Register, DRKS00011666. Registered on 9 February 2017. ClinicalTrials.gov, NCT03371810. Registered on 13 December 2017.
Convection-permitting models (CPMs) have proven their usefulness in representing precipitation on a sub-daily scale. However, investigations on sub-hourly scales are still lacking, even though these are the scales for which showers exhibit the most variability. A Lagrangian approach is implemented here to evaluate the representation of showers in a CPM, using the limited-area climate model COSMO-CLM. This approach consists of tracking 5‑min precipitation fields to retrieve different features of showers (e.g., temporal pattern, horizontal speed, lifetime). In total, 312 cases are simulated at a resolution of 0.01 ° over Central Germany, and among these cases, 78 are evaluated against a radar dataset. The model is able to represent most observed features for different types of convective cells. In addition, the CPM reproduced well the observed relationship between the precipitation characteristics and temperature indicating that the COSMO-CLM model is sophisticated enough to represent the climatological features of showers.
Myomas, also known as fibroids, are a specific characteristic of the human species. No other primates develop fibroids. At a cellular level, myomas are benign hyperplastic lesions of uterine smooth muscle cells. There are interesting theoretical concepts that link the development of myomas in humans with the highly specific process of childbirth from an upright position and the resulting need for greatly increased “expulsive” forces during labor. Myomas might be the price our species pays for our bipedal and highly intelligent existence. Myomas affect, with some variability, all ethnic groups and approximately 50% of all women during their lifetime. While some remain asymptomatic, myomas can cause significant and sometimes life-threatening uterine bleeding, pain, infertility, and, in extreme cases, ureteral obstruction and death. Traditionally, over 50% of all hysterectomies were performed for fibroids, leading to a significant healthcare burden. In this article, we review the developments of the past 20 years with regard to multiple new treatment strategies that have evolved during this time.
We present a study of the influence of disorder on the Mott metal-insulator transition for the organic charge-transfer salt κ -(BEDT-TTF) 2 Cu[N(CN) 2 ]Cl. To this end, disorder was introduced into the system in a controlled way by exposing the single crystals to X-ray irradiation. The crystals were then fine-tuned across the Mott transition by the application of continuously controllable He-gas pressure at low temperatures. Measurements of the thermal expansion and resistance show that the first-order character of the Mott transition prevails for low irradiation doses achieved by irradiation times up to 100 h. For these crystals with a moderate degree of disorder, we find a first-order transition line which ends in a second-order critical endpoint, akin to the pristine crystals. Compared to the latter, however, we observe a significant reduction of both, the critical pressure pc and the critical temperature Tc . This result is consistent with the theoretically-predicted formation of a soft Coulomb gap in the presence of strong correlations and small disorder. Furthermore, we demonstrate, similar to the observation for the pristine sample, that the Mott transition after 50 h of irradiation is accompanied by sizable lattice effects, the critical behavior of which can be well described by mean-field theory. Our results demonstrate that the character of the Mott transition remains essentially unchanged at a low disorder level. However, after an irradiation time of 150 h, no clear signatures of a discontinuous metal-insulator transition could be revealed anymore. These results suggest that, above a certain disorder level, the metal-insulator transition becomes a smeared first-order transition with some residual hysteresis.
The continuous conversion of natural wildlife habitats into agricultural areas, as well as the fragmentation of the last wildlife refuges, is increasing the interface between people and wildlife. When wildlife negatively impacts on people and vice versa, we speak about human-wildlife conflicts (HWCs). This definition includes losses on both sides and takes into consideration the rooting of most of these conflicts between different groups of interest, such as advocates for nature conservation and economic groups. The centres of highest biodiversity are located in developing countries, which are also characterized by poverty. In African and Asian countries, people living in the vicinity of national parks and other conservation areas mostly receive only little support through the government or conservation organisations. Especially for those people who are dependent on agriculture, damage to fields and harvests can have catastrophic consequences. If the species causing damage is protected by national or even international law, the farmer is not allowed to use lethal methods, but has to approach the authority in charge. If this agency, however, cannot offer appropriate support, resentment, anger or even hate develops, and the support for wildlife conservation activities declines. For this reason, HWCs were declared as one of the most important conservation topics today, being particularly relevant for large and threatened species such as the African and Asian elephant, hippopotamus and the greater one-horned rhino, as well as for large predators. Up to today, no general assessment scheme has been recommended for damage caused by protected wildlife species.
In my study, HWCs in Asia and Africa are compared, focussing on all herbivorous species identified which damaged crops. For the French NGO Awely, des animaux et des hommes, I developed a detailed assessment scheme suitable for all terrestrial ecosystems, and any type of HWCs and any species (Chapter 2). This HWC assessment scheme was used in four different study areas located in two African countries (South Luangwa/Zambia (SL), Tarangire/Tanzania (TA)) and two Asian countries (Bardia/Nepal (BA) and Manas/India (MA)). This scheme ran for six consecutive years (2009 to 2014) for Zambia, Nepal and India and two years (2010 to 2011) for Tanzania. To carry out the assessments, I trained local HWC officers (Awely Red Caps) to assess HWCs by field observations (measurement of damage, identification of species through signs of presence, landscape attributes etc.) and interviews with aggrieved parties (socio economic data). Results of this assessment are presented in Chapters 2-4.
To determine whether elephants prefer or avoid specific crop species, two field experiments were carried out, one in SL and one in BA (Chapter 5 and 6). For this, two test plots were set up and damage by elephants (and other herbivores) were quantified.
Within this doctoral thesis, 3306 damage events of 7408 aggrieved parties were analysed. In three out of the four study areas (SL, BA, MA), elephants caused the highest number of damage events compared to all other wildlife species, however, in TA, most fields were damaged by zebra. Furthermore, the greater one-horned rhino, hippopotamus, wild boar, bushpig, deer and antelope, as well as primates, caused damage to fields and harvests. Damage to houses and other property were nearly exclusively caused by elephants.
With this doctoral thesis I was able to show that season, crop availability, type and the phenological stage of the crop played an important role for crop damaging behavior of herbivores (Chapter 2). Elephants especially damaged rice, maize and wheat and preferred all crop types in a mature stage of growth. In contrast, rhinos preferred wheat to rice and similar to antelope and deer, they preferred crops at earlier stages of growth, before ripening. Crop damage by wildlife species varied strongly in size; most damages fell below 40% of the total harvest per farmer, but in several cases (3 to 8% depending on the study area), harvests were completely destroyed. Interestingly, during times of low nutritional availability in the natural habitat (dry season), crop damages in all four study areas were significantly less than during other seasons.
In all four study areas, crop protection strategies, such as active guarding in the fields, chasing wildlife with noise or fire torches or erecting barriers, were used. In some cases protection strategies were combined. Analysis of data revealed that traditional protection strategies did not reduce the costs of damage (Chapter 3). In some cases, costs of damage, on protected fields were even higher than for unprotected fields. Only in MA did strategic and cohesive guarding significantly reduce crop damage by wildlife species.
Besides damage in the fields, elephants also caused damage to properties in the villages. In search for stored staple crops, they damaged houses, grain stores and kitchens. Such damage was analysed in three study areas (SL, BA, MA) (Chapter 4). Although property damage occurred less frequently compared to crop damage in the fields, the mean cost of this damage was found to be double in BA/MA and four times higher in SL, compared to the costs of crop damage in the fields. It is further remarkable that property damage significantly increased towards the dry season, when the harvest was brought into the villages.
The findings of this study underpin the assumption that wildlife herbivores, especially elephants, are lured to fields and crops because the highly nutritional food (crop) being readily available. Traditional crop protection is cost and labour intensive and does not reduce the costs of damage. For this reason, crop types, which are thought to be not consumed by elephants were systematically tested on their attractiveness in field experiments in SL and BA (Chapter 5 and 6). In SL, lemon grass, ginger and garlic were proven to be less attractive to African elephants than maize and in BA, basil, turmeric, chamomile, coriander, mint, citronella and lemon grass were found to be less attractive to Asian elephants than rice.
The results of this doctoral thesis are relevant for the management of wildlife conservation as they can lead to new approaches to the mitigation of HWCs in African and Asian countries. Finally, specific needs for more scientific research in this field have been identified.
Most of the elements in the universe are produced via charged-particle fusion reactions during the primordial nucleosynthesis and different stellar burning stages, as well as via neutron-capture reactions. Around 35 heavy, proton-rich isotopes are bypassed by those reaction paths, the p nuclei. A series of photo-disintegration reactions occurring in supernovae, called the γ process, was suggested as a mechanisms to produce the p nuclei. Numerical simulations of the γ process have been unable to reproduce the observed abundances of the light p isotopes. Recent models showed that a series of proton capture reactions could provide the observed abundances. Hence, the cross sections of the crucial capture reactions have to be measured in order to test those assumptions.
Radiative proton captures in addition to the γ-process could reproduce the observed abundance pattern. This thesis presents preparations of a proton capture measurement on the radioactive 91Nb in standard kinematics with a calorimetric 4π setup. The 91Nb(p,γ)92Mo reaction might be the key to explain the production of one of the most abundant p-nuclei, 92Mo. So far, no experimental data for this reaction is available.
We produced a sample of 91Nb, with a half-life of 680 yr, at the Physikalisch Technische Bundesanstalt in Braunschweig, Germany, by irradiating 92Mo with protons in the energy range of 12 – 20MeV. 91Nb was produced via the reaction 92Mo(p,2p)91Nb and via 92Mo(p,pn)91Mo, where 91Mo decays to 91Nb with a half-life of 15.5min. To predict the amount of produced 91Nb the cross section of 92Mo(p, 2p) was measured. It was found to be higher than the value given by theoretical calculations with TALYS. Finally, 91Nb was chemically separated from the molybdenum carried at Paul-Scherrer- Institut, Villigen, Switzerland.
In-beam total absorption cross-section measurement of the reaction 91Nb(p,γ)92Mo with 2 MeV protons at FRANZ is planed with the produced 91Nb. A 4π BaF2 detector consisting of 41 crystals will be used. During this experiment we will measure the sum energy and the multiplicity of each event. The freshly produced 91Nb constitutes only a minor component of the sample material. The sum energy and multiplicity are crucial to distinguish the desired 91Nb(p,γ) from all the other more dominant reactions. The expected multiplicity and the efficiency of the setup were carefully simulated with DICEBOX and GEANT4. It was possible to show that background reactions can be effectively suppressed. The most important background contributions could be identified and result from 92Mo(p,γ), 19F(p,γ), and 19F(p,α).
Regulation of the antiapoptotic protein cFLIP by the glucocorticoid Dexamethasone in ALL cells
(2018)
We recently reported that the Smac mimetic BV6 and glucocorticoids, e.g. Dexamethasone (Dexa), synergize to induce cell death in acute lymphoblastic leukemia (ALL) in vitro and in vivo. Here, we discover that this synergism involves Dexa-stimulated downregulation of cellular FLICE-like inhibitory protein (cFLIP) in ALL cells. Dexa rapidly decreases cFLIPL protein levels, which is further enhanced by addition of BV6. While attenuating the activation of non-canonical nuclear factor-kappaB (NF-κB) signaling by BV6, Dexa suppresses cFLIPL protein but not mRNA levels pointing to a transcription-independent downregulation of cFLIPL by Dexa. Analysis of protein degradation pathways indicates that Dexa causes cFLIPL depletion independently of proteasomal, lysosomal or caspase pathways, as inhibitors of the proteasome, lysosomal enzymes or caspases all failed to protect from Dexa-mediated loss of cFLIPL protein. Also, Dexa alone or in combination with BV6 does not affect overall activity of the proteasome. Importantly, overexpression of cFLIPL to an extent that is no longer subject to Dexa-imposed downregulation rescues Dexa/BV6-mediated cell death. Vice versa, knockdown of cFLIP increases BV6-mediated cell death, thus mimicking the effect of Dexa. Altogether, these data demonstrate that Dexa-mediated downregulation of cFLIPL protein promotes Dexa/BV6-mediated cell death, thereby providing novel insights into the synergistic antitumor activity of this combination treatment.
Although effective antibody-based vaccines have been developed against multiple viruses, such approaches have so far failed for the human immunodeficiency virus type 1 (HIV-1). Despite the success of anti-retroviral therapy (ART) that has turned HIV-1 infection into a chronic disease and has reduced the number of new infections worldwide, a vaccine against HIV-1 is still urgently needed. We discuss here the major reasons for the failure of “classical” vaccine approaches, which are mostly due to the biological properties of the virus itself. HIV-1 has developed multiple mechanisms of immune escape, which also account for vaccine failure. So far, no vaccine candidate has been able to induce broadly neutralizing antibodies (bnAbs) against primary patient viruses from different clades. However, such antibodies were identified in a subset of patients during chronic infection and were shown to protect from infection in animal models and to reduce viremia in first clinical trials. Their detailed characterization has guided structure-based reverse vaccinology approaches to design better HIV-1 envelope (Env) immunogens. Furthermore, conserved Env epitopes have been identified, which are promising candidates in view of clinical applications. Together with new vector-based technologies, considerable progress has been achieved in recent years towards the development of an effective antibody-based HIV-1 vaccine.
The mechanisms involved in malignant transformation of mature B and T lymphocytes are still poorly understood. In a previous study, we compared gene expression profiles of the tumor cells of Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) to their normal cellular counterparts and found the basic leucine zipper protein ATF-like 3 (BATF3) to be significantly upregulated in the tumor cells of both entities. To assess the oncogenic potential of BATF3 in lymphomagenesis and to dissect the molecular interactions of BATF3 in lymphoma cells, we retrovirally transduced murine mature T and B cells with a BATF3-encoding viral vector and transplanted each population into Rag1-deficient recipients. Intriguingly, BATF3-expressing B lymphocytes readily induced B-cell lymphomas after characteristic latencies, whereas T-cell transplanted animals remained healthy throughout the observation time. Further analyses revealed a germinal center B-cell-like phenotype of most BATF3-initiated lymphomas. In a multiple myeloma cell line, BATF3 inhibited BLIMP1 expression, potentially illuminating an oncogenic action of BATF3 in B-cell lymphomagenesis. In conclusion, BATF3 overexpression induces malignant transformation of mature B cells and might serve as a potential target in B-cell lymphoma treatment.
Titanium is a biocompatible material that is frequently used for making implantable medical devices. Nanoengineering of the surface is the common method for increasing material biocompatibility, and while the nanostructured materials are well-known to represent attractive substrata for eukaryotic cells, very little information has been documented about the interaction between mammalian cells and bactericidal nanostructured surfaces. In this study, we investigated the effect of bactericidal titanium nanostructures on PC12 cell attachment and differentiation—a cell line which has become a widely used in vitro model to study neuronal differentiation. The effects of the nanostructures on the cells were then compared to effects observed when the cells were placed in contact with non-structured titanium. It was found that bactericidal nanostructured surfaces enhanced the attachment of neuron-like cells. In addition, the PC12 cells were able to differentiate on nanostructured surfaces, while the cells on non-structured surfaces were not able to do so. These promising results demonstrate the potential application of bactericidal nanostructured surfaces in biomedical applications such as cochlear and neuronal implants.
A large body of evidence suggests that the 11+ warm-up programme is effective in preventing football-related musculoskeletal injuries. However, despite considerable efforts to promote and disseminate the programme, it is unclear as to whether team head coaches are familiar with the 11+ and how they rate its feasibility. The present study aimed to gather information on awareness and usage among German amateur level football coaches. A questionnaire was administered to 7893 individuals who were in charge of youth and adult non-professional teams. Descriptive and inferential statistics were used to analyse the obtained data. A total of 1223 coaches (16%) returned the questionnaire. There was no risk of a non-response bias (p>.05). At the time of the survey, nearly half of the participants (42.6%) knew the 11+. Among the coaches who were familiar with the programme, three of four reported applying it regularly (at least once per week). Holding a license (φ = .28, p < .0001), high competitive level (Cramer-V = .13, p = .007), and coaching a youth team (φ = .1, p = .001) were associated with usage of 11+. Feasibility and suitability of the 11+ were rated similarly by aware and unaware coaches. Although a substantial share of German amateur level coaches is familiar with the 11+, more than half of the surveyed participants did not know the programme. As the non-usage does not appear to stem from a lack of rated feasibility and suitability, existing communication strategies might need to be revised.
The structural diversity of terpenoids is limited by the isoprene rule which states that all primary terpene synthase products derive from methyl-branched building blocks with five carbon atoms. With this study we discover a broad spectrum of novel terpenoids with eleven carbon atoms as byproducts of bacterial 2-methylisoborneol or 2-methylenebornane synthases. Both enzymes use 2-methyl-GPP as substrate, which is synthesized from GPP by the action of a methyltransferase. We used E. coli strains that heterologously produce different C11-terpene synthases together with the GPP methyltransferase and the mevalonate pathway enzymes. With this de novo approach, 35 different C11-terpenes could be produced. In addition to eleven known compounds, it was possible to detect 24 novel C11-terpenes which have not yet been described as terpene synthase products. Four of them, 3,4-dimethylcumene, 2-methylborneol and the two diastereomers of 2-methylcitronellol could be identified. Furthermore, we showed that an E. coli strain expressing the GPP-methyltransferase can produce the C16-terpene 6-methylfarnesol which indicates the condensation of 2-methyl-GPP and IPP to 6-methyl-FPP by the E. coli FPP-synthase. Our study demonstrates the broad range of unusual terpenes accessible by expression of GPP-methyltransferases and C11-terpene synthases in E. coli and provides an extended mechanism for C11-terpene synthases.
Aims: Carotid intima media thickness (CIMT) predicts cardiovascular (CVD) events, but the predictive value of CIMT change is debated. We assessed the relation between CIMT change and events in individuals at high cardiovascular risk.
Methods and results: From 31 cohorts with two CIMT scans (total n = 89070) on average 3.6 years apart and clinical follow-up, subcohorts were drawn: (A) individuals with at least 3 cardiovascular risk factors without previous CVD events, (B) individuals with carotid plaques without previous CVD events, and (C) individuals with previous CVD events. Cox regression models were fit to estimate the hazard ratio (HR) of the combined endpoint (myocardial infarction, stroke or vascular death) per standard deviation (SD) of CIMT change, adjusted for CVD risk factors. These HRs were pooled across studies.
In groups A, B and C we observed 3483, 2845 and 1165 endpoint events, respectively. Average common CIMT was 0.79mm (SD 0.16mm), and annual common CIMT change was 0.01mm (SD 0.07mm), both in group A. The pooled HR per SD of annual common CIMT change (0.02 to 0.43mm) was 0.99 (95% confidence interval: 0.95–1.02) in group A, 0.98 (0.93–1.04) in group B, and 0.95 (0.89–1.04) in group C. The HR per SD of common CIMT (average of the first and the second CIMT scan, 0.09 to 0.75mm) was 1.15 (1.07–1.23) in group A, 1.13 (1.05–1.22) in group B, and 1.12 (1.05–1.20) in group C.
Conclusions: We confirm that common CIMT is associated with future CVD events in individuals at high risk. CIMT change does not relate to future event risk in high-risk individuals.
Empiric antibiotics are often used in combination with mechanical debridement to treat patients suffering from periodontitis and to eliminate disease-associated pathogens. Until now, only a few next generation sequencing 16S rDNA amplicon based publications with rather small sample sizes studied the effect of those interventions on the subgingival microbiome. Therefore, we studied subgingival samples of 89 patients with chronic periodontitis (solely non-smokers) before and two months after therapy. Forty-seven patients received mechanical periodontal therapy only, whereas 42 patients additionally received oral administered amoxicillin plus metronidazole (500 and 400 mg, respectively; 3x/day for 7 days). Samples were sequenced with Illumina MiSeq 300 base pairs paired end technology (V3 and V4 hypervariable regions of the 16S rDNA). Inter-group differences before and after therapy of clinical variables (percentage of sites with pocket depth ≥ 5mm, percentage of sites with bleeding on probing) and microbiome variables (diversity, richness, evenness, and dissimilarity) were calculated, a principal coordinate analysis (PCoA) was conducted, and differential abundance of agglomerated ribosomal sequence variants (aRSVs) classified on genus level was calculated using a negative binomial regression model. We found statistically noticeable decreased richness, and increased dissimilarity in the antibiotic, but not in the placebo group after therapy. The PCoA revealed a clear compositional separation of microbiomes after therapy in the antibiotic group, which could not be seen in the group receiving mechanical therapy only. This difference was even more pronounced on aRSV level. Here, adjunctive antibiotics were able to induce a microbiome shift by statistically noticeably reducing aRSVs belonging to genera containing disease-associated species, e.g., Porphyromonas, Tannerella, Treponema, and Aggregatibacter, and by noticeably increasing genera containing health-associated species. Mechanical therapy alone did not statistically noticeably affect any disease-associated taxa. Despite the difference in microbiome modulation both therapies improved the tested clinical parameters after two months. These results cast doubt on the relevance of the elimination and/or reduction of disease-associated taxa as a main goal of periodontal therapy.
After entorhinal deafferentiation of the hippocampal dentate gyrus a reinnervation of the denervated neurons by axon collaterals can be observed. This process takes place in a matter of weeks. However, the overall functional effect on the hippocampal network is still unclear.
In an effort to investigate this effect of axonal sprouting on the neuronal network of the dentate gyrus we compared the electrophysiological response of the dentate gyrus after electric stimulation in wild-type mice (WT mice) with a normal post-lesion sprouting, with genetically modified mice with an overexpression of the growth-protein CAP23 (cytoskeleton-associated protein 23). CAP23 overexpressing mice (CAP23tg mice) are known to have an enhanced axonal growth and sprouting after lesion.
The mice (both the WT as well as the CAP23tg mice) were deeply anesthetized and a lesion of the perforant path was induced stereotactically with a wire knife. After that the mice were permitted to survive for 4-6 weeks for partial reinnervation of the dentate gyrus before they were again operated and evoked potentials were measured (extracellular recordings of evoked potentials in the dentate gyrus). Non-lesioned litter-mate mice were taken as reference. The sprouting and the correct position of the electrodes was confirmed histologically.
For electrophysiological investigation we assessed laminar profiles and calculated a current-source density (CSD). In lesioned CAP23tg mice compared to lesioned WT mice this CSD-analysis revealed a significant enhancement of the current sink in the area of deafferentiation (outer molecular layer) and a significant excitation in the granule-cell layer.
Our results show that axonal sprouting seems to enhance the excitability of granule-cells. Thus, even if an enhanced axonal sprouting might accelerate the reinnervation of denervated dendrites after lesion, but it also leads to posttraumatic hyperexcitability of the neuronal network. In a therapeutic approach of fascilitating axonal sprouting this hyperexcitability has to be taken into consideration.
Objective: The present study aims to elucidate the state of gender equality in high-quality dermatological research by analysing the representation of female authorships from January 2008 to May 2017.
Design: Retrospective, descriptive study.
Setting: 113 189 male and female authorships from 23 373 research articles published in 23 dermatological Q1 journals were analysed with the aid of the Gendermetrics Platform.
Results: 43.0% of all authorships and 50.2% of the firstauthorships, 43.7% of the coauthorships and 33.1% of the last authorships are held by women. The corresponding female-to-male ORs are 1.41 (95% CI 1.37 to 1.45) for first authorships, 1.07 (95% CI 1.04 to 1.10) for coauthorships and 0.60 (95% CI 0.58 to 0.62) for last authorships. The annual growth rates are 1.74% overall and 1.45% for first authorships, 1.53% for coauthorships and 2.97% for last authorships. Women are slightly under-represented at prestigious authorships compared with men (Prestige Index=−0.11). The under-representation remains stable in highly competitive articles attracting the highest citation rates, namely, articles with many authors and articles that were published in highest-impact journals. Multiauthor articles with male key authors are only slightly more frequently cited than those with female key authors. Women publish slightly fewer papers compared with men (47.2% women hold 43.0% of the authorships). At the level of individual journals, there is a high degree of uniformity in gender-specific authorship odds. By contrast, distinct differences at country level were revealed. The prognosis for the next decades forecasts a consecutive harmonisation of authorship odds between the two genders.
Conclusions: In high-quality dermatological research, the integration of female scholars is advanced as compared with other medical disciplines. A gender gap consists mainly in the form of a career dichotomy, with many female early career researchers and few women in academic leadership positions. However, this gender gap has been narrowed in the last decade and will likely be further reduced in the future.
In the context of limited donor pool in cardiothoracic transplantation, utilization of organs from high risk donors, such as suicidal hanging donors, while ensuring safety, is under consideration. We sought to evaluate the outcomes of lung transplantations (LTx) that use organs from this group.
Between January 2011 and December 2015, 265 LTx were performed at our center. Twenty-two recipients received lungs from donors after suicidal hanging (group 1). The remaining 243 transplantations were used as a control (group 2). Analysis of recipient and donor characteristics as well as outcomes was performed.
No statistically significant difference was found in the donor characteristics between analyzed groups, except for higher incidence of cardiac arrest, younger age and smoking history of hanging donors (P < .001, P = .022 and P = .0042, respectively). Recipient preoperative and perioperative characteristics were comparable. Postoperatively in group 1 there was a higher incidence of extracorporeal life support (27.3 vs 9.1%, P = .019). There were no significant differences in chronic lung allograft dysfunction-free survival between group 1 and 2: 92.3 vs 94% at 1 year and 65.9 vs 75.5% at 3 years (P = .99). The estimated cumulative survival rate was also similar between groups: 68.2 vs 83.2% at 1 year and 68.2% versus 72% at 3 years (P = .3758).
Hanging as a donor cause of death is not associated with poor mid-term survival or chronic lung allograft dysfunction following transplantation. These results encourage assessment of lungs from hanging donors, and their consideration for transplantation.
This study aimed to appraise two quantitative magnetic resonance imaging techniques, T2* imaging and diffusion-weighted imaging (DWI), for the diagnosis of the intervertebral disc degeneration of the cervico-thoracic junction. Influence of specific factors and diagnostic accuracy of both techniques were particularly explored. Sixty-one volunteers with neck and upper back pain were recruited and evaluated with both T2* imaging and DWI. The Pfirrmann grade, T2* relaxation time and apparent diffusion coefficient (ADC) value of each disc between C7 and T3 were recorded. Stratified analyses were performed for different anatomic levels, genders, age ranges and Pfirrmann grades. The diagnostic accuracy of both techniques was investigated using the receiver operating characteristic (ROC) curves. No statistically significant difference of either T2* relaxation time or ADC value was detected between males and females. Both parameters decreased with the increasing age and Pfirrmann grade. The ROC curves showed the higher sensitivity and specificity for T2* imaging than DWI to quantitatively identify the disc degeneration. Particularly, T2* imaging allowed for a quantitative distinguishing the normal, mild and moderate disc degeneration from the severe degeneration, which was unable to accomplish with DWI. In conclusion, we demonstrated that T2* imaging possess a better accuracy than DWI to quantitatively diagnose the intervertebral disc degeneration at the cervico-thoracic junction.
Perception, particularly in the visual domain, is drastically influenced by rhythmic changes in ambient lighting conditions. Anticipation of daylight changes by the circadian system is critical for survival. However, the neural bases of time-of-day-dependent modulation in human perception are not yet understood. We used fMRI to study brain dynamics during resting-state and close-to-threshold visual perception repeatedly at six times of the day. Here we report that resting-state signal variance drops endogenously at times coinciding with dawn and dusk, notably in sensory cortices only. In parallel, perception-related signal variance in visual cortices decreases and correlates negatively with detection performance, identifying an anticipatory mechanism that compensates for the deteriorated visual signal quality at dawn and dusk. Generally, our findings imply that decreases in spontaneous neural activity improve close-to-threshold perception.
Reconstructing the evolution of baleen whales (Mysticeti) has been problematic because morphological and genetic analyses have produced different scenarios. This might be caused by genomic admixture that may have taken place among some rorquals. We present the genomes of six whales, including the blue whale (Balaenoptera musculus), to reconstruct a species tree of baleen whales and to identify phylogenetic conflicts. Evolutionary multilocus analyses of 34,192 genome fragments reveal a fast radiation of rorquals at 10.5 to 7.5 million years ago coinciding with oceanic circulation shifts. The evolutionarily enigmatic gray whale (Eschrichtius robustus) is placed among rorquals, and the blue whale genome shows a high degree of heterozygosity. The nearly equal frequency of conflicting gene trees suggests that speciation of rorqual evolution occurred under gene flow, which is best depicted by evolutionary networks. Especially in marine environments, sympatric speciation might be common; our results raise questions about how genetic divergence can be established.