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The outset of Joyce’s A Portrait of the Artist as a Young Man presents a stage of life and language that is commonly evoked and, at the same time, systematically avoided in autobiographies as well as theoretical approaches to language: infancy. This textual strategy refers back to Augustine’s Confessiones, one of the most canonical autobiographies, reading it as a mainstay for an unconventional hypothesis: Rather that understanding infancy as an early stage of, or even before, language, Joyce expounds that the condition called infancy – the openness for receiving language while being unable to master it – accompanies all speech, be it childlike or eloquent. The article analyses Joyce’s text as one instance of a general paradox of autobiographical writing: initial aphasia. Setting out with birth or infancy, autobiographical texts precede articulate discourse. In Joyce, this paradox appears as starting point for a poetical – rather than theoretical – thinking about language, and language acquisition.
While for centuries Greek tragedies were performed only intermittently (Flashar 1991; Foley 1999; Macintosh et al. 2005; Hall and Macintosh 2005), the 1960s saw an enormous growth internationally in the staging of ancient dramas, and between 1960 and today, more Greek tragedies have been performed than in the entire period from antiquity to 1960.1 The new interest in ancient tragedy corresponded with a fundamental crisis in Western culture, issuing from the Shoah and gradually forcing its way into consciousness. After World War II, and especially since the 1960s, the question of history needed to be reconsidered. With the increasing dissolution of tradition, the interval between antiquity and the present became an unresolved problem. At the same time, a teleological understanding, which sees history as something that can be planned and calculated, had to be considered as failed, since fascism and communism "in the name of history" had erected totalitarian systems. What then appeared in this historical void?
The website Sci-Hub provides access to scholarly literature via full text PDF downloads. The site enables users to access articles that would otherwise be paywalled. Since its creation in 2011, SciHub has grown rapidly in popularity. However, until now, the extent of Sci-Hub’s coverage was unclear. As of March 2017, we find that Sci-Hub’s database contains 68.9% of all 81.6 million scholarly articles, which rises to 85.2% for those published in toll access journals. Coverage varies by discipline, with 92.8% coverage of articles in chemistry journals compared to 76.3% for computer science. Coverage also varies by publisher, with the coverage of the largest publisher, Elsevier, at 97.3%. Our interactive browser at greenelab.github.io/scihub allows users to explore these findings in more detail. We find Sci-Hub preferentially covers popular, paywalled content, containing 96.2% of citations to toll access journals since 2015. For recently requested articles by Unpaywall users, oaDOI provided access to 48.8% whereas Sci-Hub contained 81.5%. Together, oaDOI and Sci-Hub covered 94.1%, demonstrating that gaps in Sci-Hub’s coverage, especially for open access articles, can be filled using licit services. For the first time, nearly all scholarly literature is available gratis to anyone with an Internet connection. Sci-Hub’s scope suggests the subscription publishing model is becoming unsustainable.
Both hemispheres contribute to motor control beyond the innervation of the contralateral alpha motoneurons. The left hemisphere has been associated with higher-order aspects of motor control like sequencing and temporal processing, the right hemisphere with the transformation of visual information to guide movements in space. In the visuomotor context, empirical evidence regarding the latter has been limited though the right hemisphere’s specialization for visuospatial processing is well-documented in perceptual tasks. This study operationalized temporal and spatial processing demands during visuomotor processing and investigated hemispheric asymmetries in neural activation during the unimanual control of a visual cursor by grip force. Functional asymmetries were investigated separately for visuomotor planning and online control during functional magnetic resonance imaging in 19 young, healthy, right-handed participants. The expected cursor movement was coded with different visual trajectories. During planning when spatial processing demands predominated, activity was right-lateralized in a hand-independent manner in the inferior temporal lobe, occipito-parietal border, and ventral premotor cortex. When temporal processing demands overweighed spatial demands, BOLD responses during planning were left-lateralized in the temporo-parietal junction. During online control of the cursor, right lateralization was not observed. Instead, left lateralization occurred in the intraparietal sulcus. Our results identify movement phase and spatiotemporal demands as important determinants of dynamic hemispheric asymmetries during visuomotor processing. We suggest that, within a bilateral visuomotor network, the right hemisphere exhibits a processing preference for planning global spatial movement features whereas the left hemisphere preferentially times local features of visual movement trajectories and adjusts movement online.
Southern African protected areas (PAs) harbour a great diversity of animals, which represent a large potential for wildlife tourism. In this region, global change is expected to result in vegetation changes, such as bush encroachment and increases in vegetation density. However, little is known on the influence of vegetation structure on wildlife tourists’ wildlife viewing experience and satisfaction. In this study, we collected data on vegetation structure and perceived mammal densities along 196 road transects (each 5 km long) and conducted a social survey with 651 questionnaires across four PAs in three Southern African countries. Our objectives were 1) to assess visitors’ attitude towards vegetation, 2) to test the influence of perceived mammal density and vegetation structure on the easiness to spot animals, and 3) on visitors’ satisfaction during their visit to PAs. Using a Boosted Regression Tree procedure, we found mostly negative non-linear relationships between vegetation density and wildlife tourists’ experience, and positive relationships between perceived mammal densities and wildlife tourists’ experience. In particular, wildlife tourists disliked road transects with high estimates of vegetation density. Similarly, the easiness to spot animals dropped at thresholds of high vegetation density and at perceived mammal densities lower than 46 individuals per road transect. Finally, tourists’ satisfaction declined linearly with vegetation density and dropped at mammal densities smaller than 26 individuals per transect. Our results suggest that vegetation density has important impacts on tourists’ wildlife viewing experience and satisfaction. Hence, the management of PAs in savannah landscapes should consider how tourists perceive these landscapes and their mammal diversity in order to maintain and develop a sustainable wildlife tourism.
Climate change indicators are tools to assess, visualize and communicate the impacts of climate change on species and communities. Indicators that can be applied to different taxa are particularly useful because they allow comparative analysis to identify which kinds of species are being more affected. A general prediction, supported by empirical data, is that the abundance of warm-adapted species should increase over time, relative to the cool-adapted ones within communities, under increasing ambient temperatures. The community temperature index (CTI) is a community weighted mean of species’ temperature preferences and has been used as an indicator to summarize this temporal shift. The CTI has the advantages of being a simple and generalizable indicator; however, a core problem is that temporal trends in the CTI may not only reflect changes in temperature. This is because species’ temperature preferences often covary with other species attributes, and these other attributes may affect species response to other environmental drivers. Here, we propose a novel model-based approach that separates the effects of temperature preference from the effects of other species attributes on species’ abundances and subsequently on the CTI. Using long-term population data of breeding birds in Denmark and demersal marine fish in the southeastern North Sea, we find differences in CTI trends with the original approach and our model-based approach, which may affect interpretation of climate change impacts. We suggest that our method can be used to test the robustness of CTI trends to the possible effects of other drivers of change, apart from climate change.
Expression of surfactant protein B is dependent on cell density in H441 lung epithelial cells
(2017)
Background: Expression of surfactant protein (SP)-B, which assures the structural stability of the pulmonary surfactant film, is influenced by various stimuli, including glucocorticoids; however, the role that cell-cell contact plays in SP-B transcription remains unknown. The aim of the current study was to investigate the impact of cell-cell contact on SP-B mRNA and mature SP-B expression in the lung epithelial cell line H441.
Methods: Different quantities of H441 cells per growth area were either left untreated or incubated with dexamethasone. The expression of SP-B, SP-B transcription factors, and tight junction proteins were determined by qPCR and immunoblotting. The influence of cell density on SP-B mRNA stability was investigated using the transcription inhibitor actinomycin D.
Results: SP-B mRNA and mature SP-B expression levels were significantly elevated in untreated and dexamethasone-treated H441 cells with increasing cell density. High cell density as a sole stimulus was found to barely have an impact on SP-B transcription factor and tight junction mRNA levels, while its stimulatory ability on SP-B mRNA expression could be mimicked using SP-B-negative cells. SP-B mRNA stability was significantly increased in high-density cells, but not by dexamethasone alone.
Conclusion: SP-B expression in H441 cells is dependent on cell-cell contact, which increases mRNA stability and thereby potentiates the glucocorticoid-mediated induction of transcription. Loss of cell integrity might contribute to reduced SP-B secretion in damaged lung cells via downregulation of SP-B transcription. Cell density-mediated effects should thus receive greater attention in future cell culture-based research.
The mfl-riboswitch is a transcriptional off-switch, which down-regulates expression of subunit ß of ribonucleotide reductase in Mesoplasma florum upon 2´-deoxyguanosine binding. We characterized binding of 2´-deoxyguanosine to the mfl-aptamer domain (WT aptamer) and a sequence-stabilized aptamer (MT aptamer) under in vitro and ‘in-cell-like’ conditions by isothermal titration calorimetry (ITC) and nuclear magnetic resonance (NMR) spectroscopy. ‘In-celllike’ environment was simulated by Bacillus subtilis cell extract, in which both aptamers remained sufficiently stable to detect the resonances of structural elements and ligand binding in 2D NMR experiments. Under ‘in-cell-like’-environment, (i) the WT aptamer bound the endogenous metabolite guanosine and (ii) 2´-deoxyguanosine efficiently displaced guanosine from the WT aptamer. In contrast, MT aptamer exhibited moderate binding to 2´-deoxyguanosine and weak binding to guanosine. NMR experiments indicated that binding of guanosine was not limited to the aptamer domain of the riboswitch but also the full-length mfl-riboswitch bound guanosine, impacting on the regulation efficiency of the riboswitch and hinting that, in addition to 2´-deoxyguanosine, guanosine plays a role in riboswitch function in vivo. Reporter gene assays in B. subtilis demonstrated the regulation capacity of the WT aptamer, whereas the MT aptamer with lower affinity to 2´ -deoxyguanosine was not able to regulate gene expression.
Molecular detection of Bartonella henselae in 11 Ixodes ricinus ticks extracted from a single cat
(2017)
Background: Bartonella henselae is a highly prevalent, vector-borne pathogen. Transmission to humans and animals by ticks is discussed controversially. Here, we present a case report, where eleven Ixodes ricinus ticks all harbouring B. henselae DNA were removed from one single cat.
Results: The first feeding tick was tested positive for B. henselae DNA. The cat was also found to be seropositive for anti-B. henselae IgG antibodies (titer 1:640). Bartonella henselae was not cultivatable from cat blood. Ten more feeding ticks removed 7 months later contained also B. henselae DNA. Sequence analysis of the 16SrDNA and the 16S-23S internal transcribed spacer (ITS) region revealed 100% sequence homology between all ticks. Bartonella adhesin A (badA) and VirB/VirD4 type IV secretion system (virB) DNA were also detected in all ticks.
Conclusions: Our results indicate that cats may serve as a reservoir for adult ticks to acquire B. henselae. Whether this observation implies an increased threat for human and animal health needs to be resolved.
Background: Hereditary angioedema (HAE) is a rare genetic disease causing unpredictable and potentially life-threatening subcutaneous and submucosal edematous attacks. Cinryze® (Shire ViroPharma Inc., Lexington, MA, USA), a nanofiltered C1 inhibitor (C1-INH), is approved in Europe for the treatment, preprocedure prevention, and routine prophylaxis of HAE attacks, and for the routine prophylaxis of attacks in the USA. This phase 3 study assessed the safety and efficacy of 2 C1-INH doses in preventing attacks in children aged 6-11 years. Methods: A randomized single-blind crossover study was initiated in March 2014. Results for the first 6 patients completing the study are reported here. After a 12-week qualifying observation period, patients were randomly assigned to 1 of 2 C1-INH doses, 500 or 1,000 U, every 3-4 days for 12 weeks and crossed over to the alternative dose for a second 12-week period. The primary efficacy endpoint was the number of angioedema attacks per month. Results: Six females with HAE type I and a median age of 10.5 years received 2 doses of C1-INH (500 and 1,000 U). The mean (SD) difference in the number of monthly angioedema attacks between the baseline observation period and the treatment period was -1.89 (1.31) with 500 U and -1.89 (1.11) with 1,000 U. During the treatment periods, cumulative attack severity, cumulative daily severity, and the number of attacks needing acute treatment were lower. No serious adverse events or study drug discontinuations occurred. Conclusions: Interim findings from this study indicate that routine prevention with intravenous administration of C1-INH is efficacious, safe, and well tolerated in children ≥6 years of age.
Background: The challenges of delivering interventions for pregnant smokers have been poorly documented. Also, the process of promoting a physical activity intervention for pregnant smokers has not been previously recorded. This study describes the experiences of researchers conducting a randomised controlled trial of physical activity as an aid to smoking cessation during pregnancy and explores how the effectiveness of future interventions could be improved.
Methods: Two focus groups, with independent facilitators, were conducted with six researche rs who had enrolled pregnant smokers in the LEAP trial, provided the interventions, and administered the research measures. Topics included recruitment, retention and how the physical activity intervention for pregnant smokers was delivered and how it was adapted when necessary to suit the women. The focus groups were audio-recorded, transcribed verbatim and subjected to thematic analysis.
Results: Five themes emerged related to barriers or enablers to intervention delivery: (1) nature of the intervention;
(2) personal characteristics of trial participants; (3) practical issues; (4) researchers’ engagement with participants; (5)
training and support needs. Researchers perceived that participants may have been deterred by the intensive and generic nature of the intervention and the need to simultaneously quit smoking and increase physical activity. Women also appeared hampered by pregnancy ailments, social deprivation, and poor mental health. Researchers observed that their status as health professionals was valued by participants but it was challenging to maintain contact with participants. Training and support needs were identified for dealing with pregnant teenagers, participants’ friends and family, and post-natal return to smoking.
Conclusions: Future exercise interventions for smoking cessation in pregnancy may benefit by increased tailoring of the intervention to the characteristics of the women, including their psychological profile, socio-economic background, pregnancy ailments and exercise preferences. Delivering an effective physical activity intervention for smoking cessation in pregnancy may require more comprehensive training for those delivering the intervention, particularly with regard to dealing with teenage smokers and smokers’ friends and family, as well as for avoiding post-natal return to smoking.
Die Abbauzone Lagoinhos im römischen territorium metallorum Três Minas / Jales (Nordportugal)
(2017)
Over the last decades agroforestry parklands in Burkina Faso have come under increasing demographic as well as climatic pressures, which are threatening indigenous tree species that contribute substantially to income generation and nutrition in rural households. Analyzing the threats as well as the species vulnerability to them is fundamental for priority setting in conservation planning. Guided by literature and local experts we selected 16 important food tree species (Acacia macrostachya, Acacia senegal, Adansonia digitata, Annona senegalensis, Balanites aegyptiaca, Bombax costatum, Boscia senegalensis, Detarium microcarpum, Lannea microcarpa, Parkia biglobosa, Sclerocarya birrea, Strychnos spinosa, Tamarindus indica, Vitellaria paradoxa, Ximenia americana, Ziziphus mauritiana) and six key threats to them (overexploitation, overgrazing, fire, cotton production, mining and climate change). We developed a species-specific and spatially explicit approach combining freely accessible datasets, species distribution models (SDMs), climate models and expert survey results to predict, at fine scale, where these threats are likely to have the greatest impact. We find that all species face serious threats throughout much of their distribution in Burkina Faso and that climate change is predicted to be the most prevalent threat in the long term, whereas overexploitation and cotton production are the most important short-term threats. Tree populations growing in areas designated as ‘highly threatened’ due to climate change should be used as seed sources for ex situ conservation and planting in areas where future climate is predicting suitable habitats. Assisted regeneration is suggested for populations in areas where suitable habitat under future climate conditions coincides with high threat levels due to short-term threats. In the case of Vitellaria paradoxa, we suggest collecting seed along the northern margins of its distribution and considering assisted regeneration in the central part where the current threat level is high due to overexploitation. In the same way, population-specific recommendations can be derived from the individual and combined threat maps of the other 15 food tree species. The approach can be easily transferred to other countries and can be used to analyze general and species specific threats at finer and more local as well as at broader (continental) scales in order to plan more selective and efficient conservation actions in time. The concept can be applied anywhere as long as appropriate spatial data are available as well as knowledgeable experts.
Benzene is a ubiquitous, volatile pollutant present at high concentrations in toxins (e.g. tobacco smoke) known to increase cardiovascular disease (CVD) risk. Despite its prevalence, the cardiovascular effects of benzene have rarely been studied. Hence, we examined whether exposure to benzene is associated with increased CVD risk. The effects of benzene exposure in mice were assessed by direct inhalation, while the effects of benzene exposure in humans was assessed in 210 individuals with mild to high CVD risk by measuring urinary levels of the benzene metabolite trans,trans-muconic acid (t,t-MA). Generalized linear models were used to assess the association between benzene exposure and CVD risk. Mice inhaling volatile benzene had significantly reduced levels of circulating angiogenic cells (Flk-1+/Sca-1+) as well as an increased levels of plasma low-density lipoprotein (LDL) compared with control mice breathing filtered air. In the human cohort, urinary levels of t,t-MA were inversely associated several populations of circulating angiogenic cells (CD31+/34+/45+, CD31+/34+/45+/AC133–, CD34+/45+/AC133+). Although t,t-MA was not associated with plasma markers of inflammation or thrombosis, t,t-MA levels were higher in smokers and in individuals with dyslipidemia. In smokers, t,t-MA levels were positively associated with urinary metabolites of nicotine (cotinine) and acrolein (3-hydroxymercapturic acid). Levels of t,t-MA were also associated with CVD risk as assessed using the Framingham Risk Score and this association was independent of smoking. Thus, benzene exposure is associated with increased CVD risk and deficits in circulating angiogenic cells in both smokers and non-smokers.
Ageing is a progressive decline of intrinsic physiological functions. We examined the impact of ageing on the ultrastructure and function of mitochondria in mouse and fruit flies (Drosophila melanogaster) by electron cryo-tomography and respirometry. We discovered distinct age-related changes in both model organisms. Mitochondrial function and ultrastructure are maintained in mouse heart, whereas subpopulations of mitochondria from mouse liver show age-related changes in membrane morphology. Subpopulations of mitochondria from young and old mouse kidney resemble those described for apoptosis. In aged flies, respiratory activity is compromised and the production of peroxide radicals is increased. In about 50% of mitochondria from old flies, the inner membrane organization breaks down. This establishes a clear link between inner membrane architecture and functional decline. Mitochondria were affected by ageing to very different extents, depending on the organism and possibly on the degree to which tissues within the same organism are protected against mitochondrial damage.
Lymphocyte function-associated antigen 1 (LFA-1) affinity and avidity changes have been assumed to mediate adhesion to intercellular adhesion molecule-1 for T-cell conjugation to dendritic cells (DC). Although the T-cell receptor (TCR) and LFA-1 can generate intracellular signals, the immune cell adaptor protein linker for the activation of T cells (LAT) couples the TCR to downstream events. Here, we show that LFA-1 can mediate both adhesion and de-adhesion, dependent on receptor clustering. Although increased affinity mediates adhesion, LFA-1 cross-linking induced the association and activation of the protein-tyrosine kinases FAK1/PYK1 that phosphorylated LAT selectively on a single Y-171 site for the binding to adaptor complex GRB-2-SKAP1. LAT-GRB2-SKAP1 complexes were distinct from canonical LAT-GADs-SLP-76 complexes. LFA-1 cross-linking increased the presence of LAT-GRB2-SKAP1 complexes relative to LAT-GADs-SLP-76 complexes. LFA-1-FAK1 decreased T-cell-dendritic cell (DC) dwell times dependent on LAT-Y171, leading to reduced DO11.10 T cell binding to DCs and proliferation to OVA peptide. Overall, our findings outline a new model for LFA-1 in which the integrin can mediate both adhesion and de-adhesion events dependent on receptor cross-linking.
Megasynthases are large multienzyme proteins that produce a plethora of important natural compounds by catalyzing the successive condensation and modification of precursor units. Within the class of megasynthases, polyketide synthases (PKS) are responsible for the production of a large spectrum of bioactive polyketides (PK), which have frequently found their way into therapeutic applications. Rational engineering approaches have been performed during the last 25 years that seek to employ the "assembly-line synthetic concept" of megasynthases in order to deliver new bioactive compounds. Here, we highlight PKS engineering strategies in the light of the newly emerging structural information on megasynthases, and argue that fatty acid synthases (FAS) are and will be valuable objects for further developing this field.
Background: Kyrgyzstan, where HIV is concentrated in prisons and driven by injection drug use, provides a prison-based methadone maintenance therapy program as well as abstinence-oriented therapeutic community based on the 12-step model called the “Clean Zone.” We aimed to qualitatively assess how prisoners navigate between these treatment options to understand the persistence of the Clean Zone despite a lack of evidence to support its effectiveness in treating opioid use disorders.
Methods: We conducted an analysis of policy documents and over 60 h of participant observation in February 2016, which included focus groups with a convenience sample of 20 therapeutic community staff members, 110 prisoners across three male and one female prisons, and qualitative interviews with two former Clean Zone participants. Field notes containing verbatim quotes from participants were analyzed through iterative reading and discussion to understand how participants generally perceive the program, barriers to entry and retention, and implications for future treatment within prisons.
Results: Our analyses discerned three themes: pride in the mission of the Clean Zone, idealism regarding addiction treatment outcomes against all odds, and the demonization of methadone.
Conclusion: Despite low enrollment and lack of an evidence base, the therapeutic community is buttressed by the strong support of the prison administration and its clients as an “ordered” alternative to what is seen as chaotic life outside of the Clean Zone. The lack of services for Clean Zone patients after release likely contributes to high rates of relapse to drug use. The Clean Zone would benefit from integration of stabilized methadone patients combined with a post-release program.
Previous studies detected an influence of urban characteristics on song traits in passerine birds, that is, song adjustments to ambient noise in urban areas. Several studies already described the effect of weather conditions on the behavior of birds, but not the effect on song traits. We investigate, if song trait variability changes along a continuous urbanity gradient in Frankfurt am Main, Germany. We examined, for the first time on a larger scale, the influence of weather on song parameters. We made song recordings of three common passerine species: the blue and great tit (Cyanistes caeruleus (Linnaeus, 1758) and Parus major Linnaeus, 1758) and the European blackbird (Turdus merula Linnaeus, 1758). We measured different song traits and performed statistical analyses and modeling on a variety of variables—among them urbanity and weather parameters. Remarkably, we found only few cases of a significant influence of urbanity parameters on song traits. The influence of weather parameters (air pressure, atmospheric humidity, air and soil temperatures) on song traits was highly significant. Birds in Frankfurt face high noise pollution and might show different adaptations to high noise levels. The song trait variability of the investigated species is affected more by weather conditions than by urban characteristics in Frankfurt. However, the three species react differently to specific weather parameters. Smaller species seem to be more affected by weather than larger species.
Despite the growth of Open Access, potentially illegally circumventing paywalls to access scholarly publications is becoming a more mainstream phenomenon. The web service Sci-Hub is amongst the biggest facilitators of this, offering free access to around 62 million publications. So far it is not well studied how and why its users are accessing publications through Sci-Hub. By utilizing the recently released corpus of Sci-Hub and comparing it to the data of ~28 million downloads done through the service, this study tries to address some of these questions. The comparative analysis shows that both the usage and complete corpus is largely made up of recently published articles, with users disproportionately favoring newer articles and 35% of downloaded articles being published after 2013. These results hint that embargo periods before publications become Open Access are frequently circumnavigated using Guerilla Open Access approaches like Sci-Hub. On a journal level, the downloads show a bias towards some scholarly disciplines, especially Chemistry, suggesting increased barriers to access for these. Comparing the use and corpus on a publisher level, it becomes clear that only 11% of publishers are highly requested in comparison to the baseline frequency, while 45% of all publishers are significantly less accessed than expected. Despite this, the oligopoly of publishers is even more remarkable on the level of content consumption, with 80% of all downloads being published through only 9 publishers. All of this suggests that Sci-Hub is used by different populations and for a number of different reasons, and that there is still a lack of access to the published scientific record. A further analysis of these openly available data resources will undoubtedly be valuable for the investigation of academic publishing.
Peer review of research articles is a core part of our scholarly communication system. In spite of its importance, the status and purpose of peer review is often contested. What is its role in our modern digital research and communications infrastructure? Does it perform to the high standards with which it is generally regarded? Studies of peer review have shown that it is prone to bias and abuse in numerous dimensions, frequently unreliable, and can fail to detect even fraudulent research. With the advent of Web technologies, we are now witnessing a phase of innovation and experimentation in our approaches to peer review. These developments prompted us to examine emerging models of peer review from a range of disciplines and venues, and to ask how they might address some of the issues with our current systems of peer review. We examine the functionality of a range of social Web platforms, and compare these with the traits underlying a viable peer review system: quality control, quantified performance metrics as engagement incentives, and certification and reputation. Ideally, any new systems will demonstrate that they out-perform current models while avoiding as many of the biases of existing systems as possible. We conclude that there is considerable scope for new peer review initiatives to be developed, each with their own potential issues and advantages. We also propose a novel hybrid platform model that, at least partially, resolves many of the technical and social issues associated with peer review, and can potentially disrupt the entire scholarly communication system. Success for any such development relies on reaching a critical threshold of research community engagement with both the process and the platform, and therefore cannot be achieved without a significant change of incentives in research environments.
Este trabalho pretende fazer uma síntese da inserção de Axel Honneth no quadro das teorias da justiça. Para isso, se apresenta o debate entre comunitaristas e liberais, juntamente ao procedimentalismo contemporâneo, e as críticas de Honneth a essas posições. Assim o trabalho apresenta o esboço teórico de justiça como reconhecimento em Honneth, realizado com base no conceito de eticidade formal e no método da reconstrução normativa.
Hematotoxicity is one of the major side effects of chemotherapy. The aim of this study was to examine the association between single nucleotide polymorphisms (SNPs) and hematotoxicity in breast cancer patients in a subset of patients of the SUCCESS prospective phase III chemotherapy study. All patients (n = 1678) received three cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by three cycles of docetaxel or docetaxel/gemcitabine, depending on randomization. Germline DNA was genotyped for 246 SNPs selected from a previous genome-wide association study (GWAS) in a panel of lymphoblastoid cell lines, with gemcitabine toxicity as the phenotype. All SNPs were tested for their value in predicting grade 3 or 4 neutropenic or leukopenic events (NLEs). Their prognostic value in relation to overall survival and disease-free survival was also tested.
None of the SNPs was found to be predictive for NLEs during treatment with docetaxel/gemcitabine. Two SNPs in and close to the PIGB gene significantly improved the prediction of NLEs after FEC, in addition to the factors of age and body surface area. The top SNP (rs12050587) had an odds ratio of 1.38 per minor allele (95% confidence interval, 1.17 to 1.62). No associations were identified for predicting disease-free or overall survival.
Genetic variance in the PIGB gene may play a role in determining interindividual differences in relation to hematotoxicity after FEC chemotherapy.
Evidence of widespread wildfires in a coal seam from the middle Permian of the North China Basin
(2017)
The North China Basin is the largest coal-bearing basin in China, and has an areal extent of 800,000 km2. We analyzed 138 coal samples and in situ pillar coal samples of the middle Permian from this basin by macropetrography, microscope, scanning electron microscope, gas chromatography, and gas chromatography–mass spectrometer in order to study wildfires. High contents of inertinite (charcoal) and natural coke particles observed in coal samples indicate that vegetation in precursor mires and peats of the middle Permian coal from north China was exposed to far-ranging wildfires. In addition, high-molecular-weight polycyclic aromatic hydrocarbons were detected in the coal samples. These aromatic compounds were formed under high temperatures and provide further evidence of wildfire. These wildfires would have discharged significant CO and CO2 gases into the atmosphere and affected the paleoclimate and paleoecosystem.
Coccolithophores are an abundant phytoplankton group that exhibit remarkable diversity in their biology, ecology and calcitic exoskeletons (coccospheres). Their extensive fossil record is a testament to their important biogeochemical role and is a valuable archive of biotic responses to environmental change stretching back over 200 million years. However, to realise the full potential of this archive for (palaeo-)biology and biogeochemistry requires an understanding of the physiological processes that underpin coccosphere architecture. Using culturing experiments on four modern coccolithophore species (Calcidiscus leptoporus, Calcidiscus quadriperforatus, Helicosphaera carteri and Coccolithus braarudii) from three long-lived families, we investigate how coccosphere architecture responds to shifts from exponential (rapid cell division) to stationary (slowed cell division) growth phases as cell physiology reacts to nutrient depletion. These experiments reveal statistical differences in coccosphere size and the number of coccoliths per cell between these two growth phases, specifically that cells in exponential-phase growth are typically smaller with fewer coccoliths, whereas cells experiencing growth-limiting nutrient depletion have larger coccosphere sizes and greater numbers of coccoliths per cell. Although the exact numbers are species-specific, these growth-phase shifts in coccosphere geometry demonstrate that the core physiological responses of cells to nutrient depletion result in increased coccosphere sizes and coccoliths per cell across four different coccolithophore families (Calcidiscaceae, Coccolithaceae, Isochrysidaceae and Helicosphaeraceae), a representative diversity of this phytoplankton group. Building on this, the direct comparison of coccosphere geometries in modern and fossil coccolithophores enables a proxy for growth phase to be developed that can be used to investigate growth responses to environmental change throughout their long evolutionary history. Our data also show that changes in growth rate and coccoliths per cell associated with growth-phase shifts can substantially alter cellular calcite production. Coccosphere geometry is therefore a valuable tool for accessing growth information in the fossil record, providing unprecedented insights into the response of species to environmental change and the potential biogeochemical consequences.
Mean age of stratospheric air can be derived from observations of sufficiently long-lived trace gases with approximately linear trends in the troposphere. Mean age can serve as a tracer to investigate stratospheric transport and long-term changes in the strength of the overturning Brewer–Dobson circulation of the stratosphere. For this purpose, a low-cost method is required in order to allow for regular observations up to altitudes of about 30 km. Despite the desired low costs, high precision and accuracy are required in order to determine mean age. We present balloon-borne AirCore observations from two midlatitude sites: Timmins in Ontario/Canada and Lindenberg in Germany. During the Timmins campaign, five AirCores sampled air in parallel with a large stratospheric balloon and were analysed for CO2, CH4 and partly CO. We show that there is good agreement between the different AirCores (better than 0.1 %), especially when vertical gradients are small. The measurements from Lindenberg were performed using small low-cost balloons and yielded very comparable results. We have used the observations to extend our long-term data set of mean age observations at Northern Hemisphere midlatitudes. The time series now covers more than 40 years and shows a small, statistically non-significant positive trend of 0.15 ± 0.18 years decade−1. This trend is slightly smaller than the previous estimate of 0.24 ± 0.22 years decade−1 which was based on observations up to the year 2006. These observations are still in contrast to strong negative trends of mean age as derived from some model calculations.
AirCore-HR : a high-resolution column sampling to enhance the
vertical description of CH₄ and CO₂
(2017)
An original and innovative sampling system called AirCore was presented by NOAA in 2010 (Karion et al., 2010). It consists of a long ( > 100 m) and narrow (< 1 cm) stainless steel tube that can retain a profile of atmospheric air. The captured air sample has then to be analyzed with a gas analyzer for trace mole fraction. In this study, we introduce a new AirCore aiming to improve resolution along the vertical with the objectives to (i) better capture the vertical distribution of CO2 and CH4, (ii) provide a tool to compare AirCores and validate the estimated vertical resolution achieved by AirCores. This (high-resolution) AirCore-HR consists of a 300 m tube, combining 200 m of 0.125 in. (3.175 mm) tube and a 100 m of 0.25 in. (6.35 mm) tube. This new configuration allows us to achieve a vertical resolution of 300 m up to 15 km and better than 500 m up to 22 km (if analysis of the retained sample is performed within 3 h). The AirCore-HR was flown for the first time during the annual StratoScience campaign from CNES in August 2014 from Timmins (Ontario, Canada). High-resolution vertical profiles of CO2 and CH4 up to 25 km were successfully retrieved. These profiles revealed well-defined transport structures in the troposphere (also seen in CAMS-ECMWF high-resolution forecasts of CO2 and CH4 profiles) and captured the decrease of CO2 and CH4 in the stratosphere. The multi-instrument gondola also carried two other low-resolution AirCore-GUF that allowed us to perform direct comparisons and study the underlying processing method used to convert the sample of air to greenhouse gases vertical profiles. In particular, degrading the AirCore-HR derived profiles to the low resolution of AirCore-GUF yields an excellent match between both sets of CH4 profiles and shows a good consistency in terms of vertical structures. This fully validates the theoretical vertical resolution achievable by AirCores. Concerning CO2 although a good agreement is found in terms of vertical structure, the comparison between the various AirCores yields a large and variable bias (up to almost 3 ppm in some parts of the pro- files). The reasons of this bias, possibly related to the drying agent used to dry the air, are still being investigated. Finally, the uncertainties associated with the measurements are assessed, yielding an average uncertainty below 3 ppb for CH4 and 0.25 ppm for CO2 with the major source of uncertainty coming from the potential loss of air sample on the ground and the choice of the starting and ending point of the collected air sample inside the tube. In an ideal case where the sample would be fully retained, it would be possible to know precisely the pressure at which air was sampled last and thus to improve the overall uncertainty to about 0.1 ppm for CO2 and 2 ppb for CH4
Nucleation modeling of the Antarctic stratospheric CN layer and derivation of sulfuric acid profiles
(2017)
Recent analysis of long-term balloon-borne measurements of Antarctic stratospheric condensation nuclei (CN) between July and October showed the formation of a volatile CN layer at 21–27 km altitude in a background of existing particles. We use the nucleation model SAWNUC to simulate these CN in subsiding air parcels and study their nucleation and coagulation characteristics. Our simulations confirm recent analysis that the development of the CN layer can be explained with neutral sulfuric acid–water nucleation and we show that outside the CN layer the measured CN concentrations are well reproduced just considering coagulation and the subsidence of the air parcels. While ion-induced nucleation is expected as the dominating formation process at higher temperatures, it does not play a significant role during the CN layer formation as the charged clusters recombine too fast. Further, we derive sulfuric acid concentrations for the CN layer formation. Our concentrations are about 1 order of magnitude higher than previously presented concentrations as our simulations consider that nucleated clusters have to grow to CN size and can coagulate with preexisting particles. Finally, we calculate threshold sulfuric acid profiles that show which concentration of sulfuric acid is necessary for nucleation and growth to observable size. These threshold profiles should represent upper limits of the actual sulfuric acid outside the CN layer. According to our profiles, sulfuric acid concentrations seem to be below midlatitude average during Antarctic winter but above midlatitude average for the CN layer formation.
Disruption of the blood-air barrier, which is formed by lung microvascular endothelial and alveolar epithelial cells, is a hallmark of acute lung injury. It was shown that alveolar epithelial cells release an unidentified soluble factor that enhances the barrier function of lung microvascular endothelial cells. In this study we reveal that primarily prostaglandin (PG) E2 accounts for this endothelial barrier-promoting activity. Conditioned media from alveolar epithelial cells (primary ATI-like cells) collected from BALB/c mice and A549 cells increased the electrical resistance of pulmonary human microvascular endothelial cells, respectively. This effect was reversed by pretreating alveolar epithelial cells with a cyclooxygenase-2 inhibitor or by blockade of EP4 receptors on endothelial cells, and in A549 cells also by blocking the sphingosine-1-phosphate1 receptor. Cyclooxygenase-2 was constitutively expressed in A549 cells and in primary ATI-like cells, and was upregulated by lipopolysaccharide treatment. This was accompanied by enhanced PGE2 secretion into conditioned media. Therefore, we conclude that epithelium-derived PGE2 is a key regulator of endothelial barrier integrity via EP4 receptors under physiologic and inflammatory conditions. Given that pharmacologic treatment options are still unavailable for diseases with compromised air-blood barrier, like acute lung injury, our data thus support the therapeutic potential of selective EP4 receptor agonists.
Background: Red blood cell (RBC) depletion is a standard graft manipulation technique for ABO-incompatible bone marrow (BM) transplants. The BM processing module for Spectra Optia, “BMC”, was previously introduced. We here report the largest series to date of routine quality data after performing 50 clinical-scale RBC-depletions.
Methods: Fifty successive RBC-depletions from autologous (n = 5) and allogeneic (n = 45) BM transplants were performed with the Spectra Optia BMC apheresis suite. Product quality was assessed before and after processing for volume, RBC and leukocyte content; RBC-depletion and stem cell (CD34+ cells) recovery was calculated there from. Clinical engraftment data were collected from 26/45 allogeneic recipients.
Results: Median RBC removal was 98.2% (range 90.8–99.1%), median CD34+ cell recovery was 93.6%, minimum recovery being 72%, total product volume was reduced to 7.5% (range 4.7–23.0%). Products engrafted with expected probability and kinetics. Performance indicators were stable over time.
Discussion: Spectra Optia BMC is a robust and efficient technology for RBC-depletion and volume reduction of BM, providing near-complete RBC removal and excellent CD34+ cell recovery.
A high proportion of patients with breast cancer develop bone metastases, yet data on routine treatment with bone-targeted agents (BTA) are rare. We report real-life outcome data of patients with breast cancer metastasised to the bone treated by office-based oncologists in Germany.
The ongoing, prospective, multicentre, population-based cohort study Tumour Registry Breast Cancer (TMK) was started in 2007 in 140 centres across Germany.
This interim analysis of 1094 patients with bone metastases revealed differences among the tumour subtypes: at start of first-line therapy, 36% of the patients with hormone receptor (HR)-positive and only 20% of the patients with HR-negative tumours presented with bone-only metastasis. The majority of patients with bone metastases (89%, n = 976) received BTA therapy. In 2014–2015, 37% of the patients received the bisphosphonate zoledronic acid and 36% the antibody denosumab. Median duration of BTA therapy was 20 months (interquartile range 31.5 months), starting a median of 3 weeks after diagnosis of bone metastases, and ending a median of 7 weeks before death. The median overall survival (OS) also varied among the types of metastasis at start of first-line therapy ranging from 54 months (95% confidence interval [CI] 37.6–70.8), 38 months (95% CI 29.4–44.2) to 28 months (95% CI 24.2–31.0) for patients with bone-only metastases, non-visceral with or without bone metastases and visceral with or without bone metastases respectively.
We show that choice and duration of BTA therapies are in conformity with guidelines applicable in Germany. To our knowledge, this is the first presentation of data on incidence, metastatic pattern, treatment and survival of patients with bone metastases in routine practice.
Background: Infections with the hepatitis C virus (HCV) are a global public health problem. Long-term consequences are the development of liver cirrhosis and hepatocellular carcinoma. Newly introduced direct acting antivirals, especially interferon-free regimens, have improved rates of sustained viral response above 90% in most patient groups and allow treating patients who were ineligible for treatment in the past. These new regimens have replaced former treatment and are recommended by current guidelines. However, there is an ongoing discussion on high pharmaceutical prices. Our aim was to assess the long-term cost-effectiveness of treating hepatitis C genotype 1 patients with sofosbuvir/ledipasvir (SOF/LDV) treatment in Germany.
Material and Methods: We used a Markov cohort model to simulate disease progression and assess cost-effectiveness. The model calculates lifetime costs and outcomes (quality-adjusted life years, QALYs) of SOF/LDV and other strategies. Patients were stratified by treatment status (treatment-naive and treatment-experienced) and absence/presence of cirrhosis. Different treatment strategies were compared to prior standard of care. Sensitivity analyses were performed to evaluate model robustness.
Results: Base-case analyses results show that in treatment-naive non-cirrhotic patients treatment with SOF/LDV dominates the prior standard of care (is more effective and less costly). In cirrhotic patients an incremental cost-effectiveness ratio (ICER) of 3,383 €/QALY was estimated. In treatment-experienced patients ICERs were 26,426 €/QALY and 1,397 €/QALY for treatment-naive and treatment-experienced patients, respectively. Robustness of results was confirmed in sensitivity analyses.
Conclusions: Our analysis shows that treatment with SOF/LDV is cost-effective compared to prior standard of care in all patient groups considering international costs per QALY thresholds.
Three new species of the genus Carychium O.F. Müller, 1773, Carychium hardiei Jochum & Weigand, sp. n., Carychium belizeense Jochum & Weigand, sp. n. and Carychium zarzaae Jochum & Weigand, sp. n. are described from the Southeastern United States, Belize and Panama, respectively. In two consecutive molecular phylogenetic studies of worldwide members of Carychiidae, the North and Central American morphospecies Carychium mexicanum Pilsbry, 1891 and Carychium costaricanum E. von Martens, 1898 were found to consist of several evolutionary lineages. Although the related lineages were found to be molecularly distinct from the two nominal species, the consequential morphological and taxonomic assessment of these lineages is still lacking. In the present paper, the shells of these uncovered Carychium lineages are assessed by comparing them with those of related species, using computer tomography for the first time for this genus. The interior diagnostic characters are emphasized, such as columellar configuration in conjunction with the columellar lamella and their relationship in context of the entire shell. These taxa are morphologically described and formally assigned their own names.
Introduction: For management of complicated retinal detachments, a pars plana vitrectomy with temporary silicone oil (SO) fill is the method of choice. According to literature, the retinal redetachment rate varies between <10% and >70% with around 36% in our own group (retrospective data analysis, n = 119 eyes).
Methods: The main goal was to reduce the retinal redetachment rate. Standard operating procedures (SOPs) and evaluation protocols (EVALPs) were developed to prospectively analyse risk factors. Lab analysis of SO was performed, and the role of surgical experience was evaluated and investigated with Eyesi®.
Results: We achieved a significant reduction of the retinal redetachment rate (to 6.80%, n = 101, p = 0.002). After surgery with SO injection, neither further membrane peeling (in 16.5%) nor retinal laser coagulation (in 100%) during revision surgery had a significant effect on the reattachment rate (p = 0.167, p = 0.23), while extensive additional laser coagulation reduced visual acuity (p = 0.01). A 3-port approach had to be set up to complete SO removal. A difference in success rate depending on surgical experience was confirmed, and the performance in Eyesi correlated with that in the patients' eye.
Conclusions: A SOP- and EVALP-based management and new strategies to secure the surgical performance seem to be essential for successful surgery.
We present results on transverse momentum (pT) and rapidity (y) differential production cross sections, mean transverse momentum and mean transverse momentum square of inclusive J/ψ and ψ(2S) at forward rapidity (2.5 < y < 4) as well as ψ(2S)-to-J/ψ cross section ratios. These quantities are measured in pp collisions at center of mass energies s√=5.02 and 13 TeV with the ALICE detector. Both charmonium states are reconstructed in the dimuon decay channel, using the muon spectrometer. A comprehensive comparison to inclusive charmonium cross sections measured at s√=2.76, 7 and 8 TeV is performed. A comparison to non-relativistic quantum chromodynamics and fixed-order next-to-leading logarithm calculations, which describe prompt and non-prompt charmonium production respectively, is also presented. A good description of the data is obtained over the full pT range, provided that both contributions are summed. In particular, it is found that for pT > 15 GeV/c the non-prompt contribution reaches up to 50% of the total charmonium yield.
We present an in-depth study of masses and decays of excited scalar and pseudoscalar q¯q states in the Extended Linear Sigma Model (eLSM). The model also contains ground-state scalar, pseudoscalar, vector and axial-vector mesons. The main objective is to study the consequences of the hypothesis that the f0(1790) resonance, observed a decade ago by the BES Collaboration and recently by LHCb, represents an excited scalar quarkonium. In addition we also analyse the possibility that the new a0(1950) resonance, observed recently by BABAR, may also be an excited scalar state. Both hypotheses receive justification in our approach although there appears to be some tension between the simultaneous interpretation of f0(1790)/a0(1950) and pseudoscalar mesons η(1295), π(1300), η(1440) and K(1460) as excited q¯q states.
GPR116 (ADGRF5) and ELTD1 (ADGRL4) belong to different subfamilies of the adhesion G-protein-coupled receptor group but are both expressed in endothelial cells. We therefore analyzed their functions in mice lacking these receptors. While loss of GPR116 or ELTD1 alone had no obvious effect on cardiovascular or kidney function, mice lacking both, GPR116 and ELTD1, showed malformations of the aortic arch arteries and the cardiac outflow tract leading to perinatal lethality in about 50% of the mutants. In addition to cardiovascular malformations, surviving mice developed renal thrombotic microangiopathy as well as hemolysis and splenomegaly, and their lifespan was significantly reduced. Loss of GPR116 and ELTD1 specifically in endothelial cells or neural crest-derived cells did not recapitulate any of the phenotypes observed in GPR116-ELTD1 double deficient mice, indicating that loss of GPR116 and ELTD1 expressed by other cells accounts for the observed cardiovascular and renal defects.
Inhibition of the IκB kinase complex (IKK) has been implicated in the therapy of several chronic inflammatory diseases including inflammatory bowel diseases. In this study, using mice with an inactivatable IKKα kinase (IkkαAA/AA), we show that loss of IKKα function markedly impairs epithelial regeneration in a model of acute colitis. Mechanistically, this is caused by compromised secretion of cytoprotective IL-18 from IKKα-mutant intestinal epithelial cells because of elevated caspase 12 activation during an enhanced unfolded protein response (UPR). Induction of the UPR is linked to decreased ATG16L1 stabilization in IkkαAA/AA mice. We demonstrate that both TNF-R and nucleotide-binding oligomerization domain stimulation promote ATG16L1 stabilization via IKKα-dependent phosphorylation of ATG16L1 at Ser278. Thus, we propose IKKα as a central mediator sensing both cytokine and microbial stimulation to suppress endoplasmic reticulum stress, thereby assuring antiinflammatory function during acute intestinal inflammation.
The family Gymnophthalmidae contains nearly 235 species with a distribution range from southern Mexico to central Argentina as well as in the Antilles. Among gymnophthalmids, the genus Colobosaura is a member of the tribe Iphisini, and currently is considered monotypic (C. modesta). The diversity of the tribe was studied recently, with the erection of several new genera. In this work genetic and morphological data of specimens of Colobosaura recently collected in Paraguay were analyzed. Genetic (16S barcode) data indicate that these samples are not conspecific with C. modesta and they are allocated to the nominal species C. kraepelini. Because the original primary type of the latter taxon is considered to be lost, a neotype (SMF 101370) is designated for this species and a redescription provided based on our material. Colobosaura kraepelini is distributed in the Humid Chaco, being the only member of the whole tribe in this ecoregion.
The ability to learn sequential behaviors is a fundamental property of our brains. Yet a long stream of studies including recent experiments investigating motor sequence learning in adult human subjects have produced a number of puzzling and seemingly contradictory results. In particular, when subjects have to learn multiple action sequences, learning is sometimes impaired by proactive and retroactive interference effects. In other situations, however, learning is accelerated as reflected in facilitation and transfer effects. At present it is unclear what the underlying neural mechanism are that give rise to these diverse findings. Here we show that a recently developed recurrent neural network model readily reproduces this diverse set of findings. The self-organizing recurrent neural network (SORN) model is a network of recurrently connected threshold units that combines a simplified form of spike-timing dependent plasticity (STDP) with homeostatic plasticity mechanisms ensuring network stability, namely intrinsic plasticity (IP) and synaptic normalization (SN). When trained on sequence learning tasks modeled after recent experiments we find that it reproduces the full range of interference, facilitation, and transfer effects. We show how these effects are rooted in the network’s changing internal representation of the different sequences across learning and how they depend on an interaction of training schedule and task similarity. Furthermore, since learning in the model is based on fundamental neuronal plasticity mechanisms, the model reveals how these plasticity mechanisms are ultimately responsible for the network’s sequence learning abilities. In particular, we find that all three plasticity mechanisms are essential for the network to learn effective internal models of the different training sequences. This ability to form effective internal models is also the basis for the observed interference and facilitation effects. This suggests that STDP, IP, and SN may be the driving forces behind our ability to learn complex action sequences.
Earliest expansion of animal husbandry beyond the Mediterranean zone in the sixth millennium BC
(2017)
Since their domestication in the Mediterranean zone of Southwest Asia in the eighth millennium BC, sheep, goats, pigs and cattle have been remarkably successful in colonizing a broad variety of environments. The initial steps in this process can be traced back to the dispersal of farming groups into the interior of the Balkans in the early sixth millennium BC, who were the first to introduce Mediterranean livestock beyond its natural climatic range. Here, we combine analysis of biomolecular and isotopic compositions of lipids preserved in prehistoric pottery with faunal analyses of taxonomic composition from the earliest farming sites in southeast Europe to reconstruct this pivotal event in the early history of animal husbandry. We observe a marked divergence between the (sub)Mediterranean and temperate regions of Southeast Europe, and in particular a significant increase of dairying in the biochemical record coupled with a shift to cattle and wild fauna at most sites north of the Balkan mountain range. The findings strongly suggest that dairying was crucial for the expansion of the earliest farming system beyond its native bioclimatic zone.
Background: All European countries need to increase the number of health professionals in the near future. Most efforts have not brought the expected results so far. The current notion is that this is mainly related to the fact that female physicians will clearly outnumber their male colleagues within a few years in nearly all European countries. Still, women are underrepresented in leadership and research positions throughout Europe.
Objectives: The MedGoFem project addresses multiple perspectives with the participation of multiple stakeholders. The goal is to facilitate the implementation of Gender Equality Plans (GEP) in university hospitals; thereby, transforming the working conditions for women working as researchers and highly qualified physicians simultaneously. Our proposed innovation, a crosscutting topic in all research and clinical activities, must become an essential part of university hospital strategic concepts.
Methods: We capture the current status with gender-sensitive demographic data concerning medical staff and conduct Web-based surveys to identify cultural, country-specific, and interdisciplinary factors conducive to women’s academic success. Individual expectations of employees regarding job satisfaction and working conditions will be visualized based on “personal construct theory” through repertory grids. An expert board working out scenarios and a gender topic agenda will identify culture-, nation-, and discipline-specific aspects of gender equality. University hospitals in 7 countries will establish consensus groups, which work on related topics. Hospital management supports the consensus groups, valuates group results, and shares discussion results and suggested measures across groups. Central findings of the consensus groups will be prepared as exemplary case studies for academic teaching on research and work organization, leadership, and management.
Results: A discussion group on gender equality in academic medicine will be established on an internationally renowned open-research platform. Project results will be published in peer-reviewed journals with high-impact factors. In addition, workshops on gender dimension in research using the principles of Gendered Innovation will be held. Support and consulting services for hospitals will be introduced in order to develop a European consulting service.
Conclusions: The main impact of the project will be the implementation of innovative GEP tailored to the needs of university hospitals, which will lead to measurable institutional change in gender equality. This will impact the research at university hospitals in general, and will improve career prospects of female researchers in particular. Simultaneously, the gender dimension in medical research as an innovation factor and mandatory topic will be strengthened and integrated in each individual university hospital research activity. Research funding organizations can use the built knowledge to include mandatory topics for funding applications to enforce the use and implementation of GEP in university hospitals.
Background: PINK1 deficiency causes the autosomal recessive PARK6 variant of Parkinson’s disease. PINK1 activates ubiquitin by phosphorylation and cooperates with the downstream ubiquitin ligase PARKIN, to exert quality control and control autophagic degradation of mitochondria and of misfolded proteins in all cell types.
Methods: Global transcriptome profiling of mouse brain and neuron cultures were assessed in protein-protein interaction diagrams and by pathway enrichment algorithms. Validation by quantitative reverse transcriptase polymerase chain reaction and immunoblots was performed, including human neuroblastoma cells and patient primary skin fibroblasts.
Results: In a first approach, we documented Pink1-deleted mice across the lifespan regarding brain mRNAs. The expression changes were always subtle, consistently affecting “intracellular membrane-bounded organelles”. Significant anomalies involved about 250 factors at age 6 weeks, 1300 at 6 months, and more than 3500 at age 18 months in the cerebellar tissue, including Srsf10, Ube3a, Mapk8, Creb3, and Nfkbia. Initially, mildly significant pathway enrichment for the spliceosome was apparent. Later, highly significant networks of ubiquitin-mediated proteolysis and endoplasmic reticulum protein processing occurred. Finally, an enrichment of neuroinflammation factors appeared, together with profiles of bacterial invasion and MAPK signaling changes—while mitophagy had minor significance. Immunohistochemistry showed pronounced cellular response of Iba1-positive microglia and GFAP-positive astrocytes; brain lipidomics observed increases of ceramides as neuroinflammatory signs at old age.
In a second approach, we assessed PINK1 deficiency in the presence of a stressor. Marked dysregulations of microbial defense factors Ifit3 and Rsad2 were consistently observed upon five analyses: (1) Pink1 −/− primary neurons in the first weeks after brain dissociation, (2) aged Pink1 −/− midbrain with transgenic A53T-alpha-synuclein overexpression, (3) human neuroblastoma cells with PINK1-knockdown and murine Pink1 −/− embryonal fibroblasts undergoing acute starvation, (4) triggering mitophagy in these cells with trifluoromethoxy carbonylcyanide phenylhydrazone (FCCP), and (5) subjecting them to pathogenic RNA-analogue poly(I:C). The stress regulation of MAVS, RSAD2, DDX58, IFIT3, IFIT1, and LRRK2 was PINK1 dependent. Dysregulation of some innate immunity genes was also found in skin fibroblast cells from PARK6 patients.
Conclusions: Thus, an individual biomarker with expression correlating to progression was not identified. Instead, more advanced disease stages involved additional pathways. Hence, our results identify PINK1 deficiency as an early modulator of innate immunity in neurons, which precedes late stages of neuroinflammation during alpha-synuclein spreading.
The Gini index is a measure of the inequality of a distribution that can be derived from Lorenz curves. While commonly used in, e.g., economic research, it suffers from ambiguity via lack of Lorenz dominance preservation. Here, investigation of large sets of empirical distributions of incomes of the World’s countries over several years indicated firstly, that the Gini indices are centered on a value of 33.33% corresponding to the Gini index of the uniform distribution and secondly, that the Lorenz curves of these distributions are consistent with Lorenz curves of log-normal distributions. This can be employed to provide a Lorenz dominance preserving equivalent of the Gini index. Therefore, a modified measure based on log-normal approximation and standardization of Lorenz curves is proposed. The so-called UGini index provides a meaningful and intuitive standardization on the uniform distribution as this characterizes societies that provide equal chances. The novel UGini index preserves Lorenz dominance. Analysis of the probability density distributions of the UGini index of the World’s counties income data indicated multimodality in two independent data sets. Applying Bayesian statistics provided a data-based classification of the World’s countries’ income distributions. The UGini index can be re-transferred into the classical index to preserve comparability with previous research.
Background: The importance of the Internet as a medium for publishing and sharing health and medical information has increased considerably during the last decade. Nonetheless, comprehensive knowledge and information are scarce and difficult to find, especially for rare diseases. Additionally, the quality of health or medical information about rare diseases is frequently difficult to assess for the patients and their family members.
Objective: The aim of this study is to assess the quality of information on the Internet about rare diseases. Additionally, the study aims to evaluate if the quality of information on rare diseases varies between different information supplier categories.
Methods: A total of 13 quality criteria for websites providing medical information about rare diseases were transferred to a self-disclosure questionnaire. Identified providers of information on the Internet about rare diseases were invited to fill out the questionnaire. The questionnaire contained questions about the information provider in general (eg, supplier category, information category, language, use of quality certificates, and target group) and about quality aspects that reflect the 13 quality criteria. Differences in subgroup analyses were performed using t tests.
Results: We identified 693 websites containing information about rare diseases. A total of 123 questionnaires (17.7%) were completely filled out by the information suppliers. For the remaining identified suppliers (570/693, 82.3%), the questionnaires were filled out by the authors based on the information available on their website. In many cases, the quality of websites was proportionally low. Furthermore, subgroup analysis showed no statistically significant differences between the quality of information provided by support group/patient organization compared to medical institution (P=.19). The quality of information by individuals (patient/relative) was significantly lower compared to information provided by support group/patient organization (P=.001), medical institution (P=.009), and other associations and sponsoring bodies (P=.001) as well.
Conclusions: Overall, the quality of information on the Internet about rare diseases is low. Quality certificates are rarely used and important quality criteria are often not fulfilled completely. Additionally, some information categories are underrepresented (eg, information about psychosocial counseling, social-legal advice, and family planning). Nevertheless, due to the high amount of information provided by support groups, this study shows that these are extremely valuable sources of information for patients suffering from a rare disease and their relatives.
Objective: The aim of this study was to report the basic cerebrospinal fluid (CSF) profile in patients with primary progressive multiple sclerosis (PPMS).
Methods: The results of CSF analysis from 254 patients with PPMS were collected at four university hospitals in Germany. Routine CSF parameters and different indices of intrathecal immunoglobulin synthesis were evaluated. We assessed possible correlations between the various CSF parameters and the expanded disability status scale (EDSS) both at the time of lumbar puncture and during the course of the disease.
Results: The median cell count and albumin concentration in the CSF did not deviate from normal values. The CSF-serum albumin-quotient (QALB) was elevated in 29.6% of the patients, while intrathecal immunoglobulin G (IgG) oligoclonal bands (OCBs) were detected in 91.1% of the patients. CSF-lactate levels as well as local IgM- and IgA-synthesis were correlated with the yearly disease progression rate, as assessed by EDSS.
Conclusion: We present the results of the hitherto largest and most detailed CSF biomarker profile in a cohort of 254 patients with PPMS. As reported previously, OCBs are the most sensitive marker for intrathecal IgG synthesis. CSF-lactate concentrations are positively correlated with the progression rate, which might suggest that mitochondrial dysfunction plays a relevant role in PPMS. The negative correlation between intrathecally produced IgM and IgA and disease progression may indicate their hitherto unexplored protective role.
Non-lethal genotyping of Tribolium castaneum adults using genomic DNA extracted from wing tissue
(2017)
The red flour beetle Tribolium castaneum has become the second most important insect model organism and is frequently used in developmental biology, genetics and pest-associated research. Consequently, the methodological arsenal increases continuously, but many routinely applied techniques for Drosophila melanogaster and other insect species are still unavailable. For example, a protocol for non-lethal genotyping has not yet been adapted but is particularly useful when individuals with known genotypes are required for downstream experiments. In this study, we present a workflow for non-lethal genotyping of T. castaneum adults based on extracting genomic DNA from wing tissue. In detail, we describe a convenient procedure for wing dissection and a custom method for wing digestion that allows PCR-based genotyping of up to fifty adults in less than an afternoon with a success rate of about 86%. The amount of template is sufficient for up to ten reactions while viability and fertility of the beetles are preserved. We prove the applicability of our protocol by genotyping the white / scarlet gene pair alleles from the black-eyed San Bernadino wild-type and white-eyed Pearl recessive mutant strains spanning four generations. Non-lethal genotyping has the potential to improve and accelerate many workflows: Firstly, during the establishment process of homozygous cultures or during stock keeping of cultures that carry recessively lethal alleles, laborious test crossing is replaced by non-lethal genotyping. Secondly, in genome engineering assays, non-lethal genotyping allows the identification of appropriate founders before they are crossed against wild-types, narrowing the efforts down to only the relevant individuals. Thirdly, non-lethal genotyping simplifies experimental strategies, in which genotype and behavior should be correlated, since the genetic configuration of potential individuals can be determined before the actual behavior assays is performed.
Background: Treatment of patients presenting with possible acute myocardial infarction (AMI) is based on timely diagnosis and proper risk stratification aided by biomarkers. We aimed at evaluating the predictive value of GDF-15 in patients presenting with symptoms suggestive of AMI.
Methods: Consecutive patients presenting with suspected AMI were enrolled in three study centers. Cardiovascular events were assessed during a follow-up period of 6 months with a combined endpoint of death or MI.
Results: From the 1818 enrolled patients (m/f = 1208/610), 413 (22.7%) had an acute MI and 63 patients reached the combined endpoint. Patients with MI and patients with adverse outcome had higher GDF-15 levels compared with non-MI patients (967.1pg/mL vs. 692.2 pg/L, p<0.001) and with event-free patients (1660 pg/mL vs. 756.6 pg/L, p<0.001). GDF-15 levels were lower in patients with SYNTAX score ≤ 22 (797.3 pg/mL vs. 947.2 pg/L, p = 0.036). Increased GDF-15 levels on admission were associated with a hazard ratio of 2.1 for death or MI (95%CI: 1.67–2.65, p<0.001) in a model adjusted for age and sex and of 1.57 (1.13–2.19, p = 0.008) adjusted for the GRACE score variables. GDF-15 showed a relevant reclassification with regards to the GRACE score with an overall net reclassification index (NRI) of 12.5% and an integrated discrimination improvement (IDI) of 14.56% (p = 0.006).
Conclusion: GDF-15 is an independent predictor of future cardiovascular events in patients presenting with suspected MI. GDF-15 levels correlate with the severity of CAD and can identify and risk-stratify patients who need coronary revascularization.
In mammals, acoustic communication plays an important role during social behaviors. Despite their ethological relevance, the mechanisms by which the auditory cortex represents different communication call properties remain elusive. Recent studies have pointed out that communication-sound encoding could be based on discharge patterns of neuronal populations. Following this idea, we investigated whether the activity of local neuronal networks, such as those occurring within individual cortical columns, is sufficient for distinguishing between sounds that differed in their spectro-temporal properties. To accomplish this aim, we analyzed simple pure-tone and complex communication call elicited multi-unit activity (MUA) as well as local field potentials (LFP), and current source density (CSD) waveforms at the single-layer and columnar level from the primary auditory cortex of anesthetized Mongolian gerbils. Multi-dimensional scaling analysis was used to evaluate the degree of “call-specificity” in the evoked activity. The results showed that whole laminar profiles segregated 1.8-2.6 times better across calls than single-layer activity. Also, laminar LFP and CSD profiles segregated better than MUA profiles. Significant differences between CSD profiles evoked by different sounds were more pronounced at mid and late latencies in the granular and infragranular layers and these differences were based on the absence and/or presence of current sinks and on sink timing. The stimulus-specific activity patterns observed within cortical columns suggests that the joint activity of local cortical populations (as local as single columns) could indeed be important for encoding sounds that differ in their acoustic attributes.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic, Th17-derived cytokine thought to critically contribute to the pathogenesis of diverse autoimmune diseases, including rheumatoid arthritis and psoriasis. Treatment with monoclonal antibodies that block GM-CSF activity is associated with favorable therapeutic effects in patients with rheumatoid arthritis. We evaluated the role of GM-CSF as a potential target for therapeutic interference in psoriasis using a combined pharmacologic and genetic approach and the mouse model of imiquimod-induced psoriasiform dermatitis (IMQPD). Neutralization of murine GM-CSF by an anti-GM-CSF antibody ameliorated IMQPD. In contrast, genetic deficiency in GM-CSF did not alter the course of IMQPD, suggesting the existence of mechanisms compensating for chronic, but not acute, absence of GM-CSF. Further investigation uncovered an alternative pathogenic pathway for IMQPD in the absence of GM-CSF characterized by an expanded plasmacytoid dendritic cell population and release of IFNα and IL-22. This pathway was not activated in wild-type mice during short-term anti-GM-CSF treatment. Our investigations support the potential value of GM-CSF as a therapeutic target in psoriatic disease. The discovery of an alternative pathogenic pathway for psoriasiform dermatitis in the permanent absence of GM-CSF, however, suggests the need for monitoring during therapeutic use of long-term GM-CSF blockade.
Treatment with tyrosine kinase inhibitors is the standard of care for Philadelphia chromosome positive leukemias. However the eradication of leukemia initiating cells remains a challenge. Circumstantial evidence suggests that the cytokine microenvironment may play a role in BCR-ABL mediated leukemogenesis and in imatinib resistance. Gene expression analyses of BCR-ABL positive ALL long-term cultured cells revealed strong reduction of SOCS mRNA expression after imatinib treatment, thereby demonstrating a strong inhibition of cytokine signaling. In this study we employed SOCS1—a strong inhibitor of cytokine signaling—as a tool to terminate external cytokine signals in BCR-ABL transformed cells in vitro and in vivo. In colony formation assays with primary bone marrow cells, expression of SOCS1 decreased colony numbers under pro-proliferative cytokines, while it conferred growth resistance to anti-proliferative cytokines. Importantly, co-expression of SOCS1 with BCR-ABL led to the development of a MPD phenotype with a prolonged disease latency compared to BCR-ABL alone in a murine bone marrow transplantation model. Interestingly, SOCS1 co-expression protected 20% of mice from MPD development. In summary, we conclude that under pro-proliferative cytokine stimulation at the onset of myeloproliferative diseases SOCS1 acts as a tumor suppressor, while under anti-proliferative conditions it exerts oncogenic function. Therefore SOCS1 can promote opposing functions depending on the cytokine environment.
Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of the majority of the 500+ human protein kinases remains unknown. We have developed physical and virtual collections of small molecule inhibitors, which we call chemogenomic sets, that are designed to inhibit the catalytic function of almost half the human protein kinases. In this manuscript we share our progress towards generation of a comprehensive kinase chemogenomic set (KCGS), release kinome profiling data of a large inhibitor set (Published Kinase Inhibitor Set 2 (PKIS2)), and outline a process through which the community can openly collaborate to create a KCGS that probes the full complement of human protein kinases.
The efficacy of cisplatin-based chemotherapy in cancer is limited by the occurrence of innate and acquired drug resistance. In order to better understand the mechanisms underlying acquired cisplatin resistance, we have compared the adenocarcinoma-derived non-small cell lung cancer (NSCLC) cell line A549 and its cisplatin-resistant sub-line A549rCDDP2000 with regard to cisplatin resistance mechanisms including cellular platinum accumulation, DNA-adduct formation, cell cycle alterations, apoptosis induction and activation of key players of DNA damage response. In A549rCDDP2000 cells, a cisplatin-induced G2/M cell cycle arrest was lacking and apoptosis was reduced compared to A549 cells, although equitoxic cisplatin concentrations resulted in comparable platinum-DNA adduct levels. These differences were accompanied by changes in the expression of proteins involved in DNA damage response. In A549 cells, cisplatin exposure led to a significantly higher expression of genes coding for proteins mediating G2/M arrest and apoptosis (mouse double minute 2 homolog (MDM2), xeroderma pigmentosum complementation group C (XPC), stress inducible protein (SIP) and p21) compared to resistant cells. This was underlined by significantly higher protein levels of phosphorylated Ataxia telangiectasia mutated (pAtm) and p53 in A549 cells compared to their respective untreated control. The results were compiled in a preliminary model of resistance-associated signaling alterations. In conclusion, these findings suggest that acquired resistance of NSCLC cells against cisplatin is the consequence of altered signaling leading to reduced G2/M cell cycle arrest and apoptosis.
Na+/H+ exchange is essential for survival of all organisms, having a role in the regulation of the intracellular Na+ concentration, pH and cell volume. Furthermore, Na+/H+ exchangers were shown to be involved in the virulence of the bacterium Yersinia pestis, indicating they might be potential targets for novel antibiotic treatments. The model system for Na+/H+ exchangers is the NhaA transporter from Escherichia coli, EcNhaA. Therefore, the general transport mechanism of NhaA exchangers is currently well characterized. However, much less is known about NhaB exchangers, with only a limited number of studies available. The pathogen Klebsiella pneumoniae, which is a major source of nosocomial infection, possesses three electrogenic Na+/H+ exchangers, KpNhaA1, KpNhaA2 and KpNhaB, none of which have been previously investigated. Our aim in this study was to functionally characterize KpNhaB using solid supported membrane-based electrophysiology as the main investigation technique, and thus provide the first electrophysiological investigation of an NhaB Na+/H+ exchanger. We found that NhaB can be described by the same competition-based mechanism that was shown to be valid for electrogenic NhaA and NapA, and for electroneutral NhaP Na+/H+ exchangers. For comparison we also characterized the activity of KpNhaA1 and KpNhaA2 and found that the three exchangers have complementary activity profiles, which is likely a survival advantage for K. pneumoniae when faced with environments of different salinity and pH. This underlines their importance as potential antibiotic drug targets.
Psoriasis is a frequent and often severe inflammatory skin disease, characterized by altered epidermal homeostasis. Since we found previously that Akt/mTOR signaling is hyperactivated in psoriatic skin, we aimed at elucidating the role of aberrant mTORC1 signaling in this disease. We found that under healthy conditions mTOR signaling was shut off when keratinocytes switch from proliferation to terminal differentiation. Inflammatory cytokines (IL-1β, IL-17A, TNF-α) induced aberrant mTOR activity which led to enhanced proliferation and reduced expression of differentiation markers. Conversely, regular differentiation could be restored if mTORC1 signaling was blocked. In mice, activation of mTOR through the agonist MHY1485 also led to aberrant epidermal organization and involucrin distribution. In summary, these results not only identify mTORC1 as an important signal integrator pivotal for the cells fate to either proliferate or differentiate, but emphasize the role of inflammation-dependent mTOR activation as a psoriatic pathomechanism.
Two theories address the origin of repeating patterns, such as hair follicles, limb digits, and intestinal villi, during development. The Turing reaction–diffusion system posits that interacting diffusible signals produced by static cells first define a prepattern that then induces cell rearrangements to produce an anatomical structure. The second theory, that of mesenchymal self-organisation, proposes that mobile cells can form periodic patterns of cell aggregates directly, without reference to any prepattern. Early hair follicle development is characterised by the rapid appearance of periodic arrangements of altered gene expression in the epidermis and prominent clustering of the adjacent dermal mesenchymal cells. We assess the contributions and interplay between reaction–diffusion and mesenchymal self-organisation processes in hair follicle patterning, identifying a network of fibroblast growth factor (FGF), wingless-related integration site (WNT), and bone morphogenetic protein (BMP) signalling interactions capable of spontaneously producing a periodic pattern. Using time-lapse imaging, we find that mesenchymal cell condensation at hair follicles is locally directed by an epidermal prepattern. However, imposing this prepattern’s condition of high FGF and low BMP activity across the entire skin reveals a latent dermal capacity to undergo spatially patterned self-organisation in the absence of epithelial direction. This mesenchymal self-organisation relies on restricted transforming growth factor (TGF) β signalling, which serves to drive chemotactic mesenchymal patterning when reaction–diffusion patterning is suppressed, but, in normal conditions, facilitates cell movement to locally prepatterned sources of FGF. This work illustrates a hierarchy of periodic patterning modes operating in organogenesis.
Pertusarialean lichens include more than 300 species belonging to several independent phylogenetic lineages. Only some of these phylogenetic clades have been comprehensively sampled for molecular data, and formally described as genera. Here we present a taxonomic treatment of a group of pertusarialean lichens formerly known as "Pertusaria amara-group", "Monomurata-group", or "Variolaria-group", which includes widespread and well-known taxa such as P. amara, P. albescens, or P. ophthalmiza. We generated a 6-locus data set with 79 OTUs representing 75 species. The distinction of the Variolaria clade is supported and consequently, the resurrection of the genus Lepra is followed. Thirty-five new combinations into Lepra are proposed and the new species Lepra austropacifica is described from mangroves in the South Pacific. Lepra is circumscribed to include species with disciform ascomata, a weakly to non-amyloid hymenial gel, strongly amyloid asci without clear apical amyloid structures, containing 1 or 2, single-layered, thin-walled ascospores. Chlorinated xanthones are not present, but thamnolic and picrolichenic acids occur frequently, as well as orcinol depsides. Seventy-one species are accepted in the genus. Although the distinction of the genus from Pertusaria is strongly supported, the relationships of Lepra remain unresolved and the genus is tentatively placed in Pertusariales incertae sedis.
We have reported previously that Short Interspersed Degenerate Retroposons of the SIDER2 subfamily, largely located within 3'UTRs of Leishmania transcripts, promote rapid turnover of mRNAs through endonucleolytic cleavage within the highly conserved second tandem 79-nt hallmark sequence (79-nt SII). Here, we used site-directed mutagenesis and in silico RNA structural studies to delineate the cis-acting requirements within 79-nt SII for cleavage and mRNA degradation. The putative cleavage site(s) and other nucleotides predicted to alter the RNA secondary structure of 79-nt SII were either deleted or mutated and their effect on mRNA turnover was monitored using a gene reporter system. We found that short deletions of 8-nt spanning the two predicted cleavage sites block degradation of SIDER2-containing transcripts, leading to mRNA accumulation. Furthermore, single or double substitutions of the dinucleotides targeted for cleavage as well as mutations altering the predicted RNA secondary structure encompassing both cleavage sites also prevent mRNA degradation, confirming that these dinucleotides are the bona fide cleavage sites. In line with these results, we show that stage-regulated SIDER2 inactivation correlates with the absence of endonucleolytic cleavage. Overall, these data demonstrate that both cleavage sites within the conserved 79-nt SII as well as RNA folding in this region are essential for SIDER2-mediated mRNA decay, and further support that SIDER2-harboring transcripts are targeted for degradation by endonucleolytic cleavage.
Dendrites form predominantly binary trees that are exquisitely embedded in the networks of the brain. While neuronal computation is known to depend on the morphology of dendrites, their underlying topological blueprint remains unknown. Here, we used a centripetal branch ordering scheme originally developed to describe river networks—the Horton-Strahler order (SO)–to examine hierarchical relationships of branching statistics in reconstructed and model dendritic trees. We report on a number of universal topological relationships with SO that are true for all binary trees and distinguish those from SO-sorted metric measures that appear to be cell type-specific. The latter are therefore potential new candidates for categorising dendritic tree structures. Interestingly, we find a faithful correlation of branch diameters with centripetal branch orders, indicating a possible functional importance of SO for dendritic morphology and growth. Also, simulated local voltage responses to synaptic inputs are strongly correlated with SO. In summary, our study identifies important SO-dependent measures in dendritic morphology that are relevant for neural function while at the same time it describes other relationships that are universal for all dendrites.
Yeast large ribosomal subunit (LSU) precursors are subject to substantial changes in protein composition during their maturation due to coordinated transient interactions with a large number of ribosome biogenesis factors and due to the assembly of ribosomal proteins. These compositional changes go along with stepwise processing of LSU rRNA precursors and with specific rRNA folding events, as revealed by recent cryo-electron microscopy analyses of late nuclear and cytoplasmic LSU precursors. Here we aimed to analyze changes in the spatial rRNA surrounding of selected ribosomal proteins during yeast LSU maturation. For this we combined a recently developed tethered tertiary structure probing approach with both targeted and high throughput readout strategies. Several structural features of late LSU precursors were faithfully detected by this procedure. In addition, the obtained data let us suggest that early rRNA precursor processing events are accompanied by a global transition from a flexible to a spatially restricted rRNA conformation. For intermediate LSU precursors a number of structural hallmarks could be addressed which include the fold of the internal transcribed spacer between 5.8S rRNA and 25S rRNA, the orientation of the central protuberance and the spatial organization of the interface between LSU rRNA domains I and III.
Mistakes in translation of messenger RNA into protein are clearly a detriment to the recombinant production of pure proteins for biophysical study or the biopharmaceutical market. However, they may also provide insight into mechanistic details of the translation process. Mistakes often involve the substitution of an amino acid having an abundant codon for one having a rare codon, differing by substitution of a G base by an A base, as in the case of substitution of a lysine (AAA) for arginine (AGA). In these cases one expects the substitution frequency to depend on the relative abundances of the respective tRNAs, and thus, one might expect frequencies to be similar for all sites having the same rare codon. Here we demonstrate that, for the ADP-ribosylation factor from yeast expressed in E. coli, lysine for arginine substitutions frequencies are not the same at the 9 sites containing a rare arginine codon; mis-incorporation frequencies instead vary from less than 1 to 16%. We suggest that the context in which the codons occur (clustering of rare sites) may be responsible for the variation. The method employed to determine the frequency of mis-incorporation involves a novel mass spectrometric analysis of the products from the parallel expression of wild type and codon-optimized genes in 15N and 14N enriched media, respectively. The high sensitivity and low material requirements of the method make this a promising technology for the collection of data relevant to other mis-incorporations. The additional data could be of value in refining models for the ribosomal translation elongation process.
Mobilization of hematopoietic stem cells (HSCs) from the bone marrow to the peripheral blood is a complex mechanism that involves adhesive and chemotactic interactions of HSCs as well as their bone marrow microenvironment. In addition to a number of non-genetic factors, genetic susceptibilities also contribute to the mobilization outcome. Identification of genetic factors associated with HSC yield is important to better understand the mechanism behind HSC mobilization. In the present study, we enrolled 148 Korean participants (56 healthy donors and 92 patients) undergoing HSC mobilization for allogeneic or autologous HSC transplantation. Among a total of 53 polymorphisms in 33 candidate genes, one polymorphism (rs11264422) in relaxin/insulin-like family peptide receptor 4 (RXFP4) gene was significantly associated with a higher HSC yield after mobilization in Koreans. However, in a set of 101 Europeans, no association was found between circulating CD34+ cell counts and rs11264422 genotype. Therefore, we suggest that the ethnic differences in subjects’ genetic background may be related to HSC mobilization. In conclusion, the relaxin—relaxin receptor axis may play an important role in HSC mobilization. We believe that the results of the current study could provide new insights for therapies that use relaxin and HSC populations, as well as a better understanding of HSC regulation and mobilization at the molecular level.
Purpose: To evaluate the effect of reduced z-axis scan coverage on diagnostic performance and radiation dose of neck CT in patients with suspected cervical abscess.
Methods: Fifty-one patients with suspected cervical abscess were included and underwent contrast-enhanced neck CT on a 2nd or 3rd generation dual-source CT system. Image acquisition ranged from the aortic arch to the upper roof of the frontal sinuses (CTstd). Subsequently, series with reduced z-axis coverage (CTred) were reconstructed starting at the aortic arch up to the orbital floor. CTstd and CTred were independently assessed by two radiologists for the presence/absence of cervical abscesses and for incidental and alternative findings. In addition, diagnostic accuracy for the depiction of the cervical abscesses was calculated for both readers. Furthermore, DLP (dose-length-product), effective dose (ED) and organ doses were calculated and compared for CTred and CTstd, using a commercially available dose management platform.
Results: A total of 41 abscesses and 3 incidental/alternative findings were identified in CTstd. All abscesses and incidental/alternative findings could also be detected on CTred resulting in a sensitivity and specificity of 1.0 for both readers. DLP, ED and organ doses of the brain, the eye lenses, the red bone marrow and the salivary glands of CTred were significantly lower than for CTstd (p<0.001).
Conclusions: Reducing z-axis coverage of neck CT allows for a significant reduction of effective dose and organ doses at similar diagnostic performance as compared to CTstd.
Alzheimer’s disease (AD) is the most common form of dementia in the elderly; important risk factors are old age and inheritance of the apolipoprotein E4 (APOE4) allele. Changes in amyloid precursor protein (APP) binding, trafficking, and sorting may be important AD causative factors. Secretase-mediated APP cleavage produces neurotoxic amyloid-beta (Aβ) peptides, which form lethal deposits in the brain. In vivo and in vitro studies have implicated sortilin-related receptor (SORL1) as an important factor in APP trafficking and processing. Recent in vitro evidence has associated the APOE4 allele and alterations in the SORL1 pathway with AD development and progression. Here, we analyzed SORL1 expression in neural stem cells (NSCs) from AD patients carrying null, one, or two copies of the APOE4 allele. We show reduced SORL1 expression only in NSCs of a patient carrying two copies of APOE4 allele with increased Aβ/SORL1 localization along the degenerated neurites. Interestingly, SORL1 binding to APP was largely compromised; this could be almost completely reversed by γ-secretase (but not β-secretase) inhibitor treatment. These findings may yield new insights into the complex interplay of SORL1 and AD pathology and point to NSCs as a valuable tool to address unsolved AD-related questions in vitro.
Serine/arginine-protein kinase 1 (SRPK1) regulates alternative splicing of VEGF-A to pro-angiogenic isoforms and SRPK1 inhibition can restore the balance of pro/antiangiogenic isoforms to normal physiological levels. The lack of potency and selectivity of available compounds has limited development of SRPK1 inhibitors, with the control of alternative splicing by splicing factor-specific kinases yet to be translated. We present here compounds that occupy a binding pocket created by the unique helical insert of SRPK1, and trigger a backbone flip in the hinge region, that results in potent (<10 nM) and selective inhibition of SRPK1 kinase activity. Treatment with these inhibitors inhibited SRPK1 activity and phosphorylation of serine/arginine splicing factor 1 (SRSF1), resulting in alternative splicing of VEGF-A from pro-angiogenic to antiangiogenic isoforms. This property resulted in potent inhibition of blood vessel growth in models of choroidal angiogenesis in vivo. This work identifies tool compounds for splice isoform selective targeting of pro-angiogenic VEGF, which may lead to new therapeutic strategies for a diversity of diseases where dysfunctional splicing drives disease development.
The transcription factor Meis1 drives myeloid leukemogenesis in the context of Hox gene overexpression but is currently considered undruggable. We therefore investigated whether myeloid progenitor cells transformed by Hoxa9 and Meis1 become addicted to targetable signaling pathways. A comprehensive (phospho)proteomic analysis revealed that Meis1 increased Syk protein expression and activity. Syk upregulation occurs through a Meis1-dependent feedback loop. By dissecting this loop, we show that Syk is a direct target of miR-146a, whose expression is indirectly regulated by Meis1 through the transcription factor PU.1. In the context of Hoxa9 overexpression, Syk signaling induces Meis1, recapitulating several leukemogenic features of Hoxa9/Meis1-driven leukemia. Finally, Syk inhibition disrupts the identified regulatory loop, prolonging survival of mice with Hoxa9/Meis1-driven leukemia.
Background: This study aims at identifying orthodontic activities with the highest frequency of unfavorable/awkward and static postures held over a period of more than 4 s based on kinematic analysis. Moreover, a separate analysis of static postures for orthodontic and non-orthodontic activities serves to evaluate the duration for which these particular postures are assumed.
Methods: In total, 21 (13f/8 m) orthodontists (age: 31.5 ± 3.8 years) participated in this study. CUELA, a personal measurement system, was used to collect kinematic data for all orthodontic activities in a working day. Angle values of the head and torso were evaluated in accordance with ergonomic standards. Only those postures that were held statically for 4 s and longer were selected for further analysis. Alongside the kinematic analysis, the activities performed on-site were also subject to a detailed computerized analysis. The synchronization of data collected from both measurements arranges the patterns of posture found chronologically and in conjunction with the orthodontic activities performed ((I) "treatment" (II) "office" and (III) "other activities").
Results: For (I) we observed an anterior inclination of the head and torso area as well as a twist of the head and neck area to the right. We found anterior back inclination and lateral back torsion to the right for (II) and (III). If, furthermore, we differentiate the duration of static postures, there are primarily short to medium-term (4–30s) static postures identified for (I). Also, categories (II) and (III) predominantly demonstrate static back postures with a duration of up to 30 s. With regard to (II) we observed that the back is ventrally inclined for 10.1% of the total activity duration.
Conclusions: During treatment static strains are observed in the entire head and torso area. On the contrary, static postures prevalent in the torso area are essential for activities of the other categories, particularly office work. These findings allow for a careful selection of unfavorable and static postures for each of the activities performed and help to develop specific preventive measures.
Background: Many fungal species occur across a variety of habitats. Particularly lichens, fungi forming symbioses with photosynthetic partners, have evolved remarkable tolerances for environmental extremes. Despite their ecological importance and ubiquity, little is known about the genetic basis of adaption in lichen populations. Here we studied patterns of genome-wide differentiation in the lichen-forming fungus Lasallia pustulata along an altitudinal gradient in the Mediterranean region. We resequenced six populations as pools and identified highly differentiated genomic regions. We then detected gene-environment correlations while controlling for shared population history and pooled sequencing bias, and performed ecophysiological experiments to assess fitness differences of individuals from different environments.
Results: We detected two strongly differentiated genetic clusters linked to Mediterranean and temperate-oceanic climate, and an admixture zone, which coincided with the transition between the two bioclimates. High altitude individuals showed ecophysiological adaptations to wetter and more shaded conditions. Highly differentiated genome regions contained a number of genes associated with stress response, local environmental adaptation, and sexual reproduction.
Conclusions: Taken together our results provide evidence for a complex interplay between demographic history and spatially varying selection acting on a number of key biological processes, suggesting a scenario of ecological speciation.
Background: Transient receptor potential cation channel subfamily V member 1 (TRPV1) are sensitive to heat, capsaicin, pungent chemicals and other noxious stimuli. They play important roles in the pain pathway where in concert with proinflammatory factors such as leukotrienes they mediate sensitization and hyperalgesia. TRPV1 is the target of several novel analgesics drugs under development and therefore, TRPV1 genetic variants might represent promising candidates for pharmacogenetic modulators of drug effects.
Methods: A next-generation sequencing (NGS) panel was created for the human TRPV1 gene and in addition, for the leukotriene receptors BLT1 and BLT2 recently described to modulate TRPV1 mediated sensitisation processes rendering the coding genes LTB4R and LTB4R2 important co-players in pharmacogenetic approaches involving TRPV1. The NGS workflow was based on a custom AmpliSeq™ panel and designed for sequencing of human genes on an Ion PGM™ Sequencer. A cohort of 80 healthy subjects of Western European descent was screened to evaluate and validate the detection of exomic sequences of the coding genes with 25 base pair exon padding.
Results: The amplicons covered approximately 97% of the target sequence. A median of 2.81 x 10 6 reads per run was obtained. This identified approximately 140 chromosome loci where nucleotides deviated from the reference sequence GRCh37 hg19 comprising the three genes TRPV1, LTB4R and LTB4R2. Correspondence between NGS and Sanger derived nucleotide sequences was 100%.
Conclusions: Results suggested that the NGS approach based on AmpliSeq™ libraries and Ion Personal Genome Machine (PGM) sequencing is a highly efficient mutation detection method. It is suitable for large-scale sequencing of TRPV1 and functionally related genes. The method adds a large amount of genetic information as a basis for complete analysis of TRPV1 ion channel genetics and its functional consequences.
Drug product performance testing is an important part of quality-by-design approaches, but this process often lacks the underlying mechanistic understanding of the complex interactions between the disintegration and dissolution processes involved. Whereas a recent draft guideline by the US Food and Drug Administration (FDA) has allowed the replacement of dissolution testing with disintegration testing, the mentioned criteria are not globally accepted. This study provides scientific justification for using disintegration testing rather than dissolution testing as a quality control method for certain immediate release (IR) formulations. A mechanistic approach, which is beyond the current FDA criteria, is presented. Dissolution testing via United States Pharmacopeial Convention Apparatus II at various paddle speeds was performed for immediate and extended release formulations of metronidazole. Dissolution profile fitting via DDSolver and dissolution profile predictions via DDDPlus™ were performed. The results showed that Fickian diffusion and drug particle properties (DPP) were responsible for the dissolution of the IR tablets, and that formulation factors (eg, coning) impacted dissolution only at lower rotation speeds. Dissolution was completely formulation controlled if extended release tablets were tested and DPP were not important. To demonstrate that disintegration is the most important dosage form attribute when dissolution is DPP controlled, disintegration, intrinsic dissolution and dissolution testing were performed in conventional and disintegration impacting media (DIM). Tablet disintegration was affected by DIM and model fitting to the Korsmeyer–Peppas equation showed a growing effect of the formulation in DIM. DDDPlus was able to predict tablet dissolution and the intrinsic dissolution profiles in conventional media and DIM. The study showed that disintegration has to occur before DPP-dependent dissolution can happen. The study suggests that disintegration can be used as performance test of rapidly disintegrating tablets beyond the FDA criteria. The scientific criteria and justification is that dissolution has to be DPP dependent, originated from active pharmaceutical ingredient characteristics and formulations factors have to be negligible.
Wir erleben eine enorme Beschleunigung, besonders im Berufsleben. Unser Alltag ist überfrachtet von Dringlichem und Deadlines. Und dann mit über 60 folgt der Ausstieg aus dem ausgefüllten, für manche erfüllten Berufsleben: Welche Risiken birgt dieser Übergang? Dazu der Sozialpsychologe Prof. Rolf Haubl (65) im Gespräch mit Ulrike Jaspers (60).
Verschlafen? Ausgeschlafen!
(2017)
Robert Anton ist zuständig für die Pflege und Entwicklung der Außenanlagen aller Campi der Universität und Technischer Leiter des Wissenschaftsgartens am Riedberg. Mit seinem Team sorgt er nicht nur dafür, dass die Grünanlagen schön aussehen, sondern er stellt auch Pflanzen für Vorlesungen und Praktika bereit, unterstützt die Wissenschaftler bei Freilandversuchen und bildet Gärtner aus. Diese Aufgaben füllen seine Zeit aus. Sein oberster Taktgeber ist dabei der Rhythmus der Natur. An diesem Wintertag hat er deswegen auch Zeit, sich mit mir zu unterhalten. "Im Winter geht alles etwas geruhsamer. Da räumen wir auf, spülen Blumentöpfe und bereiten die Aussaat im Frühling vor." ...
Lässt sich eine dominierende Zeitvorstellung für unsere Epoche ausmachen? Ist die moderne Unruhe eine neue Unruhe? Solche Fragen gehören zu den zentralen Themen von Christoph Cornelißen, Professor für Neueste Geschichte an der Goethe-Universität, dessen Forschungsschwerpunkte Historiografie-Geschichte und die Geschichte der Erinnerungskulturen einschließen.
Kernarbeitszeit oder Überstunden – solche Begriffe tauchen heute in Arbeitsverträgen kaum noch auf. Ist ein Problem zu lösen, dann geschieht das eben auch nachts oder am Wochenende. 84 Prozent der Arbeitnehmer sind mit ihrem Smartphone auch außerhalb der Arbeitszeit im Standby-Modus. Flexible Arbeitszeiten und individualisierte Arbeitsmodelle bringen zwar dem Einzelnen mehr Freiheiten, um den Alltag seinen Lebensumständen anzupassen, führen aber auch zur Entgrenzung der Arbeit, nicht selten mit gravierenden sozialen und besonders gesundheitlichen Folgen.
Leuchtend Licht und liebliches Leben : über Zeit und Glück bei Walter Benjamin und Marcel Proust
(2017)
Wenn das menschliche Leben der Vergänglichkeit unterworfen ist, wie kann der Mensch dann Glück erfahren? Für Walter Benjamin offenbart sich Glück nur in kurzen Momenten als eine Erlösung von der linear fortschreitenden Zeit, und das geschieht in der Begegnung mit der Kunst. Marcel Proust sucht das Glück in der wiedergefundenen Zeit der Erinnerung – auch dies bleiben Erfahrungen des Augenblicks.
Die Blockchain hält nicht nur Banken, Börsen und ihre Aufseher in Atem. Auch Wissenschaftler der Goethe-Universität sind ganz vorne dabei, wenn es um diese neue Technologie und andere Varianten der Distributed-Ledger-Technologie geht. Zu deren vielfältigen Verheißungen zählt die Abwicklung von Geld- und Handelsgeschäften nahezu in Echtzeit.
Was Du heute kannst besorgen, das verschiebe nicht auf morgen: Dieser sprichwörtliche Rat kommt nicht von ungefähr. Viele von uns schieben oft wochenlang eine Aufgabe vor sich her – häufig mit schlechtem Gewissen. Doch woher kommt das ewige Aufschieben eigentlich? Wer ist davon betroffen? Und was kann man dagegen tun?
Dringlichkeiten geben häufig den Takt im Alltag vor. Denn Wettbewerbsdruck und damit verbundene Beschleunigung verändern nicht nur die Arbeitswelt, sondern auch den Familienalltag und die individuelle Lebensführung. Doch weshalb gewinnen im Umgang mit der Zeit Kriterien der Effizienz und "Rendite" so leicht an Bedeutung? Offenbar wird es keineswegs nur als leidvoll erlebt, sich daran anzupassen.
Jede Zeitnische will ausgefüllt sein mit Chatten, Spielen oder E-Mails-Abrufen. Zeit, die für das Innehalten und Durchatmen fehlt. Bestimmen die digitalen Medien unser Leben, begeben wir uns wie Geiseln in ihre Abhängigkeit? Oder ist es umgekehrt: Können wir überhaupt erst mit ihrer Hilfe ein selbstbestimmteres Leben führen?
Sie rast, sie schleicht, sie fließt, sie tröpfelt: Obwohl der Tag immer 24 Stunden hat, nehmen wir die Zeit sehr unterschiedlich wahr. In der Kindheit tickt die innere Uhr anders als in der Rushhour des Lebens oder kurz vor dem Tod. Aber nicht nur das Alter spielt eine Rolle, sondern viele weitere Faktoren beeinflussen unser Zeitempfinden.
Laut jüdischem Kalender entstand die Welt vor genau 5778 Jahren, nach der Bibel vor 6021 Jahren. Doch als Forscher begannen, auf und in der Erde selbst nach Spuren ihres Alters zu suchen, mussten sie die Zahl immer weiter nach oben korrigieren. Nach heutigen Datierungsmethoden ist unser Planet zwischen 4,5 und 4,6 Milliarden Jahre alt.
In cancer medicine, particularly in drug research and development, structural changes in professionalism can be observed as examples. This field is characterized by a strong tension between social expectations concerning the control of existential risks to health, on the one hand, and strong commercial interests of a shareholder value-driven industry, on the other hand. Based on a qualitative empirical analysis, two subfields within the field of cancer medicine are reconstructed. One of these subfields—colon cancer therapy—could be interpreted as representing a renewal of the knowledge-power nexus. The pattern of the other subfield—brain tumour research—refers to a much more vulnerable professionalism. Both fields are characterized by development in professional work, which could be described with the hybridization concept. Therefore, the contrast between the two empirical examples presented still challenges the theoretical interpretation of contemporary professionalism.
Multimorbilidad en medicina de familia y los principios Ariadne : un enfoque centrado en la persona
(2017)
La multimorbilidad, definida como la presencia de dos o más enfermedades crónicas en un mismo individuo, conlleva consecuencias negativas para la persona e importantes retos para los sistemas sanitarios. En atención primaria, donde recae esencialmente la atención de este grupo de pacientes, la consulta es más compleja que la de un paciente con una única enfermedad debido, entre otros, al hecho de tener que manejar mayor cantidad de información clínica, disponer de poca evidencia científica para abordar la multimorbilidad, y tener que coordinar la labor de múltiples profesionales para garantizar la continuidad asistencial. Además, para poder implementar correctamente los planes de tratamiento en estos pacientes es necesario un proceso de toma de decisiones compartida médico-paciente. Entre las distintas herramientas disponibles para apoyar dicho proceso, recientemente se ha desarrollado una dirigida específicamente a pacientes con multimorbilidad en atención primaria y que se describe en el presente artículo: los principios Ariadne.
Epilepsy is a complex neurological disorder which can severely affect neuronal function. Some patients may experience status epilepticus, a life-threatening state of ongoing seizure activity associated with postictal cognitive dysfunction. However, the molecular mechanisms by which status epilepticus influences brain function beyond seizure activity remain not well understood. Here, we addressed the question of whether pilocarpine-induced status epilepticus affects synaptopodin (SP), an actin-binding protein, which regulates the ability of neurons to express synaptic plasticity. This makes SP an interesting marker for epilepsy-associated alterations in synaptic function. Indeed, single dose intraperitoneal pilocarpine injection (250 mg/kg) in three-month-old male C57BL/6J mice leads to a rapid reduction in hippocampal SP-cluster sizes and numbers (in CA1 stratum radiatum of the dorsal hippocampus; 90 min after injection). In line with this observation (and previous work using SP-deficient mice), a defect in the ability to induce long-term potentiation (LTP) of Schaffer collateral-CA1 synapses is observed. Based on these findings we propose that status epilepticus could exert its aftereffects on cognition at least in part by perturbing SP-dependent mechanisms of synaptic plasticity.
IFN-lambda (IFNλ) is a member of the type III IFN family and is reported to possess anti-pathogen, anti-cancer, and immunomodulatory properties; however, there are limited data regarding its impact on host immune responses in vivo. We performed longitudinal and comprehensive immunosurveillance to assess the ability of pegylated (peg)-IFNλ to augment antiviral host immunity as part of a clinical trial assessing the efficacy of peg-IFNλ in chronic hepatitis B (CHB) patients. These patients were pretreated with directly acting antiviral therapy (entecavir) for 12 weeks with subsequent addition of peg-IFNλ for up to 32 weeks. In a subgroup of patients, the addition of peg-IFNλ provoked high serum levels of antiviral cytokine IL-18. We also observed the enhancement of natural killer cell polyfunctionality and the recovery of a pan-genotypic HBV-specific CD4+ T cells producing IFN-γ with maintenance of HBV-specific CD8+ T cell antiviral and cytotoxic activities. It was only in these patients that we observed strong virological control with reductions in both viral replication and HBV antigen levels. Here, we show for the first time that in vivo peg-IFNλ displays significant immunostimulatory properties with improvements in the main effectors mediating anti-HBV immunity. Interestingly, the maintenance in HBV-specific CD8+ T cells in the presence of peg-IFNλ is in contrast to previous studies showing that peg-IFNα treatment for CHB results in a detrimental effect on the functionality of this important antiviral T cell compartment.
Young children are at greatest risk of exposure to lead and its effects. Although lead is one of the most widely used elements with known health hazard, there is little data on the blood lead level (BLL) of children in the Kathmandu Valley. Thus, this study aimed to assess factors associated with high BLL in children who were 6–36 months of age and resided in the Kathmandu Valley. In this hospital-based cross-sectional study 6–36 month-old children visiting the Paediatrics Outpatient Department of Tribhuvan University Teaching Hospital, Patan Hospital, and Siddhi Memorial Hospital were enrolled. All three hospitals are located in different areas inside the Kathmandu Valley. Written informed consent was obtained from the parents, and exposure data were collected using a structured questionnaire. Portable Anodic Stripping Voltammetry (ASV) was used to determine BLLs in children. Data were analyzed using SPSS version 16. Of 312 children enrolled in the study, 64.4% had BLLs ≥5μg/dl. A significant association was found between BLL and exposure to enamel paints in the household in the form of painting materials used in different parts of the house like walls, windows and doors (p = 0.001). Furthermore, multivariate analyses showed that BLLs were 4.5 times higher in children playing with dirt and dust (p = 0.006) and that children belonging to the community of lower caste/ethnicity groups had significantly higher BLLs compared to those from the upper caste groups (p = 0.02). Our study demonstrated that children living in households that have used enamel paints, children belonging to lower caste/ethnic groups, and children frequently playing with dirt and dust had significantly higher BLLs. The results of this study highlight the importance of policy decisions to limit environmental lead contamination, and to roll out awareness building measures designed to limit lead exposure and break the poverty cycle associated with chronic lead poisoning.
Background: Only few authors have analyzed the impact of workplace conflicts and the resulting stress on the risk of developing cardiovascular disorders. The goal of this study was to analyze the association between workplace conflicts and cardiovascular disorders in patients treated by German general practitioners.
Methods: Patients with an initial documentation of a workplace conflict experience between 2005 and 2014 were identified in 699 general practitioner practices (index date). We included only those who were between the ages of 18 and 65 years, had a follow-up time of at least 180 days after the index date, and had not been diagnosed with angina pectoris, myocardial infarction, coronary heart diseases, or stroke prior to the documentation of the workplace mobbing. In total, the study population consisted of 7,374 patients who experienced conflicts and 7,374 controls for analysis. The main outcome measure was the incidence of angina pectoris, myocardial infarction, and stroke correlated with workplace conflict experiences.
Results: After a maximum of five years of follow-up, 2.9% of individuals who experienced workplace conflict were affected by cardiovascular diseases, while only 1.4% were affected in the control group (p-value <0.001). Workplace conflict was associated with a 1.63-fold increase in the risk of developing cardiovascular diseases. Finally, the impact of workplace conflict was higher for myocardial infarction (OR=2.03) than for angina pectoris (OR=1.79) and stroke (OR=1.56).
Conclusions: Overall, we found a significant association between workplace conflicts and cardiovascular disorders.
Ice nucleating particles over the eastern mediterranean measured by unmanned aircraft systems
(2017)
During an intensive field campaign on aerosol, clouds, and ice nucleation in the Eastern Mediterranean in April 2016, we measured the abundance of ice nucleating particles (INPs) in the lower troposphere from unmanned aircraft systems (UASs). Aerosol samples were collected by miniaturized electrostatic precipitators onboard the UASs at altitudes up to 2.5 km. The number of INPs in these samples, which are active in the deposition and condensation modes at temperatures from −20 to −30 °C, were analyzed immediately after collection on site using the ice nucleus counter FRIDGE (FRankfurt Ice nucleation Deposition freezinG Experiment). During the 1-month campaign, we encountered a series of Saharan dust plumes that traveled at several kilometers' altitude. Here we present INP data from 42 individual flights, together with aerosol number concentrations, observations of lidar backscattering, dust concentrations derived by the dust transport model DREAM (Dust Regional Atmospheric Model), and results from scanning electron microscopy. The effect of the dust plumes is reflected by the coincidence of INPs with the particulate matter (PM), the lidar signal, and the predicted dust mass of the model. This suggests that mineral dust or a constituent related to dust was a major contributor to the ice nucleating properties of the aerosol. Peak concentrations of above 100 INPs std L−1 were measured at −30 °C. The INP concentration in elevated plumes was on average a factor of 10 higher than at ground level. Since desert dust is transported for long distances over wide areas of the globe predominantly at several kilometers' altitude, we conclude that INP measurements at ground level may be of limited significance for the situation at the level of cloud formation.
In search for new natural products, which may lead to the development of new drugs for all kind of applications, novel methods are needed. Here we describe the identification of electrophilic natural products in crude extracts via their reactivity against azide as a nucleophile followed by their subsequent enrichment using a cleavable azide-reactive resin (CARR). Using this approach, natural products carrying epoxides and α,β-unsaturated enones as well as several unknown compounds were identified in crude extracts from entomopathogenic Photorhabdus bacteria.