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This paper presents a search for the t-channel exchange of an R-parity violating scalar top quark ( \(\tilde{t}\) ) in the e\(^±\) μ\(^∓\) continuum using 2.1 fb\(^{−1}\) of data collected by the ATLAS detector in √s=7 TeV pp collisions at the Large Hadron Collider. Data are found to be consistent with the expectation from the Standard Model backgrounds. Limits on R-parity-violating couplings at 95 % C.L. are calculated as a function of the scalar top mass (m\(_\tilde{t}\)). The upper limits on the production cross section for pp→eμX, through the t-channel exchange of a scalar top quark, ranges from 170 fb for m\(_\tilde{t}\)=95 GeV to 30 fb for m\(_\tilde{t}\)=1000 GeV.
The ATLAS detector at the Large Hadron Collider is used to search for high-mass resonances decaying to an electron-positron pair or a muon-antimuon pair. The search is sensitive to heavy neutral Z′ gauge bosons, Randall-Sundrum gravitons, Z* bosons, techni-mesons, Kaluza-Klein Z/γ bosons, and bosons predicted by Torsion models. Results are presented based on an analysis of pp collisions at a center-of-mass energy of 7 TeV corresponding to an integrated luminosity of 4.9 fb\(^{−1}\) in the e\(^+\)e\(^−\) channel and 5.0 fb\(^{−1}\) in the μ\(^+\)μ\(^−\)channel. A Z′ boson with Standard Model-like couplings is excluded at 95 % confidence level for masses below 2.22 TeV. A Randall-Sundrum graviton with coupling k/\(\overline M_{Pl}\)=0.1 is excluded at 95 % confidence level for masses below 2.16 TeV. Limits on the other models are also presented, including Technicolor and Minimal Z′ Models.
This letter reports on a search for hypothetical heavy neutrinos, N, and right-handed gauge bosons, W R, in events with high transverse momentum objects which include two reconstructed leptons and at least one hadronic jet. The results were obtained from data corresponding to an integrated luminosity of 2.1 fb\(^{−1}\) collected in proton–proton collisions at √s=7 TeV with the ATLAS detector at the CERN Large Hadron Collider. No excess above the Standard Model background expectation is observed. Excluded mass regions for Majorana and Dirac neutrinos are presented using two approaches for interactions that violate lepton and lepton-flavor numbers. One approach uses an effective operator framework, the other approach is guided by the Left–Right Symmetric Model. The results described in this letter represent the most stringent limits to date on the masses of heavy neutrinos and W\(_R\) bosons obtained in direct searches.
A search for doubly charged Higgs bosons decaying to pairs of electrons and/or muons is presented. The search is performed using a data sample corresponding to an integrated luminosity of 4.7 fb\(^{−1}\) of pp collisions at √s = 7 TeV collected by the ATLAS detector at the LHC. Pairs of prompt, isolated, high-p\(_T\) leptons with the same electric charge (\(e^±e^±, e^±μ^±, μ^±μ^±\)) are selected, and their invariant mass distribution is searched for a narrow resonance. No significant excess over Standard Model background expectations is observed, and limits are placed on the cross section times branching ratio for pair production of doubly charged Higgs bosons. The masses of doubly charged Higgs bosons are constrained depending on the branching ratio into these leptonic final states. Assuming pair production, coupling to left-handed fermions, and a branching ratio of 100 % for each final state, masses below 409 GeV, 375 GeV, and 398 GeV are excluded for \(e^±e^±, e^±μ^±\), and \(μ^±μ^±\), respectively.
The results of a search for charged Higgs bosons are presented. The analysis is based on 4.6fb\(^{−1}\) of proton-proton collision data at √s=7TeV collected by the ATLAS experiment at the Large Hadron Collider, using top quark pair events with a τ lepton in the final state. The data are consistent with the expected background from Standard Model processes. Assuming that the branching ratio of the charged Higgs boson to a τ lepton and a neutrino is 100 %, this leads to upper limits on the branching ratio of top quark decays to a b quark and a charged Higgs boson between 5% and 1% for charged Higgs boson masses ranging from 90 GeV to 160 GeV, respectively. In the context of the m\(^{max}_h\) scenario of the MSSM, tan β above 12-26, as well as between 1 and 2-6, can be excluded for charged Higgs boson masses between 90 GeV and 150 GeV.
In models of anomaly-mediated supersymmetry breaking (AMSB), the lightest chargino is predicted to have a lifetime long enough to be detected in collider experiments. This letter explores AMSB scenarios in pp collisions at √s=7 TeV by attempting to identify decaying charginos which result in tracks that appear to have few associated hits in the outer region of the tracking system. The search was based on data corresponding to an integrated luminosity of 1.02 fb\(^{−1}\) collected with the ATLAS detector in 2011. The p\(_T\) spectrum of candidate tracks is found to be consistent with the expectation from Standard Model background processes and constraints on the lifetime and the production cross section were obtained. In the minimal AMSB framework with m\(_{3/2}\)<32 TeV, m\(_0\)<1.5 TeV, tanβ=5 and μ>0, a chargino having mass below 92 GeV and a lifetime between 0.5 ns and 2 ns is excluded at 95 % confidence level.
Search for anomalous production of prompt like-sign lepton pairs at √s=7TeV with the ATLAS detector
(2012)
An inclusive search for anomalous production of two prompt, isolated leptons with the same electric charge is presented. The search is performed in a data sample corresponding to 4.7 fb\(^{−1}\) of integrated luminosity collected in 2011 at √s=7TeV with the ATLAS detector at the LHC. Pairs of leptons (e\(^{±}\)e\(^{±}\), e\(^{±}\)μ\(^{±}\), and μ\(^{±}\)μ\(^{±}\)) with large transverse momentum are selected, and the dilepton invariant mass distribution is examined for any deviation from the Standard Model expectation. No excess is found, and upper limits on the production cross section of like-sign lepton pairs from physics processes beyond the Standard Model are placed as a function of the dilepton invariant mass within a fiducial region close to the experimental selection criteria. The 95% confidence level upper limits on the cross section of anomalous e\(^{±}\)e\(^{±}\), e\(^{±}\)μ\(^{±}\), or μ\(^{±}\)μ\(^{±}\) production range between 1.7 fb and 64 fb depending on the dilepton mass and flavour combination.
The results of a search for direct pair production of heavy top-quark partners in 4.7 fb\(^{−1}\) of integrated luminosity from pp collisions at √s=7 TeV collected by the ATLAS detector at the LHC are reported. Heavy top-quark partners decaying into a top quark and a neutral non-interacting particle are searched for in events with two leptons in the final state. No excess above the Standard Model expectation is observed. Limits are placed on the mass of a supersymmetric scalar top and of a spin-1/2 top-quark partner. A spin-1/2 top-quark partner with a mass between 300 GeV and 480 GeV, decaying to a top quark and a neutral non-interacting particle lighter than 100 GeV, is excluded at 95% confidence level.
A search for a fermiophobic Higgs boson using diphoton events produced in proton-proton collisions at a centre-of-mass energy of √s=7 TeV is performed using data corresponding to an integrated luminosity of 4.9 fb\(^{−1}\) collected by the ATLAS experiment at the Large Hadron Collider. A specific benchmark model is considered where all the fermion couplings to the Higgs boson are set to zero and the bosonic couplings are kept at the Standard Model values (fermiophobic Higgs model). The largest excess with respect to the background-only hypothesis is found at 125.5 GeV, with a local significance of 2.9 standard deviations, which reduces to 1.6 standard deviations when taking into account the look-elsewhere effect. The data exclude the fermiophobic Higgs model in the ranges 110.0–118.0 GeV and 119.5–121.0 GeV at 95 % confidence level.
The infectious intracellular lifestyle of Salmonella enterica relies on the adaptation to nutritional conditions within the Salmonella-containing vacuole (SCV) in host cells. We summarize latest results on metabolic requirements for Salmonella during infection. This includes intracellular phenotypes of mutant strains based on metabolic modeling and experimental tests, isotopolog profiling using (13)C-compounds in intracellular Salmonella, and complementation of metabolic defects for attenuated mutant strains towards a comprehensive understanding of the metabolic requirements of the intracellular lifestyle of Salmonella. Helpful for this are also genomic comparisons. We outline further recent studies and which analyses of intracellular phenotypes and improved metabolic simulations were done and comment on technical required steps as well as progress involved in the iterative refinement of metabolic flux models, analyses of mutant phenotypes, and isotopolog analyses. Salmonella lifestyle is well-adapted to the SCV and its specific metabolic requirements. Salmonella metabolism adapts rapidly to SCV conditions, the metabolic generalist Salmonella is quite successful in host infection.
The thesis enhances the strategy of non-destructive fluorescence read-out in rylene bisimide-diarylethene containing photochromic systems. The fluorescence of the emitter unit is quenched by a photoinduced electron transfer only to one of the isomeric forms of the photochrome. The driving force of the fuorescence-quenching electron transfer was calculated by the help of the Rehm-Weller equation. The novel photochromic systems satisfy the necessary requirements for non-destructive read-out in write/read/erase fluorescent memory devices.
Rumination has been defined as a mode of responding to distress that involves passively focusing one's attention on symptoms of distress without taking action. This dysfunctional response style intensifies depressed mood, impairs interpersonal problem solving, and leads to more pessimistic future perspectives and less social support. As most of these results were obtained from younger people, it remains unclear how age affects ruminative thinking. Three hundred members of the general public ranging in age from 15 to 87 years were asked about their ruminative styles using the Response Styles Questionnaire (RSQ), depression and satisfaction with life. A Mokken Scale analysis confirmed the two-factor structure of the RSQ with brooding and reflective pondering as subcomponents of rumination. Older participants (63 years and older) reported less ruminative thinking than other age groups. Life satisfaction was associated with brooding and highest for the earlier and latest life stages investigated in this study.
Background. Nitric oxide (NO)-signal transduction plays an important role in renal ischemia/reperfusion (I/R) injury. NO produced by endothelial NO-synthase (eNOS) has protective functions whereas NO from inducible NO-synthase (iNOS) induces impairment. Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor (PPAR)-gamma agonist exerted beneficial effects after renal I/R injury, so we investigated whether this might be causally linked with NOS imbalance. Methods. RGZ (5 mg/kg) was administered i.p. to SD-rats (f) subjected to bilateral renal ischemia (60 min). Following 24 h of reperfusion, inulin-and PAH-clearance as well as PAH-net secretion were determined. Morphological alterations were graded by histopathological scoring. Plasma NOx-production was measured. eNOS and iNOS expression was analyzed by qPCR. Cleaved caspase 3 (CC3) was determined as an apoptosis indicator and ED1 as a marker of macrophage infiltration in renal tissue. Results. RGZ improves renal function after renal I/R injury (PAH-/inulin-clearance, PAH-net secretion) and reduces histomorphological injury. Additionally, RGZ reduces NOx plasma levels, ED-1 positive cell infiltration and CC3 expression. iNOS-mRNA is reduced whereas eNOS-mRNA is increased by RGZ. Conclusion. RGZ has protective properties after severe renal I/R injury. Alterations of the NO pathway regarding eNOS and iNOS could be an explanation of the underlying mechanism of RGZ protection in renal I/R injury.
ATP dependent chromatin remodeling complexes are multifactorial complexes that utilize the energy of ATP to rearrange the chromatin structure. The changes in chromatin structure lead to either increased or decreased DNA accessibility. SWI/SNF is one of such complex. The SWI/SNF complex is involved in both transcription activation and transcription repression. The ATPase subunit of SWI/SNF is called SWI2/SNF2 in yeast and Brahma, Brm, in Drosophila melanogaster. In mammals there are two paralogs of the ATPase subunit, Brm and Brg1. Recent studies have shown that the human Brm is involved in the regulation of alternative splicing. The aim of this study was to investigate the role of Brm in pre-mRNA processing. The model systems used were Chironomus tentans, well suited for in situ studies and D. melanogaster, known for its full genome information. Immunofluorescent staining of the polytene chromosome indicated that Brm protein of C. tentans, ctBrm, is associated with several gene loci including the Balbiani ring (BR) puffs. Mapping the distribution of ctBrm along the BR genes by both immuno-electron microscopy and chromatin immunoprecipitation showed that ctBrm is widely distributed along the BR genes. The results also show that a fraction of ctBrm is associated with the nascent BR pre-mRNP. Biochemical fractionation experiments confirmed the association of Brm with the RNP fractions, not only in C. tentans but also in D. melanogaster and in HeLa cells. Microarray hybridization experiments performed on S2 cells depleted of either dBrm or other SWI/SNF subunits show that Brm affects alternative splicing and 3´ end formation. These results indicated that BRM affects pre-mRNA processing as a component of SWI/SNF complexes. 1
It is of interest to define bacterial toxin biochemical properties to use them as molecular-syringe devices in order to deliver enzymatic activities into host cells. Binary toxins of the AB7/8-type are among the most potent and specialized bacterial protein toxins. The B subunits oligomerize to form a pore that binds with high affinity host cell receptors and the enzymatic A subunit. This allows the endocytosis of the complex and subsequent injection of the A subunit into the cytosol of the host cells. Here we report that the addition of an N-terminal His6-tag to different proteins increased their binding affinity to the protective antigen (PA) PA63-channels, irrespective if they are related (C2I) or unrelated (gpJ, EDIN) to the AB7/8-family of toxins. His6-EDIN exhibited voltage-dependent increase of the stability constant for binding by a factor of about 25 when the trans-side corresponding to the cell interior was set to 270 mV. Surprisingly, the C. botulinum toxin C2II-channel did not share this feature of PA63. Cell-based experiments demonstrated that addition of an N-terminal His6-tag promoted also intoxication of endothelial cells by C2I or EDIN via PA63. Our results revealed that addition of His6-tags to several factors increase their binding properties to PA63 and enhance the property to intoxicate cells.
RNase P processes the 5'-end of tRNAs. An essential catalytic RNA has been demonstrated in Bacteria, Archaea and the nuclei of most eukaryotes; an organism-specific number of proteins complement the holoenzyme. Nuclear RNase P from yeast and humans is well understood and contains an RNA, similar to the sister enzyme RNase MRP. In contrast, no protein subunits have yet been identified in the plant enzymes, and the presence of a nucleic acid in RNase P is still enigmatic. We have thus set out to identify and characterize the subunits of these enzymes in two plant model systems. Expression of the two known Arabidopsis MRP RNA genes in vivo was verified. The first wheat MRP RNA sequences are presented, leading to improved structure models for plant MRP RNAs. A novel mRNA encoding the central RNase P/MRP protein Pop1p was identified in Arabidopsis, suggesting the expression of distinct protein variants from this gene in vivo. Pop1p-specific antibodies precipitate RNase P activity and MRP RNAs from wheat extracts. Our results provide evidence that in plants, Pop1p is associated with MRP RNAs and with the catalytic subunit of RNase P, either separately or in a single large complex.
Background: There are few studies of the effects of nasal snuff and environmental factors on the risk of nasal cancer. This study aimed to investigate the impact of using nasal snuff and of other risk factors on the risk of nasal cancer in German men.
Methods: A population-based case-control study was conducted in the German Federal States of Bavaria and Baden-Wurttemberg. Tumor registries and ear, nose and throat departments provided access to patients born in 1926 or later.
Results: Telephone interviews were conducted with 427 cases (mean age 62.1 years) and 2.401 population-based controls (mean age 60.8 years). Ever-use of nasal snuff was associated with an odds ratio (OR) for nasal cancer of 1.45 (95% confidence interval [CI] 0.88-2.38) in the total study population, whereas OR in smokers was 2.01 (95% CI 1.00-4.02) and in never smokers was 1.10 (95% CI 0.43-2.80). The OR in ever-smokers vs. never-smokers was 1.60 (95% CI 1.24-2.07), with an OR of 1.06 (95% CI 1.05-1.07) per pack-year smoked, and the risk was significantly decreased after quitting smoking. Exposure to hardwood dust for at least 1 year resulted in an OR of 2.33 (95% CI 1.40-3.91) in the total population, which was further increased in never-smokers (OR 4.89, 95% CI 1.92-12.49) in analyses stratified by smoking status. The OR for nasal cancer after exposure to organic solvents for at least 1 year was 1.53 (1.17-2.01). Ever-use of nasal sprays/nasal lavage for at least 1 month rendered an OR of 1.59 (1.04-2.44). The OR after use of insecticides in homes was 1.48 (95% CI 1.04-2.11).
Conclusions: Smoking and exposure to hardwood dust were confirmed as risk factors for nasal carcinoma. There is evidence that exposure to organic solvents, and in-house use of insecticides could represent novel risk factors. Exposure to asbestos and use of nasal snuff were risk factors in smokers only.
Ziel dieser klinisch prospektiven Studie ist es bei über 80 jährigen Patienten mit moderater und hochgradiger AS echokardiographische Parameter zu identifizieren, die die langfristige Prognose für diese Patienten quantifizieren können. Methodik: Es wurde bei 118 Patienten eine konventionelle echokardiographische Standarduntersuchung und eine Gewebedoppleruntersuchung durchgeführt. Zudem wurden die aktuellen klinischen Daten erhoben. Nach durchschnittlich 641 ± 224.2 wurde eine telefonische Follow Up Untersuchung durchgeführt. Ergebnisse: Die Patienten wurden anhand der konventionellen echokardiographischen Parameter in 5 Gruppen eingeteilt. Eine hochgradige Aortenstenose mit reduziertem Gradienten und reduzierter EF ist mittels der Standardechokardiographiedaten von einer moderaten AS signifikant unterscheidbar. Besser gelingt es jedoch eine Niedrig Gradient AS mit der mittels Gewebedoppler ermittelten Strainrate und der Ringmotion von einer mittelgradigen AS zu unterscheiden. Die Patienten aus der Gruppe mit einer hochgradigen AS und einem hohen Gradienten wiesen das höchste Risiko eines kardialen Todes auf. Es stellte sich heraus, dass diese Patienten mittels Ringmotion und Strainrate signifikant von den Patienten mit einem niedrigeren Risiko unterschieden werden können. Zusammenfassung: Die Detektion des Grades der AS mit zusätzlich der Ringmotion und der Strainrate hat signifikante Vorteile gegenüber der Risikoquantifizierung über die EF und den Druckgradienten über der Aortenklappe alleine. Dies liefert wiederum eine bessere Einschätzung bezüglich der Dringlichkeit und Planung des Zeitpunktes für einen operativen Aortenklappenersatz, da alleine mit den Parametern der EF und des Gradienten die eigentlichen Hochrisikopatienten nicht ausreichend erfasst werden.
Many organisms evolved an endogenous clock to adapt to the daily environmental changes caused by the earth’s rotation. Light is the primary time cue (“Zeitgeber”) for entrainment of circadian clocks to the external 24-h day. In Drosophila, several visual pigments are known to mediate synchronization to light: The blue-light photopigment Cryptochrome (CRY) and six well-described rhodopsins (Rh1-Rh6). CRY is present in the majority of clock neurons as well as in the compound eyes, whereas the location of rhodopsins is restricted to the photoreceptive organs – the compound eyes, the ocelli and the HB-eyelets. CRY is thought to represent the key photoreceptor of Drosophila’s circadian clock. Nevertheless, mutant flies lacking CRY (cry01) are able to synchronize their locomotor activity rhythms to light-dark (LD) cycles, but need significantly longer than wild-type flies. In this behavior, cry01 mutants strongly resemble mammalian species that do not possess any internal photoreceptors and perceive light information exclusively through their photoreceptive organs (eyes). Thus, a mammalian-like phase-shifting behavior would be expected in cry01 flies. We investigated this issue by monitoring a phase response curve (PRC) of cry01 and wild-type flies to 1-h light pulses of 1000 lux irradiance. Indeed, cry01 mutants produced a mammalian-similar so called type 1 PRC of comparatively low amplitude (< 25% of wild-type) with phase delays to light pulses during the early subjective night and phase advances to light pulses during the late subjective night (~1 h each). Despite the predominant role of CRY, the visual system contributes to the light sensitivity of the fly’s circadian clock, mainly around dawn and dusk. Furthermore, this phase shifting allows for the slow re-entrainment which we observed in cry01 mutants to 8-h phase delays of the LD 12 h:12 h cycle. However, cry01 also showed surprising differences in their shifting ability: First of all, their PRC was characterized by a second dead zone in the middle of the subjective night (ZT17-ZT19) in addition to the usual unresponsiveness during the subjective day. Second, in contrast to wild-type flies, cry01 mutants did not increase their shift of activity rhythms neither in response to longer stimuli nor to light pulses of higher irradiance. In contrast, both 6-h light pulses of 1000 lux and 1-h light pulses of 10,000 lux light intensity during the early subjective night even resulted in phase advances instead of the expected delays. Thus, CRY seems to be not only responsible for the high light sensitivity of the wild-type circadian clock, but is apparently also involved in integrating and processing light information. Rhodopsin 7 (Rh7) is a yet uncharacterized protein, but became a good photoreceptor candidate due to sequence similarities to the six known Drosophila Rhs. The second part of this thesis investigated the expression pattern of Rh7 and its possible functions, especially in circadian photoreception. Furthermore, we were interested in a potential interaction with CRY and thus, tested cry01 and rh70 cry01 mutants as well. Rh1 is the main visual pigment of the Drosophila compound eye and expressed in six out of eight photoreceptors cells (R1-R6) in each of the ~800 ommatidia. Motion vision depends exclusively on Rh1 function but, moreover, Rh1 plays an important structural role and assures proper photoreceptor cell development and maintenance. In order to investigate its possible photoreceptive function, we expressed Rh7 in place of Rh1. Rh7 was indeed able to overtake the role of Rh1 in both aspects: It prevented retinal degeneration and mediated the optomotor response (OR), a motion vision-dependent behavior. At the transcriptional level, rh7 is expressed at approximately equal amounts in adult fly brains and retinas. Due to a reduced specificity of anti-Rh7 antibodies, we could not verify this result at the protein level. However, analysis of rh7 null mutants (rh70) suggested different Rh7 functions in vivo. Previous experiments strongly indicated an increased sensitivity of the compound eyes in the absence of Rh7 and suggested impaired light adaptation. We aimed to test this hypothesis at the levels of circadian photoreception. Locomotor activity rhythms are a reliable output of the circadian clock. Rh70 mutant flies generally displayed a wild-type similar bimodal activity pattern comprising morning (M) and evening (E) activity bouts. Activity monitoring supported the proposed “shielding” function, since rh70 mutants behaved like wild-type flies experiencing high irradiances. Under all investigated conditions, their activity peaks lay further apart resulting in a prolonged midday break. The behavior of cry01 mutants was mainly characterized by an unexpectedly high flexibility in the timing of M and E activity bouts which allowed tracking of lights-on and lights-off even under extreme photoperiods. Activity profiles of the corresponding rh70 cry01 double mutants reflected neither synergistic nor antagonistic effects of Rh7 and CRY and were dominated by a broad E activity peak. In the future, the different circadian phenotypes will be further investigated on the molecular level by analysis of clock protein cycling in the underlying pacemaker neurons. The work of this thesis confirmed that Rh7 is indeed able to work as a photoreceptor and to initiate the classical phototransduction cascade. On the other hand, it provided further evidence at the levels of circadian photoreception that Rh7 might serve as a shielding pigment for Rh1 in vivo, thereby mediating proper light adaptation.
The development of insecticides requires valid risk assessment procedures to avoid causing harm to beneficial insects and especially to pollinators such as the honeybee Apis mellifera. In addition to testing according to current guidelines designed to detect bee mortality, tests are needed to determine possible sublethal effects interfering with the animal's vitality and behavioral performance. Several methods have been used to detect sublethal effects of different insecticides under laboratory conditions using olfactory conditioning. Furthermore, studies have been conducted on the influence insecticides have on foraging activity and homing ability which require time-consuming visual observation. We tested an experimental design using the radiofrequency identification (RFID) method to monitor the influence of sublethal doses of insecticides on individual honeybee foragers on an automated basis. With electronic readers positioned at the hive entrance and at an artificial food source, we obtained quantifiable data on honeybee foraging behavior. This enabled us to efficiently retrieve detailed information on flight parameters. We compared several groups of bees, fed simultaneously with different dosages of a tested substance. With this experimental approach we monitored the acute effects of sublethal doses of the neonicotinoids imidacloprid (0.15-6 ng/bee) and clothianidin (0.05-2 ng/bee) under field-like circumstances. At field-relevant doses for nectar and pollen no adverse effects were observed for either substance. Both substances led to a significant reduction of foraging activity and to longer foraging flights at doses of >= 0.5 ng/bee (clothianidin) and >= 1.5 ng/bee (imidacloprid) during the first three hours after treatment. This study demonstrates that the RFID-method is an effective way to record short-term alterations in foraging activity after insecticides have been administered once, orally, to individual bees. We contribute further information on the understanding of how honeybees are affected by sublethal doses of insecticides.
Ziel der retrospektiven Studie war es, den Einfluss der prothetischen Restauration, beziehungsweise der Position des Pfeilers im Zahnbogen sowie der Art des restaurierten Zahnes auf das Überleben von mit Stift-Stumpfaufbauten rekonstruierten Zähnen zu untersuchen. Die verschiedenen Parameter, die zu Erfolg oder Misserfolg geführt haben, sollten analysiert werden, um gegebenenfalls deren Einfluss auf die Verweildauer der Stift-Stumpfaufbauten beziehungsweise der damit versorgten Zähne in Form einer Überlebenszeitanalyse zu untersuchen Seit 1999 wurden Patienten, die in der Klinik mit einem Stift-Stumpfaufbau versorgt worden waren, protokollarisch erfasst. Die koronal stark zerstörten Zähne wurden durch ein weitgehend standardisiertes Behandlungsverfahren rekonstruiert und mit diversen prothetischen Restaurationen versehen. Das Patientenkollektiv umfasste 195 Patienten mit 320 Stift-Stumpfaufbauten. Zur Überlebenszeitanalyse kam die Methode nach Kaplan-Meier zum Einsatz. Die gruppenbezogenen Überlebenskurven wurden mittels Log-Rang-Test auf statistische Signifikanz getestet. Die häufigsten Misserfolgsgründe stellten Dezementierungen der Stift-Stumpfauf- bauten und Entzündungszeichen mit apikalen Läsionen dar. Die Ergebnisse dieser Studie zeigten, dass der Erfolg einer postendodontischen Stiftverankerung je nach Zahntyp und Art der prothetischen Versorgung variierte. Festsitzende prothetische Restaurationen auf der Basis eines Stift-Stumpfaufbaus im Frontzahn- und Prämolarenbereich hatten eine relativ hohe Überlebeswahrscheinlichkeit, vor allem wenn sie Brückenpfeiler waren. War der mit einem Stift-Stumpfaufbau rekonstruierte Zahn aber endständig in der Zahnreihe, überdurchschnittlichen Belastungen ausgesezt - wie der Eckzahn - oder diente als endständiger Pfeiler einer herausnehmbaren teleskopierenden Prothese, waren frühzeitige Komplikationen wahrscheinlich. Die Ergebnisse zeigten, dass eine primäre Verblockung die Überlebenswahrscheinlichkeit von Innenteleskopkronen positiv beeinflussen konnte.
Die Auswertung des Patientenkollektivs von 2000 bis 2004 an der Chirurgischen Universitätsklinik Würzburg ergab 63 Patienten (Gruppe 1), die einer Minoramputation und
59 Patienten die einer Minor- mit konsekutiver Majoramputation (Gruppe 2) infolge pAVK unterzogen wurden. Eine Abhängigkeit zwischen Alter und Majornachamputationsrate konnte nicht festgestellt werden, jedoch eine Tendenz beim Einfluss von Comorbiditäten wie Diabetes mellitus und dialysepflichtiger Niereninsuffizienz auf die Wundheilung und Liegedauer.
Die Anzahl an durchgeführten gefäßchirurgischen Eingriffen wie PTA und Bypass-Operation lag in beiden Gruppen mit 65% bzw. 72% im Vergleich zur Literatur im Standardbereich.
Eine hohe Rate an gefäßmedizinischer Diagnostik und Therapie scheint auch bei fortgeschrittener pAVK (Grad IV) erforderlich, um die Notwendigkeit von Amputationen
insbesondere die Anzahl an Majoramputationen zu verringern. Bei hoher und mit Gruppe 1 vergleichbarer Interventionsrate in Gruppe 2 lässt sich allerdings auch erkennen, dass trotz Ausschöpfung dieser Massnahmen die Rate an Majoramputationen und damit des
Beinverlustes hoch ist.
Positiv zu werten ist, dass es bei über 50% der Amputierten ausgereicht hat, eine Amputation im Fussbereich (Minoramputation) durchzuführen. Bei diesen 63 Patienten, war bei 58 Patienten sogar nur ein Eingriff nötig. Ferner handelte es sich bei den Majoramputationen in der Mehrzahl um Unterschenkelamputation, und somit um einen nur partiellen Beinverlust . 76% der durchgeführten ersten Majoramputationen erfolgten in den ersten beiden Monaten nach vorausgegangener Minoramputation, die größte Anzahl innerhalb des ersten Monats. Auch die letzte Amputation, die definitive Versorgung, erfolgte
in den meisten Fällen innerhalb der ersten beiden Monate nach Primäreingriff. Somit ist ein nur unwesentlicher Aufschub bis zur definitiven Versorgung ersichtlich.
Der Versuch einer Konsolidierung der Ischämiefolgen (Gangrän) mittels Minoramputation scheint bei fortgeschrittener pAVK im Stadium IV nach Ausschöpfung der
gefäßmedizinischen Diagnostika und Interventionen somit immer gerechtfertigt, und sollte wenn möglich einer Majoramputation vorgezogen werden.
Die durchschnittliche Krankenhausverweildauer in der Gruppe der Minoramputationen lag bei 28 Tagen, in der Gruppe 2 der Majoramputationen bei 39 Tagen. Die Mortalitätsrate ergibt einen deutlich erhöhten Wert in der Gruppe der Majoramputationen. Die Dreijahresmortalität betrug in der Gruppe der Minoramputationen 20% und der Majoramputationen 58%. Es zeigte sich eine Zunahme der Mortalität mit zunehmender
Amputationshöhe und zunehmender Zahl der Amputationen. Diese Daten lassen sich mit 52 aktuellen Literaturangaben durchaus vergleichen und beweisen die schlechte Prognose für AVK-Patienten, bei denen eine Majoramputation unausweichlich ist.
Insgesamt ist es wichtig, dass ein Team aus Chirurgen, Gefäßchirurgen, Radiologen und Angiologen kooperativ zusammen arbeitet, um dem Patienten, eine für ihn
beste Versorgung anbieten zu können. Hier sollte auch nicht vor einem oft höheren Patientenalter zurückgeschreckt werden, denn häufig konnte gerade bei diesen Patienten durch eine Bypass-Operation eine sonst vermutlich unumgängliche Amputation im Unter- bzw.
Oberschenkelbereich verhindert werden.
Objective: The objective of this study was to investigate the applicability of microanalytical methods with high spatial resolution to the characterization of the composition and corrosion behavior of two bracket systems.
Material and methods: The surfaces of six nickel-free brackets and six nickel-containing brackets were examined for signs of corrosion and qualitative surface analysis using an electron probe microanalyzer (EPMA), prior to bonding to patient's tooth surfaces and four months after clinical use. The surfaces were characterized qualitatively by secondary electron (SE) images and back scattered electron (BSE) images in both compositional and topographical mode. Qualitative and quantitative wavelength-dispersive analyses were performed for different elements, and by utilizing qualitative analysis the relative concentration of selected elements was mapped two-dimensionally. The absolute concentration of the elements was determined in specially prepared brackets by quantitative analysis using pure element standards for calibration and calculating correction-factors (ZAF).
Results: Clear differences were observed between the different bracket types. The nickel-containing stainless steel brackets consist of two separate pieces joined by a brazing alloy. Compositional analysis revealed two different alloy compositions, and reaction zones on both sides of the brazing alloy. The nickel-free bracket was a single piece with only slight variation in element concentration, but had a significantly rougher surface. After clinical use, no corrosive phenomena were detectable with the methods applied. Traces of intraoral wear at the contact areas between the bracket slot and the arch wire were verified. Conclusion: Electron probe microanalysis is a valuable tool for the characterization of element distribution and quantitative analysis for corrosion studies.
Respiratory sinus arrhythmia (RSA) is related to cardiac vagal outflow and the respiratory pattern. Prior infant studies have not systematically examined respiration rate and tidal volume influences on infant RSA or the extent to which infants' breathing is too fast to extract a valid RSA. We therefore monitored cardiac activity, respiration, and physical activity in 23 six-month old infants during a standardized laboratory stressor protocol. On average, 12.6% (range 0-58.2%) of analyzed breaths were too short for RSA extraction. Higher respiration rate was associated with lower RSA amplitude in most infants, and lower tidal volume was associated with lower RSA amplitude in some infants. RSA amplitude corrected for respiration rate and tidal volume influences showed theoretically expected strong reductions during stress, whereas performance of uncorrected RSA was less consistent. We conclude that stress-induced changes of peak-valley RSA and effects of variations in breathing patterns on RSA can be determined for a representative percentage of infant breaths. As expected, breathing substantially affects infant RSA and needs to be considered in studies of infant psychophysiology.
From November 2nd - 4th 2012, the 4th NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Again more than 60 participants, predominantly at the doctoral student or postdoc level, gathered to share their latest findings in the fields of neurovascular research, neurodegeneration and neuroinflammation. Like in the previous years, the symposium provided an excellent platform for scientific exchange and the presentation of innovative projects in the stimulating surroundings of the Brandenburg outback. This year’s keynote lecture on the pathophysiological relevance of neuronal networks was given by Christian Gerloff, Head of the Department of Neurology at the University Clinic of Hamburg-Eppendorf. Another highlight of the meeting was the awarding of the NEUROWIND e.V. prize for young scientists working in the field of experimental neurology. The award is donated by the Merck Serono GmbH, Darmstadt, Germany and is endowed with 20.000 Euro. This year the jury decided unanimously to adjudge the award to Michael Gliem from the Department of Neurology at the University Clinic of Düsseldorf (group of Sebastian Jander), Germany, for his outstanding work on different macrophage subsets in the pathogenesis of ischemic stroke published in the Annals of Neurology in 2012.
From November 4th- 6th 2011, the 3rd NEUROWIND e.V. meeting was held in Motzen, Brandenburg, Germany. Like in the previous years, the meeting provided an excellent platform for scientific exchange and the presentation of innovative projects for young colleagues in the fields of neurovascular research, neuroinflammation and neurodegeneration. As kick-off to the scientific sessions, Reinhard Hohlfeld, Head of the Institute for Clinical Neuroimmunology in Munich, gave an illustrious overview on the many fascinations of neuroimmunologic research. A particular highlight on the second day of the meeting was the award of the 1’st NEUROWIND e.V. prize for young academics in the field of experimental neurology. This award is posted for young colleagues under the age of 35 with a significant achievement in the field of neurovascular research, neuroinflammation or neurodegeneration and comprises an amount of 20.000 Euro, founded by Merck Serono GmbH, Darmstadt. Germany. The first prize was awarded to Ivana Nikic from Martin Kerschensteiner’s group in Munich for her brilliant work on a reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis, published in Nature Medicine in 2011. This first prize award ceremony was a great incentive for the next call for proposals now upcoming in 2012.
A recent genome-wide association study in patients with panic disorder (PD) identified a risk haplotype consisting of two single-nucleotide polymorphisms (SNPs) (rs7309727 and rs11060369) located in intron 3 of TMEM132D to be associated with PD in three independent samples. Now we report a subsequent confirmation study using five additional PD case-control samples (n = 1670 cases and n 2266 controls) assembled as part of the Panic Disorder International Consortium (PanIC) study for a total of 2678 cases and 3262 controls in the analysis. In the new independent samples of European ancestry (EA), the association of rs7309727 and the risk haplotype rs7309727-rs11060369 was, indeed, replicated, with the strongest signal coming from patients with primary PD, that is, patients without major psychiatric comorbidities (n 1038 cases and n 2411 controls). This finding was paralleled by the results of the meta-analysis across all samples, in which the risk haplotype and rs7309727 reached P-levels of P = 1.4e-8 and P = 1.1e-8, respectively, when restricting the samples to individuals of EA with primary PD. In the Japanese sample no associations with PD could be found. The present results support the initial finding that TMEM132D gene contributes to genetic susceptibility for PD in individuals of EA. Our results also indicate that patient ascertainment and genetic background could be important sources of heterogeneity modifying this association signal in different populations.
Reorganisation der Zellkontakte der Endothelbarriere bei der Stabilisierung durch cAMP und Rac1
(2012)
Zwischen Blutkompartiment und umliegenden Interstitium besteht eine Barriere, die durch eine einzelne Schicht aus Endothelzellen gebildet wird. Essentiell für diese Barriere, deren Funktion in der Begrenzung des Austausches von Flüssigkeit und gelösten Stoffen liegt, sind interzelluläre Junktionen, welche die Endothelzellen miteinander verbinden. Durch eine gestörte Funktion und Regulation der Endothelbarriere entstehen beim Menschen verschiedene Pathologien wie zum Beispiel Ödeme, hämorrhagischer Schlaganfall und vaskuläre Malformationen.
Es ist bekannt, dass cAMP die Endothelbarriere zum Teil durch Aktivierung der kleinen GTPase Rac1 stabilisiert. Trotz der großen medizinischen Relevanz dieses Signalweges, sind die damit einhergehenden Effekte auf die interzellulären Kontakte auf ultrastruktureller Ebene weitgehend unbekannt.
In mikrovaskulären Endothelzellkulturen kam es ähnlich wie in intakten Mikrogefäßen zur Stärkung der Barrierefunktion. So resultierte sowohl nach Behandlung mit Forskolin und Rolipram (F/R), welche zur Steigerung der intrazellulären cAMP-Spiegel führen, als auch nach Zugabe von 8-(4-chlorophenylthio)-2´-O-methyladenosin-3´,5´-cyclic monophosphorothioate (O-Me-cAMP), einem selektiven Aktivator des cAMP nachgeschalteten Epac/Rap1-Signalweges, ein Anstieg des TER; außerdem konnte durch beide Substanzen (F/R und O-Me-cAMP) die Aktivierung von Rac1 induziert werden. Desweiteren wurde eine verstärkte Intensität und Linearisierung des Immunfluoreszenzsignals der Zelljunktionsproteine VE-Cadherin und Claudin5 entlang der Zellgrenzen beobachtet.
In der ultrastrukturellen Analyse der interzellulären Kontaktzonen-Architektur zeigte sich unter F/R- oder O-Me-cAMP-Exposition ein signifikanter Anstieg an komplexen Interdigitationen. Diese komplexen Strukturen waren dadurch charakterisiert, dass sich die Membranen benachbarter Zellen, die durch zahlreiche endotheliale Junktionen stabilisiert wurden, über vergleichsweise lange Distanzen eng aneinanderlegten, so dass ein deutlich verlängerter Interzellularspalt resultierte. Die Inhibition der Rac1-Aktivierung durch NSC-23766 verminderte die Barrierefunktion und blockierte effektiv die O-Me-cAMP-vermittelte Barrierestabilisierung und Reorganisation der Kontaktzone einschließlich der Junktionsproteine.
Demgegenüber konnte die F/R-vermittelte Barrierestabilisierung durch NSC-23766 nicht beeinträchtigt werden.
Parallel dazu durchgeführte Experimente mit makrovaskulären Endothelien zeigten, dass es in diesem Zelltyp unter Bedingungen erhöhter cAMP-Konzentrationen weder zur Rac1-Aktivierung noch zur Barrierestärkung oder Kontaktzonen-Reorganisation kam.
Diese Ergebnisse deuten darauf hin, dass in mikrovaskulären Endothelien Rac1-vermittelte Änderungen der Kontaktzonen-Morphologie zur cAMP-induzierten Barrierestabilisierung beitragen.
Renal Perfusion in Scleroderma Patients Assessed by Microbubble-Based Contrast-Enhanced Ultrasound
(2012)
Abstract: Objectives: Renal damage is common in scleroderma. It can occur acutely or chronically. Renal reserve might already be impaired before it can be detected by laboratory findings. Microbubble-based contrast-enhanced ultrasound has been demonstrated to improve blood perfusion imaging in organs. Therefore, we conducted a study to assess renal perfusion in scleroderma patients utilizing this novel technique. Materials and Methodology: Microbubble-based contrast agent was infused and destroyed by using high mechanical index by Siemens Sequoia (curved array, 4.5 MHz). Replenishment was recorded for 8 seconds. Regions of interests (ROI) were analyzed in renal parenchyma, interlobular artery and renal pyramid with quantitative contrast software (CUSQ 1.4, Siemens Acuson, Mountain View, California). Time to maximal Enhancement (TmE), maximal enhancement (mE) and maximal enhancement relative to maximal enhancement of the interlobular artery (mE%A) were calculated for different ROIs. Results: There was a linear correlation between the time to maximal enhancement in the parenchyma and the glomerular filtration rate. However, the other parameters did not reveal significant differences between scleroderma patients and healthy controls. Conclusion: Renal perfusion of scleroderma patients including the glomerular filtration rate can be assessed using microbubble-based contrast media.
Background. The purpose of this study was to identify determinants of renal disease progression in adults with Fabry disease during treatment with agalsidase beta.
Methods. Renal function was evaluated in 151 men and 62 women from the Fabry Registry who received agalsidase beta at an average dose of 1 mg/kg/2 weeks for at least 2 years. Patients were categorized into quartiles based on slopes of estimated glomerular filtration rate (eGFR) during treatment. Multivariate logistic regression analyses were used to identify factors associated with renal disease progression.
Results. Men within the first quartile had a mean eGFR slope of –0.1 mL/min/1.73m2/year, whereas men with the most rapid renal disease progression (Quartile 4) had a mean eGFR slope of –6.7 mL/min/1.73m2/year. The risk factor most strongly associated with renal disease progression was averaged urinary protein:creatinine ratio (UP/Cr) ≥1 g/g (odds ratio 112, 95% confidence interval (95% CI) 4–3109, P = 0.0054). Longer time from symptom onset to treatment was also associated with renal disease progression (odds ratio 19, 95% CI 2–184, P = 0.0098). Women in Quartile 4 had the highest averaged UP/Cr (mean 1.8 g/g) and the most rapid renal disease progression: (mean slope –4.4 mL/min/1.73m2/year).
Conclusions. Adults with Fabry disease are at risk for progressive loss of eGFR despite enzyme replacement therapy, particularly if proteinuria is ≥1 g/g. Men with little urinary protein excretion and those who began receiving agalsidase beta sooner after the onset of symptoms had stable renal function. These findings suggest that early intervention may lead to optimal renal outcomes.
Background: Remote ischemic conditioning is gaining interest as potential method to induce resistance against ischemia reperfusion injury in a variety of clinical settings. We performed a systematic review and meta-analysis to investigate whether remote ischemic conditioning reduces mortality, major adverse cardiovascular events, length of stay in hospital and in the intensive care unit and biomarker release in patients who suffer from or are at risk for ischemia reperfusion injury.
Methods and Results: Medline, EMBASE and Cochrane databases were searched for randomized clinical trials comparing remote ischemic conditioning, regardless of timing, with no conditioning. Two investigators independently selected suitable trials, assessed trial quality and extracted data. 23 studies in patients undergoing cardiac surgery (15 studies), percutaneous coronary intervention (four studies) and vascular surgery (four studies), comprising in total 1878 patients, were included in this review. Compared to no conditioning, remote ischemic conditioning did not reduce mortality (odds ratio 1.22 [95% confidence interval 0.48, 3.07]) or major adverse cardiovascular events (0.65 [0.38, 1.14]). However, the incidence of myocardial infarction was reduced with remote ischemic conditioning (0.50 [0.31, 0.82]), as was peak troponin release (standardized mean difference -0.28 [-0.47, -0.09]).
Conclusion: There is no evidence that remote ischemic conditioning reduces mortality associated with ischemic events; nor does it reduce major adverse cardiovascular events. However, remote ischemic conditioning did reduce the incidence of peri-procedural myocardial infarctions, as well as the release of troponin.
Das Ziel dieser Promotion ist der Aufbau eines dreMR Setups für einen klinischen 1,5T Scanner, das die Relaxations-Dispersions-Bildgebung ermöglicht, und die anschließende Ergründung von möglichst vielen Anwendungsfeldern von dreMR. Zu der Aufgabe gehört die Bereitstellung der zugrunde liegenden Theorie, der Bau des experimentellen Setups (Offset-Spule und Stromversorgung) sowie die Programmierung der nötigen Software. Mit dem gebauten Setup konnten zwei große Anwendungsfelder — dreMR Messungen mit und ohne Kontrastmitteln — untersucht werden.
Introduction: Sleep disturbances are common in adolescents and adversely affect performance, social contact, and susceptibility to stress. We investigated the hypothesis of a relationship between sleep and health-related quality of life (HRQoL), and applied self- and proxy ratings. Materials and Methods: The sample comprised 92 adolescents aged 11–17 years. All participants and their parents completed a HRQoL measure and the Sleep Disturbance Scale for Children (SDSC ). Children with SDSC T -scores above the normal range (above 60) were classified as poor sleepers. Results: According to self- and proxy ratings, good sleepers reported significantly higher HRQoL than poor sleep- ers. Sleep disturbances were significantly higher and HRQoL significantly lower in self- as compared to parental ratings. Parent-child agreement was higher for subscales measuring observable aspects. Girls experienced significantly stronger sleep disturbances and lower self-rated HRQoL than boys. Discussion: Our findings support the positive relationship of sleep and HRQoL. Furthermore, parents significantly underestimate sleep disturbances and overestimate HRQoL in their children.
The relationship between asparagine metabolism and protein concentration was investigated in soybean seed. Phenotyping of a population of recombinant inbred lines adapted to Illinois confirmed a positive correlation between free asparagine levels in developing seeds and protein concentration at maturity. Analysis of a second population of recombinant inbred lines adapted to Ontario associated the elevated free asparagine trait with two of four quantitative trait loci determining population variation for protein concentration, including a major one on chromosome 20 (linkage group I) which has been reported in multiple populations. In the seed coat, levels of asparagine synthetase were high at 50 mg and progressively declined until 150 mg seed weight, suggesting that nitrogenous assimilates are pre-conditioned at early developmental stages to enable a high concentration of asparagine in the embryo. The levels of asparaginase B1 showed an opposite pattern, being low at 50 mg and progressively increased until 150 mg, coinciding with an active phase of storage reserve accumulation. In a pair of genetically related cultivars, ∼2-fold higher levels of asparaginase B1 protein and activity in seed coat, were associated with high protein concentration, reflecting enhanced flux of nitrogen. Transcript expression analyses attributed this difference to a specific asparaginase gene, ASPGB1a. These results contribute to our understanding of the processes determining protein concentration in soybean seed.
Dementia, or any form of degenerative cognitive decline, is one of the major problems in present, and even more will be in future medicine. With Alzheimer's disease (AD) being the most prevalent, Vascular Dementia is the second most entity of dementing processes in the elderly. As diagnostic criteria are still imprecise and in many cases do not embrace early stages of the disease, recent studies have proposed more detailed classifications of the newly created condition Vascular Cognitive Impairment (VCI). Of all conditions subsumed under this term, subcortical small-vessel alterations are the most common cause for cognitive decline. The diagnosis of dementia / cognitive impairment is presently often made in late stages of the disease, when therapeutical options are poor. Thus, early detection of changes of the subcortical small vessels is desirable, when there is still time to identify and aggressively treat risk factors and underlying conditions like diabetes, hyper- or hypotension, and hyperlipidemia. This study aimed to evaluate whether cTT correlates to cognitive dysfunction, i.e. if cTT is fit as an early diagnostic tool for VCI. The study cohort included 38 patients from the Neurological Clinic of the Würzburg University hospital admitted due to diagnoses other than dementia or stroke. As a result of this study it turned out that cTT is certainly capable of fulfilling the task to easily and effectively detect and evaluate possible microvascular lesions of the brain with respect to the actual clinical relevance for the patient. When compared to the other proposed diagnostic tools, neuropsychological testing and MRI, the advantages of cTT are obvious: its measurement is a low-cost and quick procedure which would spare both patients and examiners a long neuropsychological exam or complement it. cTT is safe to assess as the only possible risks derive from the use of the contrast agent, which are rare and easily manageable. It has also proven to be more accurate in showing the extent of cognitive impairment than MRI. Finally, it is widely available. The only prerequisite is an ultrasound machine capable of transcranial color-coded duplex sonography. No cost-intensive procedures like MRI are needed. So, with neuropsychological testing remaining the gold standard, cTT here proved to be a reliable alternative which is more time- and cost-effective than MRI.
The mechanisms that enable cells to regulate their gene expression and thus their metabolism, proliferation or cellular behaviour are not only important to understand the basic biology of a living cell, but are also of crucial interest in cancerogenesis. Highly interwoven and tightly regulated pathways are the basis of a robust but also flexible regulatory network. Interference with these pathways can be either causative for tumorigenesis or can modify its outcome. The receptor tyrosine kinase (RTK) and RAS dependent pathways leading to AKT or ERK1/2 activation are of particular interest in melanoma. These signaling modules are commonly activated by different mutations that can be found in various pathway components like NRAS, BRAF or PTEN. The first part of this work deals with the diverse and versatile functions of the ERK1/2 pathway feedbackregulator MKP2 in different cellular, melanoma relevant settings. In addition, a functional role of the AP1-complex member FOSL1, an ERK1/2 transcriptional target being implicated in the regulation of proliferation, is demonstrated. Secondly, aspects of direct pharmacological inhibition of the ERK1/2 pathway with regard to the induction of apoptosis have been analysed. Due to the high frequency of melanoma related mutations occurring in the RAS/RAF/MEK/ERK pathway (e.g. NRASQ61K, BRAFV600E), inhibition of this signaling cascade is deemed to be a promising therapeutic strategy for the treatment of malignant melanoma. However, although in clinical trials mono-therapeutic treatment with MEK- or RAF inhibitors was successful in the short run, it failed to show satisfactory long-lasting effects. Hence, combination therapies using a MAPK pathway inhibitor and an additional therapy are currently under investigation. I was able to demonstrate that inhibition of MEK using the highly specific inhibitor PD184352 can have a protective effect on melanoma cells with regard to their susceptibility towards the apoptosis inducing agent cisplatin. Single application of cisplatin led to strong DNA damage and the induction of caspase-dependent apoptosis. Additional administration of the MEK inhibitor, however, strongly reduced the apoptosis inducing effect of cisplatin in several melanoma cell lines, These cells displayed an increased activation of the serine/threonine kinase AKT after MEK inhibition. This AKT activation concomitantly led to the phosphorylation of FOXO transcription factors, attenuating the cisplatin induced expression of the BH3-only protein PUMA. PUMA in turn was important to mediate the apoptosis machinery after cisplatin treatment. My results also indicate a participation of RTKs, in particular EGFR, in mediating MEK inhibitor induced activation of AKT. These results demonstrate that inhibition of the RAS/RAF/MEK/ERK signaling pathway in melanoma cell lines does not necessilary have favourable effects in a cytotoxic co-treatment situation. Instead, it can even enhance melanoma survival under pro-apoptotic conditions.
Prostanoide wirken über Prostanoid-Rezeptoren auf die Aktivierung oder Hemmung der Thrombozyten. In dieser Arbeit wurde die Existenz und Funktionsweise der Prostanoid-Rezeptoren anhand synthetischer Agonisten und Antagonisten in humanen Thrombozyten nachgewiesen. Weiter wurde untersucht, über welche Prostanoid-Rezeptoren die Signaltransduktion der natürlichen Agonisten wie PGE2, PGE1 und PGA1 vermittelt wird, sowie das Zusammenspiel der Prostanoid-Rezeptoren auf die Aktivierung oder Hemmung der Thrombozyten gezeigt. Das Vorhandensein der Prostaglandin E2 Synthase 3 wurde nachgewiesen sowie erste Anhaltspunkte für die Existenz eines Komplexes aus Prostaglandin E2 Synthase 3, Hitzeschockprotein-90 sowie Casein Kinase 2 gezeigt.
Toleranz gegenüber Selbstantigenen in den peripheren Geweben kann durch CD4+ CD25+ Foxp3+ regulatorische T-Zellen (Tregs) vermittelt werden. Diese Zellen entstehen entweder in Folge der thymischen T-Zellselektion (natürlich vorkommende Tregs, nTreg) oder durch Konversion aus naiven T-Zellen in den peripheren lymphatischen Organen (induzierte Tregs, iTregs). Im Vorfeld der Arbeit war bereits bekannt, dass Dendritische Zellen (DZ) eine wichtige Rolle bei der Generierung von iTreg spielen. Allerdings bestand weitestgehend Unklarheit darüber, welche DZ in welchem Reifungszustand dazu in der Lage sind, iTregs gegen peripher-exprimierte Selbstantigene zu induzieren. Steady-state migratorische DZ (ssmDZ) gelten in dieser Hinsicht als potentielle Kandidaten, da bekannt ist, dass diese DZ bereits unter homöostatischen Bedingungen Selbstantigene aus peripheren Geweben in die drainierenden Lymphknoten transportieren und dort T-Zellen präsentieren können. Ein Ziel der vorliegenden Arbeit war daher, den Phänotyp und die tolerogene Kapazität der ssmDZ in den hautdrainierenden Lymphknoten näher zu untersuchen. Es konnte gezeigt werden, dass ssmDZ einen semireifen MHC IIint CD40hi CD80/CD86int CCR7+ Phänotyp aufweisen und in vitro mit Hilfe von endogenem TGF-β iTregs induzieren können. Darüber hinaus belegt diese Arbeit zusammen mit weiteren Daten aus unserer Arbeitsgruppe, dass ssmDZ in transgenen K5mOVA-Mäusen zellassoziertes epidermales OVA aus der Haut in die drainierenden Lymphknoten transportieren und dort an CD4+ OVA-spezifische TZR-transgene OT-II T-Zellen präsentieren können. Innerhalb der ssmDZ konnten die Langerin+ dermalen DZ als die DZ-Subpopulation eingegrenzt werden, die für die Konversion von naiven OT-II T-Zellen in CD4+ CD25+ Foxp3+ iTregs verantwortlich war. Ferner zeigte sich, dass CD103 nicht als Marker für ssmDZ in den hautdrainierenden Lymphknoten herangezogen werden kann. Ein weiteres Ziel dieser Arbeit war, herauszufinden, welchen Einfluss der Transkriptionsfaktor RelB auf die partielle Reifung und Migration der ssmDZ hat. RelB ist ein Mitglied der NF-κB-Familie und wird mit der Reifung von DZ in Verbindung gebracht. Erste Experimente zeigten eine nukleäre Translokation von RelB in ssmDZ sowie eine verringerte Frequenz dieser DZ in den hautdrainierenden Lymphknoten von relB+/- Mäusen und Mäusen mit einer Defizienz für den RelB-Bindungspartner p52. Allerdings konnte bei Mäusen mit einer DZ-spezifischen RelB-Inaktivierung (RelBDCko Mäuse) eine erhöhte Frequenz an ssmDZ in den hautdrainierenden Lymphknoten festgestellt, die nicht auf einer Zunahme an DZ in der Haut der Tiere zurückzuführen war. Diese Ergebnisse legen einerseits die Vermutung nahe, dass es sich bei den beobachteten Effekte in den relB+/- Mäusen um DZ-extrinsische Auswirkungen auf die ssmDZ handelt. Andererseits scheint RelB unter homöostatischen Bedingungen die Erhaltung und Migration der ssmDZ eher negativ zu beeinflussen. Weitere durchflusszytometrische Analysen wiesen zudem darauf hin, dass RelB in ssmDZ die Expression von Reifungsmarkern nur partiell reguliert. So konnte auf den ssmDZ in den hautdrainierenden Lymphknoten von RelBDCko Mäusen eine erhöhte Expression von CD40 beobachtet werden, während andere Reifungsmarker wie MHC II, CD80 und CD86 nicht signifikant in ihrer Expression betroffen waren. Im Rahmen dieser Arbeit wurde zudem untersucht, wie sich eine RelB-Defizienz in DZ auf die Homöostase und Induktion von Tregs auswirkt. Die hierzu analysierten RelBDCko Mäuse wiesen eine erhöhte Frequenz und absolute Zellzahl an Tregs in allen untersuchten lymphatischen Organen (hautdrainierende Lymphknoten, Milz und Thymus) auf. Darüber hinaus war in diesen Organen auch eine verstärkte Proliferation der Tregs gegenüber den Kontrolltieren festzustellen. Weitere Untersuchungen zeigten, dass die Proliferation der Tregs in RelBDCko Mäusen in den hautdrainierenden Lymphknoten sogar stärker ausfiel als in der Milz. RelB scheint somit die tolerogene Kapazität der DZ zur Regulation der Treg-Expansion im Thymus und in der Peripherie zu beeinflussen. Unter Verwendung von neutralisierenden αIL-2-Antikörpern konnte zudem belegt werden, dass die periphere Proliferation der Tregs in den RelBDCko Mäusen von IL-2 abhängig ist. Damit einhergehend zeigten erste Vorversuche eine erhöhte IL-2-Produktion in den peripheren lymphatischen Organen von RelBDCko Mäusen. Zusammenfassend legen die Daten dieser Arbeit den Schluss nahe, dass ssmDZ in den hautdrainierenden Lymphknoten in der Lage sind, Toleranz durch Induktion von iTregs gegen epidermale Selbstantigene zu induzieren. Untersuchungen an neuartigen Mäusen mit einer konditionalen RelB-Inaktivierung spezifisch in DZ deuten darauf hin, dass die Migration und Reifung von ssmDZ partiell durch RelB reguliert wird. Da Tregs eine Schlüsselrolle bei der Erhaltung der peripheren Toleranz einnehmen, ist die Beobachtung, dass eine RelB-Defizienz in allen DZ zu einer verstärkten Treg-Proliferation und somit zu einer veränderten Treg-Homöostase führt, ein intererssanter Ausgangspunkt für weitere Untersuchungen.
Previous studies consistently reported abnormal recognition of facial expressions in depression. However, it is still not clear whether this abnormality is due to an enhanced or impaired ability to recognize facial expressions, and what underlying cognitive systems are involved. The present study aimed to examine how individuals with elevated levels of depressive symptoms differ from controls on facial expression recognition and to assess attention and information processing using eye tracking. Forty participants (18 with elevated depressive symptoms) were instructed to label facial expressions depicting one of seven emotions. Results showed that the high-depression group, in comparison with the low-depression group, recognized facial expressions faster and with comparable accuracy. Furthermore, the high-depression group demonstrated greater leftwards attention bias which has been argued to be an indicator of hyperactivation of right hemisphere during facial expression recognition.
Applications in various research areas such as signal processing, quantum computing, and computer vision, can be described as constrained optimization tasks on certain subsets of tensor products of vector spaces. In this work, we make use of techniques from Riemannian geometry and analyze optimization tasks on subsets of so-called simple tensors which can be equipped with a differentiable structure. In particular, we introduce a generalized Rayleigh-quotient function on the tensor product of Grassmannians and on the tensor product of Lagrange- Grassmannians. Its optimization enables a unified approach to well-known tasks from different areas of numerical linear algebra, such as: best low-rank approximations of tensors (data compression), computing geometric measures of entanglement (quantum computing) and subspace clustering (image processing). We perform a thorough analysis on the critical points of the generalized Rayleigh-quotient and develop intrinsic numerical methods for its optimization. Explicitly, using the techniques from Riemannian optimization, we present two type of algorithms: a Newton-like and a conjugated gradient algorithm. Their performance is analysed and compared with established methods from the literature.
Background: Regular exercise is beneficial for cardiovascular health but a recent meta-analysis indicated a relationship between extensive endurance sport and a higher risk of atrial fibrillation, an independent risk factor for stroke. However, data on the frequency of cardiac arrhythmias or (clinically silent) brain lesions during and after marathon running are missing.
Methods/Design: In the prospective observational "Berlin Beat of Running" study experienced endurance athletes underwent clinical examination (CE), 3 Tesla brain magnetic resonance imaging (MRI), carotid ultrasound imaging (CUI) and serial blood sampling (BS) within 2-3 days prior (CE, MRI, CUI, BS), directly after (CE, BS) and within 2 days after (CE, MRI, BS) the 38\(^{th}\) BMW BERLIN-MARATHON 2011. All participants wore a portable electrocardiogram (ECG)-recorder throughout the 4 to 5 days baseline study period. Participants with pathological MRI findings after the marathon, troponin elevations or detected cardiac arrhythmias will be asked to undergo cardiac MRI to rule out structural abnormalities. A follow-up is scheduled after one year.
Results: Here we report the baseline data of the enrolled 110 athletes aged 36-61 years. Their mean age was 48.8 \(\pm\) 6.0 years, 24.5% were female, 8.2% had hypertension and 2.7% had hyperlipidaemia. Participants have attended a mean of 7.5 \(\pm\) 6.6 marathon races within the last 5 years and a mean of 16 \(\pm\) 36 marathon races in total. Their weekly running distance prior to the 38\(^{th}\) BMW BERLIN-MARATHON was 65 \(\pm\) 17 km. Finally, 108 (98.2%) Berlin Beat-Study participants successfully completed the 38\(^{th}\) BMW BERLIN-MARATHON 2011.
Discussion: Findings from the "Berlin Beats of Running" study will help to balance the benefits and risks of extensive endurance sport. ECG-recording during the marathon might contribute to identify athletes at risk for cardiovascular events. MRI results will give new insights into the link between physical stress and brain damage.
Pseudorapidity gap distributions in proton-proton collisions at √s=7 TeV are studied using a minimum bias data sample with an integrated luminosity of 7.1 μb\(^{−1}\). Cross sections are measured differentially in terms of Δη\(^F\), the larger of the pseudorapidity regions extending to the limits of the ATLAS sensitivity, at η=±4.9, in which no final state particles are produced above a transverse momentum threshold pcutT. The measurements span the region 0<Δη\(^F\)<8 for 200MeV<p\(^{cut}_T\)<800MeV. At small Δη\(^F\) , the data test the reliability of hadronisation models in describing rapidity and transverse momentum fluctuations in final state particle production. The measurements at larger gap sizes are dominated by contributions from the single diffractive dissociation process (pp→Xp), enhanced by double dissociation (pp→XY) where the invariant mass of the lighter of the two dissociation systems satisfies M\(_Y\) ≲7 GeV. The resulting cross section is dσ/dΔη\(^F\) ≈1 mb for Δη\(^F\) ≳3. The large rapidity gap data are used to constrain the value of the Pomeron intercept appropriate to triple Regge models of soft diffraction. The cross section integrated over all gap sizes is compared with other LHC inelastic cross section measurements.
Understanding the emergence of species' ranges is one of the most fundamental challenges in ecology. Early on, geographical barriers were identified as obvious natural constraints to the spread of species. However, many range borders occur along gradually changing landscapes, where no sharp barriers are obvious. Mechanistic explanations for this seeming contradiction incorporate environmental gradients that either affect the spatio-temporal variability of conditions or the increasing fragmentation of habitat. Additionally, biological mechanisms like Allee effects (i.e. decreased growth rates at low population sizes or densities), condition-dependent dispersal, and biological interactions with other species have been shown to severely affect the location of range margins. The role of dispersal has been in the focus of many studies dealing with range border formation. Dispersal is known to be highly plastic and evolvable, even over short ecological time-scales. However, only few studies concentrated on the impact of evolving dispersal on range dynamics. This thesis aims at filling this gap. I study the influence of evolving dispersal rates on the persistence of spatially structured populations in environmental gradients and its consequences for the establishment of range borders. More specially I investigate scenarios of range formation in equilibrium, periods of range expansion, and range shifts under global climate change ...
We identified eukaryotic translation elongation factor 1A (eEF1A) Raf-mediated phosphorylation sites and defined their role in the regulation of eEF1A half-life and of apoptosis of human cancer cells. Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B- and C-Raf. Interestingly, S21 belongs to the first eEF1A GTP/GDP-binding consensus sequence. Phosphorylation of S21 was strongly enhanced when both eEF1A isoforms were preincubated prior the assay with C-Raf, suggesting that the eEF1A isoforms can heterodimerize thus increasing the accessibility of S21 to the phosphate. Overexpression of eEF1A1 in COS 7 cells confirmed the phosphorylation of T88 also in vivo. Compared with wt, in COS 7 cells overexpressed phosphodeficient (A) and phospho-mimicking (D) mutants of eEF1A1 (S21A/D and T88A/D) and of eEF1A2 (S21A/D), resulted less stable and more rapidly proteasome degraded. Transfection of S21 A/D eEF1A mutants in H1355 cells increased apoptosis in comparison with the wt isoforms. It indicates that the blockage of S21 interferes with or even supports C-Raf induced apoptosis rather than cell survival. Raf-mediated regulation of this site could be a crucial mechanism involved in the functional switching of eEF1A between its role in protein biosynthesis and its participation in other cellular processes.
We identified eukaryotic translation elongation factor 1A (eEF1A) Raf-mediated phosphorylation sites and defined their role in the regulation of eEF1A half-life and of apoptosis of human cancer cells. Mass spectrometry identified in vitro S21 and T88 as phosphorylation sites mediated by B-Raf but not C-Raf on eEF1A1 whereas S21 was phosphorylated on eEF1A2 by both B-and C-Raf. Interestingly, S21 belongs to the first eEF1A GTP/GDP-binding consensus sequence. Phosphorylation of S21 was strongly enhanced when both eEF1A isoforms were preincubated prior the assay with C-Raf, suggesting that the eEF1A isoforms can heterodimerize thus increasing the accessibility of S21 to the phosphate. Overexpression of eEF1A1 in COS 7 cells confirmed the phosphorylation of T88 also in vivo. Compared with wt, in COS 7 cells overexpressed phosphodeficient (A) and phospho-mimicking (D) mutants of eEF1A1 (S21A/D and T88A/D) and of eEF1A2 (S21A/D), resulted less stable and more rapidly proteasome degraded. Transfection of S21 A/D eEF1A mutants in H1355 cells increased apoptosis in comparison with the wt isoforms. It indicates that the blockage of S21 interferes with or even supports C-Raf induced apoptosis rather than cell survival. Raf-mediated regulation of this site could be a crucial mechanism involved in the functional switching of eEF1A between its role in protein biosynthesis and its participation in other cellular processes.
Background: To analyze long-term results of radiotherapy alone for stage I-III low grade follicular lymphoma and to compare outcome after extended field irradiation (EFI) and total nodal irradiation (TNI). Methods and materials: Between 1982 and 2007, 107 patients were treated with radiotherapy alone for low grade follicular lymphoma at Ann Arbor stage I (n = 50), II (n = 36) and III (n = 21); 48 and 59 patients were treated with EFI and TNI, respectively. The median total dose in the first treatment series of the diaphragmatic side with larger lymphoma burden was 38 Gy (25 Gy – 50 Gy) and after an interval of median 30 days, a total dose of 28 Gy (12.6 Gy – 45 Gy) was given in the second treatment series completing TNI. Results: After a median follow-up of 14 years for living patients, 10-years and 15-years overall survival (OS) were 64% and 50%, respectively. Survival was not significantly different between stages I, II and III. TNI and EFI resulted in 15-years OS of 65% and 34% but patients treated with TNI were younger, had better performance status and higher stage of disease compared to patients treated with EFI. In multivariate analysis, only age at diagnosis (p<0.001, relative risk [RR] 1.06) and Karnofsky performance status (p = 0.04, RR = 0.96) were significantly correlated with OS. Freedom from progression (FFP) was 58% and 56% after 10-years and 15-years, respectively. Recurrences outside the irradiated volume were significantly reduced after TNI compared to EFI; however, increased rates of in-field recurrences and extra-nodal out-of-field recurrence counterbalanced this effect resulting in no significant difference in FFP between TNI and EFI. In univariate analysis, FFP was significantly improved in stage I compared to stage II but no differences were observed between stages I/II and stage III. In multivariate analysis no patient or treatment parameter was correlated with FFP. Acute toxicity was significantly increased after TNI compared to EFI with a trend to increased late toxicity as well. Conclusions: Radiotherapy alone for stage I and II follicular lymphoma resulted in long-term OS with high rates of disease control; no benefit of TNI over EFI was observed. For stage III follicular lymphoma, TNI achieved promising OS and FFP and should be considered as a potentially curative treatment option.
In this thesis, the influence of an environment on molecules and, in particular, on the quantum control of such systems is investigated. Different approaches to describe system-bath dynamics are implemented and applied. The inclusion of a dissipation term in the system Hamiltonian leads to energy loss and relaxation to the ground state. As a first application, the isomerisation reaction in an aromatic complex is treated. It is shown that this simple model is able to reproduce results of time-resolved spectroscopic measurements. Next, the influence of noise is investigated. The incorporation of fluctuations reveals that energy is not conserved and coherences are destroyed. As an example, the quantum control of a population transfer in Na2 is examined. The efficiency of control processes is studied in dependence on the strength of the noise and different system-bath couplings. Starting with the unperturbed system, Local Control Theory is applied to construct a field which selectively transfers population into a single excited electronic state. The coupling to the bath is then switched on to monitor the dependence of the coupling strength on the transfer efficiency. The perturbation of the bath effects the Na2 molecule in such a way that potential energy curves and transition dipole moments are distorted. An important result is that already elastic collisions lead to a substantial loss of control efficiency. The most promising approach used in this thesis is the stochastic Schrödinger equation. It is equivalent to the commonly employed descriptions of system-bath dynamics within the reduced density matrix formalism. It includes decoherences and dissipation caused by elastic and inelastic collisions. Our contribution is the incorporation of laser excitation into the kinetic Monte-Carlo scheme. Thus we are able to apply this stochastic approach to the quantum control of population transfer in the sodium dimer. Because within our description it is possible to separate pure dephasing, inelastic transitions, and coherent time-evolution, we can identify the relative influence of these processes on the control efficiency. This leads to a far more physical picture of the basic processes underlying the perturbations of an environment then what a reduced density matrix description can provide. In utilising the stochastic wave function approach instead of the density matrix formalism, the computations are quite efficient. The stochastic Schrödinger equation is realised by N independent runs, where, in our case, an ensemble size of N = 1000 gives converged results. The efficiency of the laser control process is studied as a function of temperature and collision rates. A rise in temperature (or collision rate) reeffects a stronger fluctuation and thus results in a less efficient transfer by the control field. Though the Gaussian fluctuations used here do not strictly represent 'white'- noise, since a deterministic machine is not able to produce uncorrelated random numbers, an acceptable distribution is achieved by simple procedures. An improvement of the here applied algorithms would, for instance, include a more sophisticated sampling of the dephasing rates. Only one example of a control process is studied here and an application of the developed approach to other problems of quantum control is to be performed. This thesis established a systematic approach to understand quantum control in the presence of an environment.
In the context of this dissertation very long ranged exciton diffusion lengths (LD) were simulated for perylene-based materials under ideal conditions. This leads to the conclusion that the short LD values in existing materials result from an extrinsic and intrinsic immobilization. The latter, which is a specific material property, is based on a relaxation of the exciton into self-trapping states. An in-depth understanding of the atomistic processes defining self-trapping is essential to developing materials with long LD in the future, in which intrinsic immobilization is prevented. For the development of such a mechanistic understanding it is crucial that a clear relationship between molecular structure and LD is available. This is given by single crystals of diindeno perylene (DIP) and α-perylene tetracarboxylic anhydride (α-PTCDA). An extraordinary large LD of 90 nm was measured for the first one, while the latter possesses only 22 nm. Part of this thesis was to deliver reasons for this discrepancy. Only self-trapping comes into question to explain the different LD values. One reason for the different self-trapping in DIP and α-PTCDA could lie in the electronic structure. However, it was possible to demonstrate that a wide range of perylene-based materials possess no significant differences in their electronic structures. Consequently, such differences can be neglected for the explanation of immobilization mechanisms for the exciton. A further possible explanation could be polarization effects in the crystal, which influences the electronic structure of perylene based materials differently. Especially their influence on charge transfer (CT) states, which are located above the optically bright Frenkel state, was in question because such states could be stabilized by a polarizable surrounding. A significant influence of polarization effects on all considered states were excluded by using a polarizable continuum model. Hence, the small LD values in α-PTCDA are an evidence for self-trapping, which produces a crystal structure built up by π-stacks, while the one of DIP is of herringbone type. Since polarization effects can be neglected, is the dimer only via steric restrictions influenced by the crystal. Hence, a method describing self-trapping has to consider such effects, so that a mechanical embedding QM/MM approach is sufficient. Now, potential energy surfaces were calculated, on which wave packet dynamics were subsequently performed. In this way, atomistic mechanisms for the immobilization of excitons were described for the first time in organic materials. Self-trapping was studied in crystals of α-PTCDA by potential energy surfaces, which map an intermolecular shift motion of the dimer in the crystal. An immobilization of excitons occurs within 500 fs, which results from an irreversible energy loss together with a local deformation of the crystal lattice. This prevents a further transport of the exciton. In the case of DIP, this immobilization does not proceed due to high barriers. These barriers result from the herringbone type packing motif in the DIP crystal. This discrepancy in the dynamics explains the different LD values in DIP and α-PTCDA. In a further example, an exciton immobilization was found in helical π-aggregates of perylene tetracarboxylic bisimide (PBI) molecules. Self-trapping is caused by a relaxation mechanism, in which the exciton is transferred by asymmetric vibrations of the aggregate from the bright to a dark Frenkel state within 200 fs, whereby the transition is mediated by a CT state. However, the CT state is almost non-populated during the whole mechanism so that its participation could not yet be proven experimentally. This entire procedure is solely possible in helical aggregates, because only for such structures is there a CT state located next to the bright Frenkel state. At the final Frenkel state a torsional motion around the π-stacking axis is possible so that the loss in energy and the local rearrangement of the aggregate structure occurs, which means a self-trapping of the exciton. This mechanism is in perfect agreement with all available experimental data. These insights allow the conclusion that in future materials for organic solar cells an irreversible and ultrafast deformation of aggregates after photo-absorption must be avoided. Only in this way long LD values can be achieved and exciton self-trapping can be prevented. However, small LD values are always predicted in helical aggregates of perylene-based materials, because exciton immobilization occurs already due to small molecular motions. For this reason such aggregates are inappropriate for the use in organic solar cells. Long LD values are expected for aggregate structures with long intermolecular shifts or molecules with bulky substituents.
The inheritance of the histone H3 variant CENP-A in nucleosomes at centromeres following DNA replication is mediated by an epigenetic mechanism. To understand the process of epigenetic inheritance, or propagation of histones and histone variants, as nucleosomes are disassembled and reassembled in living eukaryotic cells, we have explored the feasibility of exploiting photo-activated localization microscopy (PALM). PALM of single molecules in living cells has the potential to reveal new concepts in cell biology, providing insights into stochastic variation in cellular states. However, thus far, its use has been limited to studies in bacteria or to processes occurring near the surface of eukaryotic cells. With PALM, one literally observes and 'counts' individual molecules in cells one-by-one and this allows the recording of images with a resolution higher than that determined by the diffraction of light (the so-called super-resolution microscopy). Here, we investigate the use of different fluorophores and develop procedures to count the centromere-specific histone H3 variant CENP-A\(^{Cnp1}\) with single-molecule sensitivity in fission yeast (Schizosaccharomyces pombe). The results obtained are validated by and compared with ChIP-seq analyses. Using this approach, CENP-A\(^{Cnp1}\) levels at fission yeast (S. pombe) centromeres were followed as they change during the cell cycle. Our measurements show that CENP-A(Cnp1) is deposited solely during the G2 phase of the cell cycle.