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Philosophieren heißt überleben lernen. Ursprünglich schien das Gegenteil der Fall. Bei den Stoikern hieß philosophieren sterben lernen. Doch auch sterben lernen hieß natürlich überleben lernen. Die stoische Einübung in den Tod war letztlich eine Entmächtigungsstrategie, mit der die überwältigenden täglichen Ängste in Bann gehalten werden sollten - eine elitäre, weil intellektuelle Strategie, denn sie setzte darauf, - vermeintliche - Fehlurteile zu entlarven. Wer sich vor dem Sterben fürchtet, erliegt, so die Logik dieser Philosophie, nur einer falschen Einschätzung dessen, was wirklich furchtbar und fürchtenswert ist. Hans Blumenberg hat das Ensemble der Mächte, die uns in Furcht schlagen, unter den Sammelbegriff eines "Absolutismus der Wirklichkeit" gebracht. Damit meinte er schon die archaische Situation, in der "der Mensch die Bedingungen seiner Existenz annähernd nicht in der Hand hatte und, was wichtiger ist, schlechthin nicht in seiner Hand glaubte. Er mag sich früher oder später diesen Sachverhalt der Übermächtigkeit des jeweils Anderen durch die Annahme von Übermächten gedeutet haben." Es geht dabei um die Umwandlung von Angst in Furcht, also von einem unspezifischen Ohnmachtsgefühl angesichts der Vielzahl von Bedrohungen, die oft auch nicht versteh- und erklärbar sind, in eine durchschaubare Macht, der das Übel zugeschrieben und die so auch ein Stück weit gebannt werden kann. Auch wenn der Mensch keine Waffe gegen die wirkliche Gefahr in Händen hält, so glaubt er es doch zumindest und wird durch diese Waffe handlungs- und überlebensfähig - ein, wenn man so will, narratives Placebo. Vorgeschobene imaginative Instanzen sind für Blumenberg, was der Lebensangst abhilft.
Background: Immunosuppression with calcineurin inhibitors remains the mainstay of treatment after kidney transplantation; however, long-term use of these drugs may be associated with nephrotoxicity. In this regard, the current approach is to optimise available immunosuppressive regimens to reduce the calcineurin inhibitor dose while protecting renal function without affecting the efficacy. The ATHENA study is designed to evaluate renal function in two regimens: an everolimus and reduced calcineurin inhibitor-based regimen versus a standard treatment protocol with mycophenolic acid and tacrolimus in de novo kidney transplant recipients.
Method/Design: ATHENA is a 12-month, multicentre, open-label, prospective, randomised, parallel-group study in de novo kidney transplant recipients (aged 18 years or older) receiving renal allografts from deceased or living donors. Eligible patients are randomised (1:1:1) prior to transplantation to one of the following three treatment arms: everolimus (starting dose 1.5 mg/day; C0 3–8 ng/mL) with cyclosporine or everolimus (starting dose 3 mg/day; C0 3–8 ng/mL) with tacrolimus or mycophenolic acid (enteric-coated mycophenolate sodium at 1.44 g/day or mycophenolate mofetil at 2 g/day) with tacrolimus; in combination with corticosteroids. All patients receive induction therapy with basiliximab. The primary objective is to demonstrate non-inferiority of renal function (eGFR by the Nankivell formula) in one of the everolimus arms compared with the standard group at month 12 post transplantation. The key secondary objective is to assess the incidence of treatment failure, defined as biopsy-proven acute rejection, graft loss, or death, among the treatment groups. Other objectives include assessment of the individual components of treatment failure, incidence and severity of viral infections, incidence and duration of delayed graft function, incidence of indication biopsies, slow graft function and wound healing complications, and overall safety and tolerability. Exploratory objectives include evaluation of left ventricular hypertrophy assessed by the left ventricular mass index, evolution of human leukocyte antigen and non-human leukocyte antigen antibodies, and a cytomegalovirus substudy.
Discussion: As one of the largest European multicentre kidney transplant studies, ATHENA will determine whether a de novo everolimus-based regimen can preserve renal function versus the standard of care. This study further assesses a number of clinical issues which impact long-term outcomes post transplantation; hence, its results will have a major clinical impact.
Trial registration: Clinicaltrials.gov: NCT01843348, date of registration – 18 April 2013; EUDRACT number: 2011-005238-21, date of registration – 20 March 2012
Für die Optimierung sowie Entwicklung lichtsteuerbarer Systeme für biologische Anwendungen oder neue Materialien ist ein detailliertes Verständnis der zugrunde liegenden komplexen, lichtinduzierten Prozesse eine Voraussetzung. Die Verwendung von Photoschaltern in Makromolekülen ermöglicht eine zeitliche und örtliche Kontrolle über strukturelle Änderungen sowie die entsprechend folgenden (biologischen) Funktionen durch die Verwendung von Licht als externem Auslöser.
Ein wichtiger Bestandteil dieser Arbeit befasst sich mit der Entwicklung eines auf Licht reagierenden Riboschalters, welcher die gezielte Kontrolle über Genexpression ermöglicht. Hierzu wurde eine spektroskopische Charakterisierung von verschiedenen Photoschaltern bezüglich einer Verwendung als biologischer Ligand sowie der Wechselwirkungen zwischen Azobenzolen und RNA, auch hinsichtlich ihrer Bindungsdynamiken durchgeführt. Zunächst wurde die hohe Abhängigkeit der (photo-)chemischen Eigenschaften der Azobenzole von der Wahl der Substituenten untersucht, wobei besonders die Anwendung in wässrigem Milieu betrachtet wurde. In einer detaillierten (zeitaufgelösten) Studie wurde der positionsabhängige Einfluss der Hydroxy-Substitution von Azobenzolen auf die Photoisomerisierung in wässriger Lösung untersucht. Für eine ortho-Substitution ergab sich hierbei ein alternativer Deaktivierungskanal nach Photoanregung, welcher stärker ausgeprägt ist als die Isomerisierung. Hierbei wird ein intramolekularer Protontransfer im angeregten Zustand (ESIPT) beobachtet, welcher mit einer Zeitkonstante von 0.3 ps beschrieben werden kann und in einer Keto-Spezies resultiert. Eine Keto-Enol-Tautomerie konnte für die para-Hydroxy-Substitution schon im Grundzustand beobachtet werden. Somit können beide Spezies gezielt adressiert werden. Durch Acetylierung der Hydroxygruppe verlangsamt sich die thermische Relaxation des cis-Isomer zu dem entsprechenden trans-Isomer signifikant ohne die Isomerisierung zu beeinträchtigen. Dementsprechend ermöglicht eine solche Acetylierung die Verwendung von bekannten Azobenzolderivaten als Photoschalter.
Zudem werden in dieser Arbeit zwei verschiedene Herangehensweisen in der Entwicklung eines Riboschalters beschrieben, welcher sich durch Licht regulieren lässt.
Diese sind durch kovalentes bzw. nicht-kovalentes Einbringen eines Azobenzolderivats in die RNA Struktur charakterisiert. Ein neuer Linker, welcher auf einer Desoxyribose-Struktur beruht, wird für die kovalente Anbindung des Azobenzols an den RNA Strang präsentiert, welcher eine licht-induzierte Dehybridisierung ermöglichen soll. Eine außergewöhnlich hohe Schaltamplitude mit einem cis-Gehalt von etwa 90% konnte für das Azobenzol im RNA Einzelstrang schon bei Raumtemperatur ermittelt werden. Zudem wurde der Einfluss des Photoschalters sowie der benachbarten Nukleotide in der RNA auf die Stabilität der RNA Doppelhelix untersucht. Die zweite Vorgehensweise beruht auf einer nicht-kovalenten Bindung zwischen einem Azobenzolderivat und einem RNA-Aptamer, welche lediglich für eines der Photoisomere ermöglicht wird, wodurch eine örtliche und zeitliche Kontrolle der Ligandenbindung der RNA erfolgt. Im Rahmen dieser Arbeit war es möglich zwei verschiedene photoschaltbare RNA Aptamere zu identifizieren und zu untersuchen, welche eine hohe Spezifität und Affinität aufweisen. Zudem wurde die Photoisomerisierung des Azobenzols innerhalb der RNA-Struktur sowie daraus resultierende lichtinduzierte Konformationsänderungen der RNA mittels zeitaufgelöster Anreg-/Abtastspektroskopie untersucht. Die daraus resultierende Dynamik der photoinduzierten Ligandenbindung sollte eine weitere gezielte Optimierung lichtschaltbarer biologischer Systeme erlauben.
Der zweite Teil dieser Arbeit beschäftigt sich mit der zeitaufgelösten Untersuchung eines photoschaltbaren Foldamers. Speziell wurde der strukturelle Übergang des OmPE-Foldamers 10-5 zwischen einer definierten helikalen und einer ungefalteten Konformation auf Grund der Photoisomerisierung der, in das Rückgrat integrierten, Azobenzole untersucht.
Dabei konnten die frühen (Ent-)Faltungsmechanismen des Foldamers im sub-Nanosekunden-Zeitbereich beobachtet werden, welche durch quantenmechanische Rechnungen unterstützt werden konnten. Darüberhinaus, war es möglich einen Anregungsenergietransfer vom PE-Rückgrat des Foldamers auf die Azobenzole nachzuweisen, welcher die Lebensdauer der angeregten Zustände des Systems signifikant verkürzt.
Diese Arbeit liefert wichtige Informationen zu den Reaktionspfaden, den gezielten Wechselwirkungen zwischen Photoschaltern und größeren organischen Molekülen, sowie den daraus resultierenden lichtinduzierten strukturellen Änderungen durch die Anwendung einer Vielzahl an (zeitaufgelösten) spektroskopischen Methoden. Diese Ergebnisse tragen zum weiteren Verständnis komplexer Prozesse in biologischem sowie nicht-biologischem Zusammenhang und somit zu einer weiterführenden Entwicklung neuer Systeme bei.
In this work the main emphasis is put on the investigation of relativistic shock waves and Mach cones in hot and dense matter using the microscopic transport model BAMPS, based on the relativistic Boltzmann equation. Using this kinetic approach we study the complete transition from ideal-fluid behavior to free streaming. This includes shock-wave formation in a simplified (1+1)-dimensional setup as well as the investigation of Mach-cone formation induced by supersonic projectiles and/or jets in (2+1)- and (3+1)-dimensional static and expanding systems. We further address the question whether jet-medium interactions inducing Mach cones can contribute to a double-peak structure observed in two-particle correlations in heavy-ion collision experiments. Furthermore, BAMPS is used as a benchmark to compare kinetic theory to several relativistic hydrodynamic theories in order to verify their accuracy and to find their limitations.
Using a partonic transport model we investigate the evolution of conical structures in ultrarelativistic matter. Using two different source terms and varying the transport properties of the matter we study the formation of Mach Cones. Furthermore, in an additional study we extract the two-particle correlations from the numerical calculations and compare them to an analytical approximation. The influence of the viscosity to the shape of Mach Cones and the corresponding two-particle correlations is studied by adjusting the cross section of the medium.
Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α‐mediated stress signaling
(2016)
Phosphorylation of translation initiation factor 2α (eIF2α) attenuates global protein synthesis but enhances translation of activating transcription factor 4 (ATF4) and is a crucial evolutionarily conserved adaptive pathway during cellular stresses. The serine–threonine protein phosphatase 1 (PP1) deactivates this pathway whereas prolonging eIF2α phosphorylation enhances cell survival. Here, we show that the reactive oxygen species‐generating NADPH oxidase‐4 (Nox4) is induced downstream of ATF4, binds to a PP1‐targeting subunit GADD34 at the endoplasmic reticulum, and inhibits PP1 activity to increase eIF2α phosphorylation and ATF4 levels. Other PP1 targets distant from the endoplasmic reticulum are unaffected, indicating a spatially confined inhibition of the phosphatase. PP1 inhibition involves metal center oxidation rather than the thiol oxidation that underlies redox inhibition of protein tyrosine phosphatases. We show that this Nox4‐regulated pathway robustly enhances cell survival and has a physiologic role in heart ischemia–reperfusion and acute kidney injury. This work uncovers a novel redox signaling pathway, involving Nox4–GADD34 interaction and a targeted oxidative inactivation of the PP1 metal center, that sustains eIF2α phosphorylation to protect tissues under stress.
Copeptin is the C-terminal end of pre-provasopressin released equimolar to vasopressin into circulation and recently discussed as promising cardiovascular biomarker amendatory to established markers such as troponins. Vasopressin is a cytokine synthesized in the hypothalamus. A direct release of copeptin from the heart into the circulation is implied by data from a rat model showing a cardiac origin in hearts put under cardiovascular wall stress. Therefore, evaluation of a potential release of copeptin from the human heart in acute myocardial infarction (AMI) has been done.
Noise-induced hearing loss is one of the most common auditory pathologies, resulting from overstimulation of the human cochlea, an exquisitely sensitive micromechanical device. At very low frequencies (less than 250 Hz), however, the sensitivity of human hearing, and therefore the perceived loudness is poor. The perceived loudness is mediated by the inner hair cells of the cochlea which are driven very inadequately at low frequencies. To assess the impact of low-frequency (LF) sound, we exploited a by-product of the active amplification of sound outer hair cells (OHCs) perform, so-called spontaneous otoacoustic emissions. These are faint sounds produced by the inner ear that can be used to detect changes of cochlear physiology. We show that a short exposure to perceptually unobtrusive, LF sounds significantly affects OHCs: a 90 s, 80 dB(A) LF sound induced slow, concordant and positively correlated frequency and level oscillations of spontaneous otoacoustic emissions that lasted for about 2 min after LF sound offset. LF sounds, contrary to their unobtrusive perception, strongly stimulate the human cochlea and affect amplification processes in the most sensitive and important frequency range of human hearing.
Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti‐angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin‐2 (Ang‐2) as a potential target in both naive and bevacizumab‐treated glioblastoma. Ang‐2 expression was absent in normal human brain endothelium, while the highest Ang‐2 levels were observed in bevacizumab‐treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang‐2, whereas the combined inhibition of VEGF and Ang‐2 leads to extended survival, decreased vascular permeability, depletion of tumor‐associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206+ (M2‐like) macrophages were identified as potential novel targets following anti‐angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang‐2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang‐2 may potentially overcome resistance to bevacizumab therapy.
This study aims at evaluating the combination of the tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL)-receptor 2 (TRAIL-R2)-specific antibody Drozitumab and the Smac mimetic BV6 in preclinical glioblastoma models. To this end, the effect of BV6 and/or Drozitumab on apoptosis induction and signaling pathways was analyzed in glioblastoma cell lines, primary glioblastoma cultures and glioblastoma stem-like cells. Here, we report that BV6 and Drozitumab synergistically induce apoptosis and reduce colony formation in several glioblastoma cell lines (combination index<0.1). Also, BV6 profoundly enhances Drozitumab-induced apoptosis in primary glioblastoma cultures and glioblastoma stem-like cells. Importantly, BV6 cooperates with Drozitumab to suppress tumor growth in two glioblastoma in vivo models including an orthotopic, intracranial mouse model, underlining the clinical relevance of these findings. Mechanistic studies reveal that BV6 and Drozitumab act in concert to trigger the formation of a cytosolic receptor-interacting protein (RIP) 1/Fas-associated via death domain (FADD)/caspase-8-containing complex and subsequent activation of caspase-8 and -3. BV6- and Drozitumab-induced apoptosis is blocked by the caspase inhibitor zVAD.fmk, pointing to caspase-dependent apoptosis. RNA interference-mediated silencing of RIP1 almost completely abolishes the BV6-conferred sensitization to Drozitumab-induced apoptosis, indicating that the synergism critically depends on RIP1 expression. In contrast, both necrostatin-1, a RIP1 kinase inhibitor, and Enbrel, a TNFα-blocking antibody, do not interfere with BV6/Drozitumab-induced apoptosis, demonstrating that apoptosis occurs independently of RIP1 kinase activity or an autocrine TNFα loop. In conclusion, the rational combination of BV6 and Drozitumab presents a promising approach to trigger apoptosis in glioblastoma, which warrants further investigation.
Objective We assessed the effectiveness and safety of daclatasvir (DCV) plus sofosbuvir (SOF), with or without ribavirin (RBV), in a large real-world cohort, including patients with advanced liver disease.
Design Adults with chronic HCV infection at high risk of decompensation or death within 12 months and with no available treatment options were treated in a European compassionate use programme. The recommended regimen was DCV 60 mg plus SOF 400 mg for 24 weeks; RBV addition or shorter duration was allowed at physicians' discretion. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12).
Results Of the 485 evaluable patients, 359 received DCV+SOF and 126 DCV+SOF+RBV. Most patients were men (66%), white (93%) and treatment-experienced (70%). The most frequent HCV genotypes were 1b (36%), 1a (33%) and 3 (21%), and 80% of patients had cirrhosis (42% Child–Pugh B/C; 46% Model for End-Stage Liver Disease score >10). SVR12 (modified intention-to-treat) was achieved by 91% of patients (419/460); 1 patient had virological breakthrough and 13 patients relapsed. Virological failure was not associated with treatment group (adjusted risk difference DCV+SOF minus DCV+SOF+RBV: 1.06%; 95% CI −2.22% to 4.35%). High SVR12 was observed regardless of HCV genotype or cirrhosis, liver transplant or HIV/HCV coinfection status. Twenty eight patients discontinued treatment due to adverse events (n=18) or death (n=10) and 18 died during follow-up. Deaths and most safety events were associated with advanced liver disease and not considered treatment related.
Conclusions DCV+SOF with or without RBV achieved high SVR12 and was well tolerated in a diverse cohort of patients with severe liver disease.
Trial registration number NCT0209966.
Patients with risks of ischemic injury, e.g. during circulatory arrest in cardiac surgery, or after resuscitation are subjected to therapeutic hypothermia. For aortic surgery, the body is traditionally cooled down to 18 °C and then rewarmed to body temperature. The role of hypothermia and the subsequent rewarming process on leukocyte-endothelial interactions and expression of junctional-adhesion-molecules is not clarified yet. Thus, we investigated in an in-vitro model the influence of temperature modulation during activation and transendothelial migration of leukocytes through human endothelial cells. Additionally, we investigated the expression of JAMs in the rewarming phase. Exposure to low temperatures alone during transmigration scarcely affects leukocyte extravasation, whereas hypothermia during treatment and transendothelial migration improves leukocyte-endothelial interactions. Rewarming causes a significant up-regulation of transmigration with falling temperatures. JAM-A is significantly modulated during rewarming. Our data suggest that transendothelial migration of leukocytes is not only modulated by cell-activation itself. Activation temperatures and the rewarming process are essential. Continued hypothermia significantly inhibits transendothelial migration, whereas the rewarming process enhances transmigration strongly. The expression of JAMs, especially JAM-A, is strongly modulated during the rewarming process. Endothelial protection prior to warm reperfusion and mild hypothermic conditions reducing the difference between hypothermia and rewarming temperatures should be considered.
BACKGROUND: Involuntary exposure to health-threatening environmental tobacco smoke (Combined Mainstream and Side-stream Smoke, CMSS) is a worldwide problem, causing premature death of thousands of people. CMSS consists of particulate matter (PM), one of the main sources of indoor air pollution. PM constitutes a considerable health risk for passive smokers. It is important to inform the public about brand-specific differences in CMSS-associated PM, especially in the case of brands without additives, which are therefore promoted as natural and less health-threatening.
METHODS: Mean concentrations and the area under the curve of PM10, PM2.5 and PM1 generated by Natural American Spirit cigarettes without additives and the 3R4F standard research cigarette (University of Kentucky, USA) were measured, analyzed and compared with each other. An automatic environmental tobacco smoke emitter was used to smoke 100 cigarettes, 20 of each brand, according to a standardized smoking protocol.
RESULTS: This study could show that CMSS-associated PM released from tobacco brands without additives, which are therefore promoted as natural and less harmful, are higher than expected.
CONCLUSIONS: It is highly improbable that Natural American Spirit tobacco products are a less harmful choice-at least not for passive smokers as this study could show. We conclude, the CMSS-associated PM level of every single customized brand should be measured because the origin of the tobacco and not the amount of CO, tar and nicotine (given as product information) seem to be responsible for the brand-specific PM release. This data is urgently needed to adequately inform the public about CMSS-associated PM exposure and the related health risk especially for passive smokers.
BACKGROUND: Vermeulen et al. 2014 published a meta-regression analysis of three relevant epidemiological US studies (Steenland et al. 1998, Garshick et al. 2012, Silverman et al. 2012) that estimated the association between occupational diesel engine exhaust (DEE) exposure and lung cancer mortality. The DEE exposure was measured as cumulative exposure to estimated respirable elemental carbon in μg/m(3)-years. Vermeulen et al. 2014 found a statistically significant dose-response association and described elevated lung cancer risks even at very low exposures.
METHODS: We performed an extended re-analysis using different modelling approaches (fixed and random effects regression analyses, Greenland/Longnecker method) and explored the impact of varying input data (modified coefficients of Garshick et al. 2012, results from Crump et al. 2015 replacing Silverman et al. 2012, modified analysis of Moehner et al. 2013).
RESULTS: We reproduced the individual and main meta-analytical results of Vermeulen et al. 2014. However, our analysis demonstrated a heterogeneity of the baseline relative risk levels between the three studies. This heterogeneity was reduced after the coefficients of Garshick et al. 2012 were modified while the dose coefficient dropped by an order of magnitude for this study and was far from being significant (P = 0.6). A (non-significant) threshold estimate for the cumulative DEE exposure was found at 150 μg/m(3)-years when extending the meta-analyses of the three studies by hockey-stick regression modelling (including the modified coefficients for Garshick et al. 2012). The data used by Vermeulen and colleagues led to the highest relative risk estimate across all sensitivity analyses performed. The lowest relative risk estimate was found after exclusion of the explorative study by Steenland et al. 1998 in a meta-regression analysis of Garshick et al. 2012 (modified), Silverman et al. 2012 (modified according to Crump et al. 2015) and Möhner et al. 2013. The meta-coefficient was estimated to be about 10-20 % of the main effect estimate in Vermeulen et al. 2014 in this analysis.
CONCLUSIONS: The findings of Vermeulen et al. 2014 should not be used without reservations in any risk assessments. This is particularly true for the low end of the exposure scale.
Algorithms for the Maximum Cardinality Matching Problem which greedily add edges to the solution enjoy great popularity. We systematically study strengths and limitations of such algorithms, in particular of those which consider node degree information to select the next edge. Concentrating on nodes of small degree is a promising approach: it was shown, experimentally and analytically, that very good approximate solutions are obtained for restricted classes of random graphs. Results achieved under these idealized conditions, however, remained unsupported by statements which depend on less optimistic assumptions.
The KarpSipser algorithm and 1-2-Greedy, which is a simplified variant of the well-known MinGreedy algorithm, proceed as follows. In each step, if a node of degree one (resp. at most two) exists, then an edge incident with a minimum degree node is picked, otherwise an arbitrary edge is added to the solution.
We analyze the approximation ratio of both algorithms on graphs of degree at most D. Families of graphs are known for which the expected approximation ratio converges to 1/2 as D grows to infinity, even if randomization against the worst case is used. If randomization is not allowed, then we show the following convergence to 1/2: the 1-2-Greedy algorithm achieves approximation ratio (D-1)/(2D-3); if the graph is bipartite, then the more restricted KarpSipser algorithm achieves the even stronger factor D/(2D-2). These guarantees set both algorithms apart from other famous matching heuristics like e.g. Greedy or MRG: these algorithms depend on randomization to break the 1/2-barrier even for paths with D=2. Moreover, for any D our guarantees are strictly larger than the best known bounds on the expected performance of the randomized variants of Greedy and MRG.
To investigate whether KarpSipser or 1-2-Greedy can be refined to achieve better performance, or be simplified without loss of approximation quality, we systematically study entire classes of deterministic greedy-like algorithms for matching. Therefore we employ the adaptive priority algorithm framework by Borodin, Nielsen, and Rackoff: in each round, an adaptive priority algorithm requests one or more edges by formulating their properties---like e.g. "is incident with a node of minimum degree"---and adds the received edges to the solution. No constraints on time and space usage are imposed, hence an adaptive priority algorithm is restricted only by its nature of picking edges in a greedy-like fashion. If an adaptive priority algorithm requests edges by processing degree information, then we show that it does not surpass the performance of KarpSipser: our D/(2D-2)-guarantee for bipartite graphs is tight and KarpSipser is optimal among all such "degree-sensitive" algorithms even though it uses degree information merely to detect degree-1 nodes. Moreover, we show that if degrees of both nodes of an edge may be processed, like e.g. the Double-MinGreedy algorithm does, then the performance of KarpSipser can only be increased marginally, if at all. Of special interest is the capability of requesting edges not only by specifying the degree of a node but additionally its set of neighbors. This enables an adaptive priority algorithm to "traverse" the input graph. We show that on general degree-bounded graphs no such algorithm can beat factor (D-1)/(2D-3). Hence our bound for 1-2-Greedy is tight and this algorithm performs optimally even though it ignores neighbor information. Furthermore, we show that an adaptive priority algorithm deteriorates to approximation ratio exactly 1/2 if it does not request small degree nodes. This tremendous decline of approximation quality happens for graphs on which 1-2-Greedy and KarpSipser perform optimally, namely paths with D=2. Consequently, requesting small degree nodes is vital to beat factor 1/2.
Summarizing, our results show that 1-2-Greedy and KarpSipser stand out from known and hypothetical algorithms as an intriguing combination of both approximation quality and conceptual simplicity.
Dokumentation von Best-Practice-Beispielen zum Umgang mit dem Fahren ohne (gültigen) Fahrschein
(2016)
In Deutschland und Europa versuchen Verkehrsunternehmen und -verbünde bereits seit längerer Zeit gegen das Fahren ohne (gültigen) Fahrschein vorzugehen, ihre Fahrgeldeinnahmen zu sichern und zu steigern sowie die Quote der Personen, die den ÖPNV ohne (gültiges) Ticket nutzen, zu minimieren. Auf Grundlage des ersten Arbeitspaketes (Literaturanalyse zum Stand der Forschung: Schwerdtfeger et al. 2016) wurden Maßnahmen untersucht, die zum Erreichen der genannten Ziele beitragen. Der Fokus liegt dabei auf Best Practice Beispielen, also Maßnahmen, die in der Praxis als erfolgreich hinsichtlich der Reduzierung des Fahrens ohne (gültigen) Fahrschein sowie hinsichtlich der Einnahmesicherung und -steigerung angesehen werden. Das Ergebnis der Untersuchung ist eine umfangreiche Auseinandersetzung mit Best Practice Beispielen in Bezug auf das Fahren ohne (gültigen) Fahrschein. Außerdem wurden aktuell diskutierte Ansätze alternativer Finanzierungsinstrumente hinsichtlich ihrer Eignung zur Finanzierung des ÖPNV untersucht. Zwar können alternative Finanzierungsinstrumente derzeit noch nicht als Best Practice eingestuft werden, allerdings stehen sie in direkter Beziehung zur Einnahmesicherung im ÖPNV-Sektor.
The Multilingual Assessment Instrument for Narratives (MAIN) was designed in order to assess narrative skills in children who acquire one or more languages from birth or from early age. MAIN is suitable for children from 3 to 10 years and evaluates both comprehension and production of narratives. Its design allows for the assessment of several languages in the same child, as well as for different elicitation modes: Model Story, Retelling, and Telling. MAIN contains four parallel stories, each with a carefully designed six-picture sequence. The stories are controlled for cognitive and linguistic complexity, parallelism in macrostructure and microstructure, as well as for cultural appropriateness and robustness. The instrument has been developed on the basis of extensive piloting with more than 550 monolingual and bilingual children aged 3 to 10, for 15 different languages and language combinations. Even though MAIN has not been norm-referenced yet, its standardized procedures can be used for evaluation, intervention and research purposes. MAIN is currently available in the following languages: English, Afrikaans, Albanian, Basque, Bulgarian, Croatian, Cypriot Greek, Danish, Dutch, Estonian, Finnish, French, German, Greek, Hebrew, Icelandic, Italian, Lithuanian, Norwegian, Polish, Russian, Spanish, Standard Arabic, Swedish, Turkish, Vietnamese, and Welsh.
BACKGROUND: Acetogenic bacteria are able to use CO2 as terminal electron acceptor of an anaerobic respiration, thereby producing acetate with electrons coming from H2. Due to this feature, acetogens came into focus as platforms to produce biocommodities from waste gases such as H2+CO2 and/or CO. A prerequisite for metabolic engineering is a detailed understanding of the mechanisms of ATP synthesis and electron-transfer reactions to ensure redox homeostasis. Acetogenesis involves the reduction of CO2 to acetate via soluble enzymes and is coupled to energy conservation by a chemiosmotic mechanism. The membrane-bound module, acting as an ion pump, was of special interest for decades and recently, an Rnf complex was shown to couple electron flow from reduced ferredoxin to NAD+ with the export of Na+ in Acetobacterium woodii. However, not all acetogens have rnf genes in their genome. In order to gain further insights into energy conservation of non-Rnf-containing, thermophilic acetogens, we sequenced the genome of Thermoanaerobacter kivui.
RESULTS: The genome of Thermoanaerobacter kivui comprises 2.9 Mbp with a G+C content of 35% and 2,378 protein encoding orfs. Neither autotrophic growth nor acetate formation from H2+CO2 was dependent on Na+ and acetate formation was inhibited by a protonophore, indicating that H+ is used as coupling ion for primary bioenergetics. This is consistent with the finding that the c subunit of the F1FO ATP synthase does not have the conserved Na+ binding motif. A search for potential H+-translocating, membrane-bound protein complexes revealed genes potentially encoding two different proton-reducing, energy-conserving hydrogenases (Ech).
CONCLUSIONS: The thermophilic acetogen T. kivui does not use Na+ but H+ for chemiosmotic ATP synthesis. It does not contain cytochromes and the electrochemical proton gradient is most likely established by an energy-conserving hydrogenase (Ech). Its thermophilic nature and the efficient conversion of H2+CO2 make T. kivui an interesting acetogen to be used for the production of biocommodities in industrial micobiology. Furthermore, our experimental data as well as the increasing number of sequenced genomes of acetogenic bacteria supported the new classification of acetogens into two groups: Rnf- and Ech-containing acetogens.
In the 1960s, theoretical concepts prepared the path to nuclear matter with proton and neutron numbers far beyond the nuclei known at that time. The new laboratory GSI was founded for research on reactions with heavy ions, in particular those for production of the predicted super-heavy nuclei. In this contribution it is presented how the interaction between experiment and theory resulted in a continuous improvement of the experimental set-ups on the one hand, and of the knowledge of the processes during the nuclear reaction and of the properties of the produced nuclei on the other hand. In the course of this work six new elements from 107 to 112 were produced and identified. An overview of the present status of experimental results and a comparison with theoretical interpretations is given.
Background: Due to the steadily increasing number of cancer patients worldwide the early diagnosis and treatment of cancer is a major field of research. The diagnosis of cancer is mostly performed by an experienced pathologist via the visual inspection of histo-pathological stained tissue sections. To save valuable time, low quality cryosections are frequently analyzed with diagnostic accuracies that are below those of high quality embedded tissue sections. Thus, alternative means have to be found that enable for fast and accurate diagnosis as the basis of following clinical decision making.
Methods: In this contribution we will show that the combination of the three label-free non-linear imaging modalities CARS (coherent anti-Stokes Raman-scattering), TPEF (two-photon excited autofluorescence) and SHG (second harmonic generation) yields information that can be translated into computational hematoxylin and eosin (HE) images by multivariate statistics. Thereby, a computational HE stain is generated resulting in pseudo-HE overview images that allow for identification of suspicious regions. The latter are analyzed further by Raman-spectroscopy retrieving the tissue’s molecular fingerprint.
Results: The results suggest that the combination of non-linear multimodal imaging and Raman-spectroscopy possesses the potential as a precise and fast tool in routine histopathology.
Conclusions: As the key advantage, both optical methods are non-invasive enabling for further pathological investigations of the same tissue section, e.g. a direct comparison with the current pathological gold-standard.