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Background and Objectives: Patient blood (more accurately: haemoglobin, Hb) management (PBM) aims to optimize endogenous Hb production and to minimize iatrogenic Hb loss while maintaining patient safety and optimal effectiveness of medical interventions. PBM was adopted as policy for patients by the World Health Organization (WHO), and, all the more, should be applied to healthy donors. Materials and Methods: Observational data from 489 bone marrow (BM) donors were retrospectively analysed, and principles of patient blood management were applied to healthy volunteer BM donations. Results and Conclusion: We managed to render BM aspiration safe for donors, notably completely avoiding the collection of autologous blood units and blood transfusions through iron management, establishment and curation of high-yield aspiration technique, limitation of collection volume to 1·5% of donor body weight and development of volume prediction algorithms for the requested cell dose.
Chirality is omnipresent in living nature. On the single molecule level, the response of a chiral species to a chiral probe depends on their respective handedness. A prominent example is the difference in the interaction of a chiral molecule with left or right circularly polarized light. In the present study, we show by Coulomb explosion imaging that circularly polarized light can also induce a chiral fragmentation of a planar and thus achiral molecule. The observed enantiomer strongly depends on the orientation of the molecule with respect to the light propagation direction and the helicity of the ionizing light. This finding might trigger new approaches to improve laser-driven enantioselective chemical synthesis.
Background: The West African country of Burkina Faso (BFA) is an example for the enduring importance of traditional plant use today. A large proportion of its 17 million inhabitants lives in rural communities and strongly depends on local plant products for their livelihood. However, literature on traditional plant use is still scarce and a comprehensive analysis for the country is still missing.
Methods: In this study we combine the information of a recently published plant checklist with information from ethnobotanical literature for a comprehensive, national scale analysis of plant use in Burkina Faso. We quantify the application of plant species in 10 different use categories, evaluate plant use on a plant family level and use the relative importance index to rank all species in the country according to their usefulness. We focus on traditional medicine and quantify the use of plants as remedy against 22 classes of health disorders, evaluate plant use in traditional medicine on the level of plant families and rank all species used in traditional medicine according to their respective usefulness.
Results: A total of 1033 species (50%) in Burkina Faso had a documented use. Traditional medicine, human nutrition and animal fodder were the most important use categories. The 12 most common plant families in BFA differed considerably in their usefulness and application. Fabaceae, Poaceae and Malvaceae were the plant families with the most used species. In this study Khaya senegalensis, Adansonia digitata and Diospyros mespiliformis were ranked the top useful plants in BFA. Infections/Infestations, digestive system disorders and genitourinary disorders are the health problems most commonly addressed with medicinal plants. Fabaceae, Poaceae, Asteraceae, Apocynaceae, Malvaceae and Rubiaceae were the most important plant families in traditional medicine. Tamarindus indica, Vitellaria paradoxa and Adansonia digitata were ranked the most important medicinal plants.
Conclusions: The national-scale analysis revealed systematic patterns of traditional plant use throughout BFA. These results are of interest for applied research, as a detailed knowledge of traditional plant use can a) help to communicate conservation needs and b) facilitate future research on drug screening.
Hintergrund: Der eigene Körper ist das zentrale Arbeitsinstrument eines*einer Tanzpädagog*in (TP) innerhalb der Bewegungsvermittlung. Bisher fehlen Erkenntnisse über die subjektive Wahrnehmung der eigenen berufsassoziierten Gesundheit und Zufriedenheit sowie die Identifizierung gesundheitsbelastender Berufsmerkmale.
Methodik: Im Rahmen einer fragebogenbasierten Querschnittserhebung wurde eine Kohorte von TP in Deutschland zur eigenen Gesundheit und generellen Berufszufriedenheit und belastenden Aspekten im Zusammenhang mit ihrer Berufsausübung untersucht. Zusätzlich wurden allgemeine anthropometrische und soziodemographische Merkmale erfasst. Neben der Betrachtung der Gesamtkohorte wurde auf geschlechtsspezifische Unterschiede getestet. In die statistische Analyse wurden n = 232 TP (m: 51/w: 181) im Alter von 43,1 ± 11,0 Jahren eingeschlossen.
Ergebnisse: Der allgemeine Gesundheitszustand wurde von 85,3 % der Befragten mit „befriedigend“ (26,1 %) bis „sehr gut“ (14,7 %) beurteilt. 59,2 % der Tanzpädagog*innen schätzten ihre Gesundheit „gut“ (35,3 %) bis „sehr gut“ ein. Es herrschte eine hohe Zufriedenheit mit der eigenen Berufsausübung für 80 % der Teilnehmenden. Die TP fühlten sich überwiegend in der Lage (trifft „voll & ganz“ bzw. „eher zu“), mit den physischen (75,7 %) und psychischen Berufsanforderungen (70,3 %) umzugehen. Als belastende Berufsmerkmale in der Eigenwahrnehmung können neben Zukunftsängsten (51,5 %) vor allem arbeitsorganisatorische (fehlende Zeit für Familie und Freunde bei 28,4 %) und ökonomische Aspekte (Einkommensunsicherheit bei 61,0 % und fehlende Altersabsicherung bei 65,7 %) herausgestellt werden.
Diskussion: Die Berufsausübung als TP geht mit einer hohen generellen Zufriedenheit und einem positiven Empfinden des eigenen Gesundheitszustandes einher. Eine Bestätigung dieser positiven Ergebnisse durch Verletzungs- und Erkrankungsstatistiken steht noch aus. Darüber hinaus wäre eine Verbesserung arbeitsorganisatorischer und ökonomischer Aspekte wünschenswert.
BIOfid is a specialized information service currently being developed to mobilize biodiversity data dormant in printed historical and modern literature and to offer a platform for open access journals on the science of biodiversity. Our team of librarians, computer scientists and biologists produce high-quality text digitizations, develop new text-mining tools and generate detailed ontologies enabling semantic text analysis and semantic search by means of user-specific queries. In a pilot project we focus on German publications on the distribution and ecology of vascular plants, birds, moths and butterflies extending back to the Linnaeus period about 250 years ago. The three organism groups have been selected according to current demands of the relevant research community in Germany. The text corpus defined for this purpose comprises over 400 volumes with more than 100,000 pages to be digitized and will be complemented by journals from other digitization projects, copyright-free and project-related literature. With TextImager (Natural Language Processing & Text Visualization) and TextAnnotator (Discourse Semantic Annotation) we have already extended and launched tools that focus on the text-analytical section of our project. Furthermore, taxonomic and anatomical ontologies elaborated by us for the taxa prioritized by the project’s target group - German institutions and scientists active in biodiversity research - are constantly improved and expanded to maximize scientific data output. Our poster describes the general workflow of our project ranging from literature acquisition via software development, to data availability on the BIOfid web portal (http://biofid.de/), and the implementation into existing platforms which serve to promote global accessibility of biodiversity data.
With the ongoing loss of global biodiversity, long-term recordings of species distribution patterns are increasingly becoming important to investigate the causes and consequences for their change. Therefore, the digitization of scientific literature, both modern and historical, has been attracting growing attention in recent years. To meet this growing demand the Specialised Information Service for Biodiversity Research (BIOfid) was launched in 2017 with the aim of increasing the availability and accessibility of biodiversity information. Closely tied to the research community the interdisciplinary BIOfid team is digitizing data sources of biodiversity related research and provides a modern and professional infrastructure for hosting and sharing them. As a pilot project, German publications on the distribution and ecology of vascular plants, birds, moths and butterflies covering the past 250 years are prioritized. Large parts of the text corpus defined in accordance with the needs of the relevant German research community have already been transferred to a machine-readable format and will be publicly accessible soon. Software tools for text mining, semantic annotation and analysis with respect to the current trends in machine learning are developed to maximize bioscientific data output through user-specific queries that can be created via the BIOfid web portal (https://www.biofid.de/). To boost knowledge discovery, specific ontologies focusing on morphological traits and taxonomy are being prepared and will continuously be extended to keep up with an ever-expanding volume of literature sources.
Two new species of ants (Hymenoptera: Formicidae) collected from New Caledonia are described and figured based on worker specimens: Leptogenys loarelae Ramage sp. nov. (Ponerinae, Ponerini) and Lioponera neocaledonica Jouault, Ramage & Perrichot sp. nov. (Dorylinae, Cerapachyini). All specimens were collected from the South Province of Grande Terre. These two new species are primarily distinguished from the other New Caledonian relatives by the size and shape of petiole for L. loarelae Ramage sp. nov. and by the presence of dorsolateral margins on the mesosoma for L. neocaledonica Jouault, Ramage & Perrichot sp. nov. Keys to New Caledonian Leptogenys and Lioponera are provided.
Herb induced liver injury (HILI) is a particular challenge that also applies to purported cases presumably caused by black cohosh (BC), an herb commonly used to treat menopausal symptoms. We analyzed and reviewed all published case reports and spontaneous reports of initially alleged BC hepatotoxicity regarding quality of case details and causality assessments. Shortcomings of data quality were more evident in spontaneous reports of regulatory agencies compared to published case reports, but assessments with the scale of CIOMS (Council for the International Organizations of Sciences) or its updated version revealed lack of causality for BC in all cases. The applied causality methods are structured, quantitative, and liver specific with clear preference over an ad hoc causality method or the liver unspecific Naranjo scale. Reviewing the case data and the reports dealing with quality specifications of herbal BC products, there is general lack of analysis with respect to authentication of BC in the BC products used by the patients. However, in one single regulatory study, there was a problem of BC authentication in the analysed BC products, and other reports addressed the question of impurities and adulterants in a few BC products. It is concluded that the use of BC may not exert an overt hepatotoxicity risk, but quality problems in a few BC products were evident that require additional regulatory quality specifications.
Background: School attendance during the COVID-19 pandemic is intensely debated.
Aim: In November 2020, we assessed SARS-CoV-2 infections and seroreactivity in 24 randomly selected school classes and connected households in Berlin, Germany.
Methods: We collected oro-nasopharyngeal swabs and blood samples, examining SARS-CoV-2 infection and IgG antibodies by RT-PCR and ELISA. Household members self-swabbed. We assessed individual and institutional prevention measures. Classes with SARS-CoV-2 infection and connected households were retested after 1 week.
Results: We examined 1,119 participants, including 177 primary and 175 secondary school students, 142 staff and 625 household members. SARS-CoV-2 infection occurred in eight classes, affecting each 1–2 individuals. Infection prevalence was 2.7% (95% confidence interval (CI): 1.2–5.0; 9/338), 1.4% (95% CI: 0.2–5.1; 2/140), and 2.3% (95% CI: 1.3–3.8; 14/611) among students, staff and household members. Six of nine infected students were asymptomatic at testing. We detected IgG antibodies in 2.0% (95%CI: 0.8–4.1; 7/347), 1.4% (95% CI: 0.2–5.0; 2/141) and 1.4% (95% CI: 0.6–2.7; 8/576). Prevalence increased with inconsistent facemask-use in school, walking to school, and case-contacts outside school. For three of nine households with infection(s), origin in school seemed possible. After 1 week, no school-related secondary infections appeared in affected classes; the attack rate in connected households was 1.1%.
Conclusion: School attendance under rigorously implemented preventive measures seems reasonable. Balancing risks and benefits of school closures need to consider possible spill-over infection into households. Deeper insight is required into the infection risks due to being a schoolchild vs attending school.
Background: School attendance during the SARS-CoV-2 pandemic is intensely debated. Modelling studies suggest that school closures contribute to community transmission reduction. However, data among school-attending students and staff are scarce. In November 2020, we examined SARS-CoV-2 infections and seroreactivity in 24 randomly selected school classes and connected households in Berlin, Germany.
Methods: Students and school staff were examined, oro-nasopharyngeal swabs and blood samples collected, and SARS-CoV-2 infection and IgG antibodies detected by RT-PCR and ELISA. Household members performed self-swabs. Individual and institutional infection prevention and control measures were assessed. Classes with SARS-CoV-2 infection and connected household members were re-tested after one week.
Findings: 1119 participants were examined, including 177 primary and 175 secondary school students, 142 staff, and 625 household members. Participants reported mainly cold symptoms (19·4%). SARS-CoV-2 infection occurred in eight of 24 classes affecting each 1-2 individuals. Infection prevalence was 2·7% (95%CI; 1·2-5·0%; 9/338), 1·4% (0·2-5·1%; 2/140), and 2·3% (1·3-3·8%; 14/611) among students, staff and household members, respectively, including quarantined persons. Six of nine infected students were asymptomatic. Prevalence increased with inconsistent facemask use in school, way to school on foot, and case-contacts outside school. IgG antibodies were detected in 2·0% (0·8-4·1%; 7/347), 1·4% (0·2-5·0%; 2/141) and 1·4% (0·6-2·7%; 8/576), respectively. For three of nine households with infection(s) detected at cross-sectional assessment, origin in school seemed possible. After one week, no school-related, secondary infections appeared in affected classes; the attack rate in connected households was 1·1%.
Interpretation: These data suggest that school attendance under preventive measures is feasible, provided their rigorous implementation. In balancing threats and benefits of open versus closed schools during the pandemic, parents and society need to consider possible spill-overs into their households. Deeper insight is needed into the infection risks due to being a schoolchild as compared to attending school.
In vivo inducible reverse genetics in patients' tumors to identify individual therapeutic targets
(2021)
High-throughput sequencing describes multiple alterations in individual tumors, but their functional relevance is often unclear. Clinic-close, individualized molecular model systems are required for functional validation and to identify therapeutic targets of high significance for each patient. Here, we establish a Cre-ERT2-loxP (causes recombination, estrogen receptor mutant T2, locus of X-over P1) based inducible RNAi- (ribonucleic acid interference) mediated gene silencing system in patient-derived xenograft (PDX) models of acute leukemias in vivo. Mimicking anti-cancer therapy in patients, gene inhibition is initiated in mice harboring orthotopic tumors. In fluorochrome guided, competitive in vivo trials, silencing of the apoptosis regulator MCL1 (myeloid cell leukemia sequence 1) correlates to pharmacological MCL1 inhibition in patients´ tumors, demonstrating the ability of the method to detect therapeutic vulnerabilities. The technique identifies a major tumor-maintaining potency of the MLL-AF4 (mixed lineage leukemia, ALL1-fused gene from chromosome 4) fusion, restricted to samples carrying the translocation. DUX4 (double homeobox 4) plays an essential role in patients’ leukemias carrying the recently described DUX4-IGH (immunoglobulin heavy chain) translocation, while the downstream mediator DDIT4L (DNA-damage-inducible transcript 4 like) is identified as therapeutic vulnerability. By individualizing functional genomics in established tumors in vivo, our technique decisively complements the value chain of precision oncology. Being broadly applicable to tumors of all kinds, it will considerably reinforce personalizing anti-cancer treatment in the future.
The NVX-CoV2373-vaccine has recently been licensed, although data on vaccine-induced humoral and cellular immunity towards the parental strain and variants of concern (VOCs) in comparison to dual-dose mRNA-regimens are limited. In this observational study including 66 participants, we show that NVX-CoV2373-induced IgG-levels were lower than after vaccination with BNT162b2 or mRNA-1273 (n=22 each, p=0.006). Regardless of the vaccine and despite different IgG-levels, neutralizing activity towards VOCs was highest for Delta, followed by BA.2 and BA.1. Interestingly, spike-specific CD8 T-cell levels after NVX-CoV2373-vaccination were significantly lower and were detectable in 3/22 (14%) individuals only. In contrast, spike-specific CD4 T-cells were induced in 18/22 (82%) individuals. However, CD4 T-cell levels were lower (p<0.001), had lower CTLA-4 expression (p<0.0001) and comprised less multifunctional cells co-expressing IFNγ, TNFαα and IL-2 (p=0.0007) as compared to mRNA-vaccinated individuals. Unlike neutralizing antibodies, NVX-CoV2373-induced CD4 T cells cross-reacted to all tested VOCs from Alpha to Omicron, which may hold promise to protect from severe disease.
Ziele: Das Ziel dieser offiziellen Leitlinie, die von der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG) und der Deutschen Krebsgesellschaft (DKG) publiziert und koordiniert wurde, ist es, die Früherkennung, Diagnostik, Therapie und Nachsorge des Mammakarzinoms zu optimieren.
Methoden: Der Aktualisierungsprozess der S3-Leitlinie aus 2012 basierte zum einen auf der Adaptation identifizierter Quellleitlinien und zum anderen auf Evidenzübersichten, die nach Entwicklung von PICO-(Patients/Interventions/Control/Outcome-)Fragen, systematischer Recherche in Literaturdatenbanken sowie Selektion und Bewertung der gefundenen Literatur angefertigt wurden. In den interdisziplinären Arbeitsgruppen wurden auf dieser Grundlage Vorschläge für Empfehlungen und Statements erarbeitet, die im Rahmen von strukturierten Konsensusverfahren modifiziert und graduiert wurden.
Empfehlungen: Der Teil 1 dieser Kurzversion der Leitlinie zeigt Empfehlungen zur Früherkennung, Diagnostik und Nachsorge des Mammakarzinoms: Der Stellenwert des Mammografie-Screenings wird in der aktualisierten Leitlinienversion bestätigt und bildet damit die Grundlage der Früherkennung. Neben den konventionellen Methoden der Karzinomdiagnostik wird die Computertomografie (CT) zum Staging bei höherem Rückfallrisiko empfohlen. Die Nachsorgekonzepte beinhalten Untersuchungsintervalle für die körperliche Untersuchung, Ultraschall und Mammografie, während weiterführende Gerätediagnostik und Tumormarkerbestimmungen bei der metastasierten Erkrankung Anwendung finden.
Purpose: The aim of this official guideline coordinated and published by the German Society for Gynecology and Obstetrics (DGGG) and the German Cancer Society (DKG) was to optimize the screening, diagnosis, therapy and follow-up care of breast cancer.
Methods: The process of updating the S3 guideline dating from 2012 was based on the adaptation of identified source guidelines which were combined with reviews of evidence compiled using PICO (Patients/Interventions/Control/Outcome) questions and the results of a systematic search of literature databases and the selection and evaluation of the identified literature. The interdisciplinary working groups took the identified materials as their starting point to develop recommendations and statements which were modified and graded in a structured consensus procedure.
Recommendations: Part 1 of this short version of the guideline presents recommendations for the screening, diagnosis and follow-up care of breast cancer. The importance of mammography for screening is confirmed in this updated version of the guideline and forms the basis for all screening. In addition to the conventional methods used to diagnose breast cancer, computed tomography (CT) is recommended for staging in women with a higher risk of recurrence. The follow-up concept includes suggested intervals between physical, ultrasound and mammography examinations, additional high-tech diagnostic procedures, and the determination of tumor markers for the evaluation of metastatic disease.
Activation of TRPC6 channels is essential for lung ischaemia–reperfusion induced oedema in mice
(2012)
Lung ischaemia–reperfusion-induced oedema (LIRE) is a life-threatening condition that causes pulmonary oedema induced by endothelial dysfunction. Here we show that lungs from mice lacking nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox2y/−) or the classical transient receptor potential channel 6 (TRPC6−/−) are protected from LIR-induced oedema (LIRE). Generation of chimeric mice by bone marrow cell transplantation and endothelial-specific Nox2 deletion showed that endothelial Nox2, but not leukocytic Nox2 or TRPC6, are responsible for LIRE. Lung endothelial cells from Nox2- or TRPC6-deficient mice showed attenuated ischaemia-induced Ca2+ influx, cellular shape changes and impaired barrier function. Production of reactive oxygen species was completely abolished in Nox2y/− cells. A novel mechanistic model comprising endothelial Nox2-derived production of superoxide, activation of phospholipase C-γ, inhibition of diacylglycerol (DAG) kinase, DAG-mediated activation of TRPC6 and ensuing LIRE is supported by pharmacological and molecular evidence. This mechanism highlights novel pharmacological targets for the treatment of LIRE.
The design, construction, and commissioning of the ALICE Time-Projection Chamber (TPC) is described. It is the main device for pattern recognition, tracking, and identification of charged particles in the ALICE experiment at the CERN LHC. The TPC is cylindrical in shape with a volume close to 90 m3 and is operated in a 0.5 T solenoidal magnetic field parallel to its axis.
In this paper we describe in detail the design considerations for this detector for operation in the extreme multiplicity environment of central Pb–Pb collisions at LHC energy. The implementation of the resulting requirements into hardware (field cage, read-out chambers, electronics), infrastructure (gas and cooling system, laser-calibration system), and software led to many technical innovations which are described along with a presentation of all the major components of the detector, as currently realized. We also report on the performance achieved after completion of the first round of stand-alone calibration runs and demonstrate results close to those specified in the TPC Technical Design Report.
Abrasion-ablation models and the empirical EPAX parametrization of projectile fragmentation are described. Their cross section predictions are compared to recent data of the fragmentation of secondary beams of neutron-rich, unstable 19,20,21O isotopes at beam energies near 600 MeV/nucleon as well as data for stable 17,18O beams.
Background: Platelet activating factor and tachykinins (substance P, neurokinin A, neurokinin B) are important mediators contributing to increased airway secretion in the context of different types of respiratory diseases including acute and chronic asthma. Leukotriene receptor antagonists are recommended as add-on therapy for this disease. The cys-leukotriene-1 receptor antagonist montelukast has been used in clinical asthma therapy during the last years. Besides its inhibitory action on bronchoconstriction, only little is known about its effects on airway secretions. Therefore, the aim of this study was to evaluate the effects of montelukast on platelet activating factor- and tachykinin induced tracheal secretory activity.
Methods: The effects of montelukast on platelet activating factor- and tachykinin induced tracheal secretory activity in the rat were assessed by quantification of secreted 35SO4 labelled mucus macromolecules using the modified Ussing chamber technique.
Results: Platelet activating factor potently stimulated airway secretion, which was completely inhibited by the platelet activating factor receptor antagonist WEB 2086 and montelukast. In contrast, montelukast had no effect on tachykinin induced tracheal secretory activity.
Conclusion: Cys-leukotriene-1 receptor antagonism by montelukast reverses the secretagogue properties of platelet activating factor to the same degree as the specific platelet activating factor antagonist WEB 2086 but has no influence on treacheal secretion elicited by tachykinins. These results suggest a role of montelukast in the signal transduction pathway of platelet activating factor induced secretory activity of the airways and may further explain the beneficial properties of cys-leukotriene-1 receptor antagonists.
In this report, we present the contributions, outcomes, ideas, discussions and conclusions obtained at the PaleoMaps Workshop 2019, that took place at the Institute of Geography of the University of Cologne on 23 and 24 September 2019. The twofold aim of the workshop was: (1) to provide an overview of approaches and methods that are presently used to incorporate paleoenvironmental information in human–environment interaction modeling applications, and building thereon; (2) to devise new approaches and solutions that might be used to enhance the reconstruction of past human–environmental interconnections. This report first outlines the presented papers, and then provides a joint protocol of the often extensive discussions that came up following the presentations or else during the refreshment intervals. It concludes by adressing the open points to be resolved in future research avenues, e.g., implementation of open science practices, new procedures for reviewing of publications, and future concepts for quality assurance of the often complex paleoenvironmental data. This report may serve as an overview of the state of the art in paleoenvironment mapping and modeling. It includes an extensive compilation of the basic literature, as provided by the workshop attendants, which will itself facilitate the necessary future research.
Transport of lipids across membranes is fundamental for diverse biological pathways in cells. Multiple ion-coupled transporters participate in lipid translocation, but their mechanisms remain largely unknown. Major facilitator superfamily (MFS) lipid transporters play central roles in cell wall synthesis, brain development and function, lipids recycling, and cell signaling. Recent structures of MFS lipid transporters revealed overlapping architectural features pointing towards a common mechanism. Here we used cysteine disulfide trapping, molecular dynamics simulations, mutagenesis analysis, and transport assays in vitro and in vivo, to investigate the mechanism of LtaA, a proton-dependent MFS lipid transporter essential for lipoteichoic acids synthesis in the pathogen Staphylococcus aureus. We reveal that LtaA displays asymmetric lateral openings with distinct functional relevance and that cycling through outward- and inward-facing conformations is essential for transport activity. We demonstrate that while the entire amphipathic central cavity of LtaA contributes to lipid binding, its hydrophilic pocket dictates substrate specificity. We propose that LtaA catalyzes lipid translocation by a ‘trap-and-flip’ mechanism that might be shared among MFS lipid transporters.
Transport of lipids across membranes is fundamental for diverse biological pathways in cells. Multiple ion-coupled transporters take part in lipid translocation, but their mechanisms remain largely unknown. Major facilitator superfamily (MFS) lipid transporters play central roles in cell wall synthesis, brain development and function, lipids recycling, and cell signaling. Recent structures of MFS lipid transporters revealed overlapping architectural features pointing towards a common mechanism. Here we used cysteine disulfide trapping, molecular dynamics simulations, mutagenesis analysis, and transport assays in vitro and in vivo, to investigate the mechanism of LtaA, a proton-dependent MFS lipid transporter essential for lipoteichoic acid synthesis in the pathogen Staphylococcus aureus. We reveal that LtaA displays asymmetric lateral openings with distinct functional relevance and that cycling through outward- and inward-facing conformations is essential for transport activity. We demonstrate that while the entire amphipathic central cavity of LtaA contributes to lipid binding, its hydrophilic pocket dictates substrate specificity. We propose that LtaA catalyzes lipid translocation by a ‘trap-and-flip’ mechanism that might be shared among MFS lipid transporters.
Parkinson’s disease (PD) is a neurodegenerative disorder frequent at old age characterized by atrophy of the nigrostriatal projection. Overexpression and A53T-mutation of the presynaptic, vesicle-associated chaperone alpha-synuclein are known to cause early-onset autosomal dominant PD. We previously generated mice with transgenic overexpression of human A53T-alpha-synuclein (A53T-SNCA) in dopaminergic substantia nigra neurons as a model of early PD. To elucidate the early and late effects of A53T-alpha-synuclein on the proteome of dopaminergic nerve terminals in the striatum, we now investigated expression profiles of young and old mice using two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE) and mass spectrometry. In total, 15 proteins were upregulated and 2 downregulated. Mice before the onset of motor anomalies showed an upregulation of the spot containing 14-3-3 proteins, in particular the epsilon isoform, as well as altered levels of chaperones, vesicle trafficking and bioenergetics proteins. In old mice, the persistent upregulation of 14-3-3 proteins was aggravated by an increase of glial fibrillary acidic protein (GFAP) suggesting astrogliosis due to initial neurodegeneration. Independent immunoblots corroborated GFAP upregulation and 14-3-3 upregulation for the epsilon isoform, and also detected significant eta and gamma changes. Only for 14-3-3 epsilon a corresponding mRNA increase was observed in midbrain, suggesting it is transcribed in dopaminergic perikarya and accumulates as protein in presynapses, together with A53T-SNCA. 14-3-3 proteins associate with alpha-synuclein in vitro and in pathognomonic Lewy bodies of PD brains. They act as chaperones in signaling, dopamine synthesis and stress response. Thus, their early dysregulation probably reflects a response to alpha-synuclein toxicity.
Electronic supplementary material: The online version of this article (doi:10.1007/s00702-011-0717-3) contains supplementary material, which is available to authorized users.
High field strength element systematics and Lu-Hf & Sm-Nd garnet geochronology of orogenic eclogites
(2008)
Concerning the Bulk Silicate Earth (BSE), the depleted mantle and the continental crust are thought to balance the budget of refractory and lithophile elements, resulting in complementary trace element patterns. However, the two high field strength elements (HFSE) Niob and Tantal appear to contradict this mass balance. All reservoirs of the silicate Earth exhibit subchondritic Nb/Ta ratios, possibly as a result of Nb depletion. The two HFSE Zr and Hf on the other hand seem not to be fractionated between the silicate reservoirs. They show more or less chondritic Zr/Hf ratios. In this study a series of orogenic eclogites from different localities was analyzed to determine their HFSE concentrations and to contribute to the question if eclogites could form a hidden reservoir to account for the mass imbalance of the BSE. The results show that the orogenic eclogites have subchondritic Nb/Ta ratios and near chondritic Zr/Hf ratios. The investigated eclogites show no fractionation of Nb/Ta ratios and no enrichment of Nb compared to e.g. MOR-basalts, the likely precursor of these rocks. With an average Nb/Ta ratio of 14.9 these eclogites could not balance the differences between BSE and chondrite. Additionally, with an average Nb/Ta ≈ MORB they also cannot balance the small differences in the Nb/Ta of the crust and the mantle. LA-ICPMS analyses of rutiles in these eclogites reveal a zonation of Nb/Ta ratios in this mineral, with rutile cores having higher Nb/Ta than rutile rims. As a consequence, Laser Ablation data of rutiles have to be evaluated carefully and cannot necessarily reflect a bulk rock Nb and Ta composition, although over 90% of these elements reside in rutile.
We measured the Coulomb dissociation of 16O into 4He and 12C at the R3B setup in a first campaign within FAIR Phase 0 at GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt. The goal was to improve the accuracy of the experimental data for the 12C(α,γ)16O fusion reaction and to reach lower center-ofmass energies than measured so far.
The experiment required beam intensities of 109 16O ions per second at an energy of 500 MeV/nucleon. The rare case of Coulomb breakup into 12C and 4He posed another challenge: The magnetic rigidities of the particles are so close because of the same mass-to-charge-number ratio A/Z = 2 for 16O, 12C and 4He. Hence, radical changes of the R3B setup were necessary. All detectors had slits to allow the passage of the unreacted 16O ions, while 4He and 12C would hit the detectors' active areas depending on the scattering angle and their relative energies. We developed and built detectors based on organic scintillators to track and identify the reaction products with sufficient precision.
How long does it take to emit an electron from an atom? This question has intrigued scientists for decades. As such emission times are in the attosecond regime, the advent of attosecond metrology using ultrashort and intense lasers has re-triggered strong interest on the topic from an experimental standpoint. Here, we present an approach to measure such emission delays, which does not require attosecond light pulses, and works without the presence of superimposed infrared laser fields. We instead extract the emission delay from the interference pattern generated as the emitted photoelectron is diffracted by the parent ion’s potential. Targeting core electrons in CO, we measured a 2d map of photoelectron emission delays in the molecular frame over a wide range of electron energies. The emission times depend drastically on the photoelectrons’ emission directions in the molecular frame and exhibit characteristic changes along the shape resonance of the molecule.
Bericht der Arbeitsgruppe Technik zur Vorbereitung des Programms "Retrospektive Digitalisierung von Bibliotheksbeständen" im Förderbereich "Verteilte Digitale Forschungsbibliothek" Arbeitssitzungen am 14. Mai 1996 (Frankfurt a. M.), 29.-30. Juli 1996 (München), 12.-13. Dezember 1996 (Göttingen) Mitglieder der Arbeitsgruppe: Prof. Dr. Rudolf Bayer, Technische Universität München, Fakultät für Informatik Dr. Jürgen Bunzel, Deutsche Forschungsgemeinschaft, Bonn Dr. Marianne Dörr, Bayerische Staatsbibliothek München Dr. Reinhard Ecker, Beilstein-Institut bzw. ABC Datenservice GmbH, Frankfurt/Main Dipl.-Math. Heinz-Werner Hoffmann, Hochschulbibliothekszentrum NRW, Köln (als Gast für die AG der Verbundsysteme) Dr. Norbert Lossau, Niedersächsische Staats- und Universitätsbibliothek Göttingen (DFG-Projekt ‘Verteilte Digitale Forschungsbibliothek’) Prof. Dr. Elmar Mittler, Niedersächsische Staats- und Universitätsbibliothek Göttingen Dipl.-Inf. Christian Mönch, FB Informatik der J.W. Goethe-Universität Frankfurt Dr. Wilhelm R. Schmidt, Stadt- und Universitätsbibliothek Frankfurt Dr. Hartmut Weber, Landesarchivdirektion, Stuttgart
Understanding the complexity of transcriptional regulation is a major goal of computational biology. Because experimental linkage of regulatory sites to genes is challenging, computational methods considering epigenomics data have been proposed to create tissue-specific regulatory maps. However, we showed that these approaches are not well suited to account for the variations of the regulatory landscape between cell-types. To overcome these drawbacks, we developed a new method called STITCHIT, that identifies and links putative regulatory sites to genes. Within STITCHIT, we consider the chromatin accessibility signal of all samples jointly to identify regions exhibiting a signal variation related to the expression of a distinct gene. STITCHIT outperforms previous approaches in various validation experiments and was used with a genome-wide CRISPR-Cas9 screen to prioritize novel doxorubicin-resistance genes and their associated non-coding regulatory regions. We believe that our work paves the way for a more refined understanding of transcriptional regulation at the gene-level.
Investigators in the cognitive neurosciences have turned to Big Data to address persistent replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. While there is tremendous potential to advance science through open data sharing, these efforts unveil a host of new questions about how to integrate data arising from distinct sources and instruments. We focus on the most frequently assessed area of cognition - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated raw data from 53 studies from around the world which measured at least one of three distinct verbal learning tasks, totaling N = 10,505 healthy and brain-injured individuals. A mega analysis was conducted using empirical bayes harmonization to isolate and remove site effects, followed by linear models which adjusted for common covariates. After corrections, a continuous item response theory (IRT) model estimated each individual subject’s latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance by 37% while preserving covariate effects. The effects of age, sex, and education on scores were found to be highly consistent across memory tests. IRT methods for equating scores across AVLTs agreed with held-out data of dually-administered tests, and these tools are made available for free online. This work demonstrates that large-scale data sharing and harmonization initiatives can offer opportunities to address reproducibility and integration challenges across the behavioral sciences.
In the context of workplace health promotion, physical activity programs have been shown to reduce musculoskeletal diseases and stress, and to improve the quality of life. The aim of this study was to examine the effects of using the “five-Business” stretch training device for office workers on their quality of life. A total of 313 office workers (173m/137f) participated voluntarily in this intervention–control study with an average age of 43.37 ± 11.24 (SD) years, 175.37 ± 9.35 cm in height and 75.76 ± 15.23 kg in weight, with an average BMI of 24.5 ± 3.81 kg/m2. The participants completed the stretch training twice a week for approximately 10 minutes for a duration of 12 weeks. The SF-36 questionnaire was used to evaluate the effectiveness of the intervention at baseline and after 12 weeks. Significantly improved outcomes in mental sum score (p = 0.008), physical functioning (p < 0.001), bodily pain (p = 0.01), vitality (p = 0.025), role limitations due to physical problems (p = 0.018) and mental health (p = 0.012) were shown after the stretching training. The results suggest that a 12-week stretching program for office desk workers is suitable to improve significantly their health-related quality of life.
Hintergrund: Dehntrainings sind eine Maßnahme der betrieblichen Gesundheitsförderung (BGF) für Büroangestellte zur Prävention von muskuloskeletalen Erkrankungen (MSE). Sie können zu Beweglichkeitszuwächsen führen und auf psychischer Ebene entspannen. Ziel der Studie war es, ein standardisiertes und individualisiertes Dehntraining am Gerät, das „five-Business“, auf MSE, Lebensqualität und Beweglichkeit zu untersuchen. Dies ist eine Zusammenfassung der international publizierten Ergebnisse.
Methodik: In diese Untersuchung wurden 252 Proband(innen) eingeschlossen, 156 in die Interventionsgruppe (IG), 96 in die Kontrollgruppe (KG). Die IG absolvierte für 12 Wochen 22–24 Trainingseinheiten am „five-Business“, möglichst zweimal wöchentlich. Die Datenerhebung erfolgte mittels sportmotorischer bzw. Range-of-motion(ROM)-Tests, dem Nordic Questionnaire (NQ) und dem SF-36-Fragebogen in Form einer Prä-Post-Untersuchung.
Ergebnisse: Nach der Intervention gaben im NQ signifikant weniger Proband(innen) der IG Beschwerden im oberen Rücken (p < 0,001) im Vergleich zur KG an; keine signifikanten Unterschiede wurden bei Beschwerden im Nacken, Schultern, Hüfte und dem unteren Rücken gefunden. Der mit dem SF-36 erhobene allgemeine Gesundheitszustand und die gesundheitsbezogene Lebensqualität haben sich (nach subjektiven Angaben) signifikant verbessert (Summenscore IG: p = 0,005). In den ROM-Tests waren die Prä-Post-Differenzen bei IG-Proband(innen) in der Sagittalebene (Finger-Boden-Abstand und Retroflexion; p < 0,001) und im modifizierten Schultertest nach Janda auf der linken Seite (p = 0,003) signifikant größer.
Diskussion: Trotz des in Zeitdauer und Häufigkeit relativ geringen Trainingsaufwandes wurden sowohl auf körperlicher als auch auf psychischer Ebene relevante Verbesserungen erzielt, so dass das „five-Business“-Dehntraining als BGF-Maßnahme empfohlen werden kann.
Understanding how epigenetic variation in non-coding regions is involved in distal gene-expression regulation is an important problem. Regulatory regions can be associated to genes using large-scale datasets of epigenetic and expression data. However, for regions of complex epigenomic signals and enhancers that regulate many genes, it is difficult to understand these associations. We present StitchIt, an approach to dissect epigenetic variation in a gene-specific manner for the detection of regulatory elements (REMs) without relying on peak calls in individual samples. StitchIt segments epigenetic signal tracks over many samples to generate the location and the target genes of a REM simultaneously. We show that this approach leads to a more accurate and refined REM detection compared to standard methods even on heterogeneous datasets, which are challenging to model. Also, StitchIt REMs are highly enriched in experimentally determined chromatin interactions and expression quantitative trait loci. We validated several newly predicted REMs using CRISPR-Cas9 experiments, thereby demonstrating the reliability of StitchIt. StitchIt is able to dissect regulation in superenhancers and predicts thousands of putative REMs that go unnoticed using peak-based approaches suggesting that a large part of the regulome might be uncharted water.
Rationale: Potassium (K) is a major component of several silicate minerals and seawater, and, therefore, constraining past changes in the potassium cycle is a promising way of tracing large-scale geological processes on Earth. However, [K] measurement using inductively coupled plasma mass spectrometry (ICP-MS) is challenging due to an ArH+ interference, which may be of a similar magnitude to the K+ ion beam in samples with <0.1% m/m [K].
Methods: In this work, we investigated the effect of the ArH+ interference on K/Ca data quality by comparing results from laser-ablation (LA)-ICP-MS measured in medium and high mass resolution modes and validating our LA results via solution ICP-optical emission spectroscopy (OES) and solution ICP-MS measurements. To do so, we used a wide range of geological reference materials, with a particular focus on marine carbonates, which are potential archives of past changes in the K cycle but are typically characterised by [K] < 200 μg/g. In addition, we examine the degree to which trace-element data quality is driven by downhole fractionation during LA-ICP-MS measurements.
Results: Our results show that medium mass resolution (MR) mode is sufficiently capable of minimising the effect of the ArH+ interference on K+. However, the rate of downhole fractionation for Na and K varies between different samples as a result of their differing bulk composition, resulting in matrix-specific inaccuracy. We show how this can be accounted for via downhole fractionation corrections, resulting in an accuracy of better than 1% and a long-term reproducibility (intermediate precision) of <6% (relative standard deviation) in JCp-1NP using LA-ICP-MS in MR mode.
Conclusion: Our [K] measurement protocol is demonstrably precise and accurate and applicable to a wide range of materials. The measurement of K/Ca in relatively low-[K] marine carbonates is presented here as a key example of a new application opened up by these advances.
The free energy of TAP-solutions for the SK-model of mean field spin glasses can be expressed as a nonlinear functional of local terms: we exploit this feature in order to contrive abstract REM-like models which we then solve by a classical large deviations treatment. This allows to identify the origin of the physically unsettling quadratic (in the inverse of temperature) correction to the Parisi free energy for the SK-model, and formalizes the true cavity dynamics which acts on TAP-space, i.e. on the space of TAP-solutions. From a non-spin glass point of view, this work is the first in a series of refinements which addresses the stability of hierarchical structures in models of evolving populations.
The photoelectric effect describes the ejection of an electron upon absorption of one or several photons. The kinetic energy of this electron is determined by the photon energy reduced by the binding energy of the electron and, if strong laser fields are involved, by the ponderomotive potential in addition. It has therefore been widely taken for granted that for atoms and molecules, the photoelectron energy does not depend on the electron’s emission direction, but theoretical studies have questioned this since 1990. Here, we provide experimental evidence that the energies of photoelectrons emitted against the light propagation direction are shifted toward higher values, while those electrons that are emitted along the light propagation direction are shifted to lower values. We attribute the energy shift to a nondipole contribution to the ponderomotive potential that is due to the interaction of the moving electrons with the incident photons.
The free energy of TAP-solutions for the SK-model of mean field spin glasses can be expressed as a nonlinear functional of local terms: we exploit this feature in order to contrive abstract REM-like models which we then solve by a classical large deviations treatment. This allows to identify the origin of the physically unsettling quadratic (in the inverse of temperature) correction to the Parisi free energy for the SK-model, and formalizes the true cavity dynamics which acts on TAP-space, i.e. on the space of TAP-solutions. From a non-spin glass point of view, this work is the first in a series of refinements which addresses the stability of hierarchical structures in models of evolving populations.
No association between Parkinson disease and autoantibodies against NMDA-type glutamate receptors
(2019)
Background: IgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment (n = 296) and controls (n = 295) free of neuropsychiatric disease. Detailed phenotyping and large numbers allowed statistically meaningful correlation of antibody status with diagnostic subgroups as well as quantitative indicators of disease severity and cognitive impairment.
Methods: NMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics.
Results: The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients.
Conclusion: It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own.