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Institute
Bei Cryptochromen handelt es sich um Blaulichtrezeptoren der Cryptochrom-Photolyase-Proteinfamilie (CPF). Mitglieder dieser Proteinfamilie sind in allen Domänen des Lebens zu finden und haben eine essentielle Rolle in der Reparatur der DNA sowie der lichtgesteuerten Regulation der Expression. Cryptochrome sind in der Regel keine DNA-reparierenden Proteine. Sie sind regulativ an der Steuerung der inneren Uhr und des Zellzyklus der Organismen beteiligt. In der Kieselalge Phaeodactylum tricornutum konnten bisher sechs phylogenetisch unterschiedliche Mitglieder der CPF identifiziert werden. Bei CryP handelt es sich um das einzige pflanzenähnliche Cryptochrom der photoautotrophen Diatomee. Für das Protein CryP konnte bereits ein blaulichtinduzierter Photozyklus durch die Absorption der Chromophore 5-Methenlytetrahydrofolat (MTHF) und Flavinadenindinukleotid (FAD) gezeigt werden. Außerdem ist eine regulative Wirkung des Proteins auf die Lichtsammelkomplexe (Lhc) der Diatomee bekannt. Für eine weitere Charakterisierung des CryPs wurde in dieser Arbeit zunächst das Absorptionsverhalten unter verschiedenen Wellenlängen beobachtet, um so einen Einblick in eine mögliche Aktivierung und Deaktivierung des Proteins durch Licht unterschiedlicher Wellenlängen zu erlangen. Es zeigte sich hierbei eine mit pflanzlichen Cryptochromen vergleichbare Anreicherung verschiedener Redoxzustände des FADs in Abhängigkeit von der Wellenlänge.
Für eine Aufklärung der Wirkungsweise des CryP-Proteins wurden verschiedene Hypothesen untersucht: Die phylogenetische Nähe und ein ähnliches Absorptionsverhalten des CryPs zu Cryptochromen mit Reparaturfähigkeit für einzelsträngige DNA (Cry-DASH) führte zu einer Untersuchung des Proteins als möglicher Transkriptionsfaktor. Hierfür konnte eine Kernlokalisation des Proteins nachgewiesen werden, was Rückschlüsse auf eine potentielle Regulation der Expression mittels DNA-Bindung zulässt. Außerdem wurde gezeigt, dass CryP DNA-Bindefähigkeit besitzt. Die bisher nachgewiesenen Bindungen waren jedoch unspezifischer Art. Dies konnte auch für die Promotersequenz eines der durch CryP regulierten Gene lhcf1 festgestellt werden. Auf Grund der unspezifischen DNA-Bindung wurde eine zweite Hypothese für CryP untersucht: CryP wirkt regulativ auf die Expression verschiedener Gene durch Protein-Protein-Interaktionen und ist Teil einer Reaktionskaskade zur Signalweiterleitung in P. tricornutum.
Durch die Untersuchung der zweiten Hypothese konnten drei Interaktionspartner für CryP identifiziert und eine Interaktion verifiziert werden. Hierbei handelt es sich um das Protein AAA mit einer bisher unbekannten Funktion und das Protein BolA, welches Teil der zuerst in Escherichia coli identifizierten BolA-like-Proteinfamilie ist. Außerdem konnte eine Interaktion mit dem Cold-Shock-Domänen-Protein CSDP gezeigt werden. Bei den Proteinen BolA und CSDP handelt es sich um potentiell regulierende Faktoren der Transkription und Translation, was Teil einer Reaktionskaskade sein kann. Die aus anderen Organismen bekannten Funktionen des BolA-Proteins überschneiden sich mit den in CryP-Knockdown-Mutanten beobachteten Effekten. Sie zeigen eine erhöhte Sensitivität für Stresssituationen wie abweichende Nährstoffkonzentration, Osmolaritäten und Temperaturen. Diese Beobachtungen stellen einen Zusammenhang der durch einen CryP-Knockdown beobachteten Effekte und der CryP-BolA-Interaktion her. Durch Homologien zu Cold-Shock-Proteinen aus Chlamydomonas reinhardtii gibt die CryP-Interaktion mit dem Protein CSDP Hinweise auf einen potentiellen Mechanismus zur Regulation der Lhc-Proteine, für welche zuvor ein CryP-abhängiger Effekt beschrieben war.
Über die Protein-Protein-Interaktionen hinaus wurde die Phosphorylierung des CryPs als Möglichkeit der Signalweiterleitung untersucht. Es konnte eine reversible Phosphorylierung des heterolog aus E. coli isolierten CryPs gezeigt werden. Diese zeigt Ähnlichkeiten zu bekannten Phosphorylierungen pflanzlicher Cryptochrome und gibt Hinweise auf einen Mechanismus der Signalweiterleitung.
Durch die Untersuchung der CryP-regulierten Transkription mit P. tricornutum CryP-Knockdown-Mutanten durch Next-Generation-Sequencing (NGS) konnte die Hypothese der regulativen Proteinkaskade und der Signalweiterleitung weiter bestätigt werden. Die Auswirkungen des CryPs auf die Transkription erwiesen sich als nicht auf einen Teilbereich des Metabolismus begrenzt, sondern sind in einem großen Teil der funktionellen Gengruppen in P. tricornutum zu sehen. Außerdem konnten drei Klassen CryP-regulierter Gene festgestellt werden. Kategorie 1: die ausschließlich unter Blaulicht regulierten Gene; Kategorie 2: die sowohl unter Blaulicht als auch im Dunkeln regulierten Gene und Kategorie 3: die ausschließlich im Dunkeln regulierten Gene. Ein im Dunkeln und unter Blaulicht jeweils unterschiedlicher regulativer Effekt deutet auf eine Doppelfunktion des CryPs hin. Möglicherweise hat das Cryptochrom unterschiedliche lichtabhängige und lichtunabhängige Funktionen.
Durch die Analyse der CryP-regulierten Genexpression konnte außerdem ein Zusammenhang zwischen CryP und weiteren Photorezeptoren gezeigt werden. Der CryP-Proteingehalt in der Zelle hat einen regulativen Einfluss auf das CPF1-Protein, eine Photolyase mit dualer Funktion aus der gleichen Proteinfamilie. Zusätzlich konnte auch ein Einfluss auf die Lichtsensitivität der Genexpression des Rotlichtrezeptors Phytochrom (DPH) durch CryP gezeigt werden. Vergleichbar mit höheren Pflanzen scheint ein regulatives Netzwerk der Photorezeptoren auch in der Diatomee P. tricornutum vorhanden zu sein.
Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.
Background: The Objective Structured Clinical Examination (OSCE) is increasingly used at medical schools to assess practical competencies. To compare the outcomes of students at different medical schools, we introduced standardized OSCE stations with identical checklists.
Methods: We investigated examiner bias at standardized OSCE stations for knee- and shoulder-joint examinations, which were implemented into the surgical OSCE at five different medical schools. The checklists for the assessment consisted of part A for knowledge and performance of the skill and part B for communication and interaction with the patient. At each medical faculty, one reference examiner also scored independently to the local examiner. The scores from both examiners were compared and analysed for inter-rater reliability and correlation with the level of clinical experience. Possible gender bias was also evaluated.
Results: In part A of the checklist, local examiners graded students higher compared to the reference examiner; in part B of the checklist, there was no trend to the findings. The inter-rater reliability was weak, and the scoring correlated only weakly with the examiner’s level of experience. Female examiners rated generally higher, but male examiners scored significantly higher if the examinee was female.
Conclusions: These findings of examiner effects, even in standardized situations, may influence outcome even when students perform equally well. Examiners need to be made aware of these biases prior to examining.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers potential cure to acute myeloid leukemia (AML) patients. However, infections with commensal bacteria are an important cause for non-relapse mortality (NRM). We have previously described the impact of multidrug-resistant organism (MDRO) colonization on the survival of allo-HSCT patients. In the aforementioned publication, according to consensus, we there did not consider the opportunistic gram-negative bacterium Stenotrophomonas maltophilia (S. maltophilia) to be an MDRO. Since rate of S. maltophilia colonization is increasing, and it is not known whether this poses a risk for allo-HSCT patients, we here analyzed here its effect on the previously described and now extended patient cohort. We report on 291 AML patients undergoing allo-HSCT. Twenty of 291 patients (6.9%) were colonized with S. maltophilia. Colonized patients did not differ from non-colonized patients with respect to their age, remission status before allo-HSCT, donor type and HSCT-comorbidity index. S. maltophilia colonized patients had a worse overall survival (OS) from 6 months up to 60 months (85% vs. 88.1% and 24.7% vs. 59.7%; p = 0.007) due to a higher NRM after allo-HSCT (6 months: 15% vs. 4.8% and 60 months: 40.1% vs. 16.2% p = 0.003). The main cause of mortality in colonized patients was infection (46.2% of all deaths) and in non-colonized patients relapse (58.8% of all deaths). 5/20 colonized patients developed an invasive infection with S. maltophilia. The worse OS after allo-HSCT due to higher infection related mortality might implicate the screening of allo-HSCT patients for S. maltophilia and a closer observation of colonized patients as outpatients.
This Letter presents the first direct investigation of the p-Σ0 interaction, using the femtoscopy technique in high-multiplicity pp collisions at s√ = 13 TeV measured by the ALICE detector. The Σ0 is reconstructed via the decay channel to Λγ, and the subsequent decay of Λ to pπ−. The photon is detected via the conversion in material to e+e− pairs exploiting the unique capability of the ALICE detector to measure electrons at low transverse momenta. The measured p-Σ0 correlation indicates a shallow strong interaction. The comparison of the data to several theoretical predictions obtained employing the Correlation Analysis Tool using the Schrödinger Equation (CATS) and the Lednický-Lyuboshits approach shows a reasonable agreement. The presented femtoscopic data cannot yet discriminate between different models, which is also the case for the available scattering and hypernuclei data. Nevertheless, the p-Σ0 correlation function is found to be sensitive to the strong interaction, and driven by the interplay of the different spin and isospin channels. This pioneering study demonstrates the feasibility of a femtoscopic measurement in the p-Σ0 channel and with the expected larger data samples in LHC Run 3 and Run 4, the p-Σ0 interaction will be constrained with high precision.
This paper presents the first measurements of the charge independent (CI) and charge dependent (CD) two-particle transverse momentum correlators GCI2 and GCD2 in Pb-Pb collisions at sNN−−−√ = 2.76 TeV by the ALICE collaboration. The correlators are measured as a function of pair separation in pseudorapidity (Δη) and azimuth (Δφ) and as a function of collision centrality. The correlator GCI2 exhibits a longitudinal broadening while undergoing a monotonic azimuthal narrowing from peripheral to central collisions. By contrast, GCD2 exhibits a narrowing along both dimensions towards central events. These features are not reproduced by models such as HIJING and AMPT. However, the observed narrowing of the correlators is expected to result from the stronger transverse flow profiles produced in more central collisions and the longitudinal broadening is predicted to be sensitive to momentum currents and the shear viscosity per unit of entropy density η/s of the matter produced in the collisions. The observed broadening is found to be consistent with the hypothesized lower bound of η/s and is in qualitative agreement with values obtained from anisotropic flow measurements.
Experimental results are presented on event-by-event net-proton fluctuation measurements in Pb-Pb collisions at sNN−−−√ = 2.76 TeV, recorded by the ALICE detector at the CERN LHC. These measurements have as their ultimate goal an experimental test of Lattice QCD (LQCD) predictions on second and higher order cumulants of net-baryon distributions to search for critical behavior near the QCD phase boundary. Before confronting them with LQCD predictions, account has to be taken of correlations stemming from baryon number conservation as well as fluctuations of participating nucleons. Both effects influence the experimental measurements and are usually not considered in theoretical calculations. For the first time, it is shown that event-by-event baryon number conservation leads to subtle long-range correlations arising from very early interactions in the collisions.
The pT-differential non-linear flow modes, v4,22, v5,32, v6,33 and v6,222 for π±, K± , K0S , p + p¯¯¯, Λ + Λ¯¯¯¯ and ϕ-meson have been measured for the first time at sNN−−−√ = 5.02 TeV in Pb-Pb collisions with the ALICE detector at the Large Hadron Collider. The results were obtained with a multi-particle technique, correlating the identified hadrons with reference charged particles from a different pseudorapidity region. These non-linear observables probe the contribution from the second and third order initial spatial anisotropy coefficients to higher flow harmonics. All the characteristic features observed in previous pT-differential anisotropic flow measurements for various particle species are also present in the non-linear flow modes, i.e. increase of magnitude with increasing centrality percentile, mass ordering at low pT and particle type grouping in the intermediate pT range. Hydrodynamical calculations (iEBE-VISHNU) that use different initial conditions and values of shear and bulk viscosity to entropy density ratios are confronted with the data at low transverse momenta. These calculations exhibit a better agreement with the anisotropic flow coefficients than the non-linear flow modes. These observations indicate that non-linear flow modes can provide additional discriminatory power in the study of initial conditions as well as new stringent constraints to hydrodynamical calculations.
This Letter presents the first direct investigation of the p-Σ0 interaction, using the femtoscopy technique in high-multiplicity pp collisions at s√ = 13 TeV measured by the ALICE detector. The Σ0 is reconstructed via the decay channel to Λγ, and the subsequent decay of Λ to pπ−. The photon is detected via the conversion in material to e+e− pairs exploiting the unique capability of the ALICE detector to measure electrons at low transverse momenta. The measured p-Σ0 correlation indicates a shallow strong interaction. The comparison of the data to several theoretical predictions obtained employing the Correlation Analysis Tool using the Schrödinger Equation (CATS) and the Lednický-Lyuboshits approach shows a reasonable agreement. The presented femtoscopic data cannot yet discriminate between different models, which is also the case for the available scattering and hypernuclei data. Nevertheless, the p-Σ0 correlation function is found to be sensitive to the strong interaction, and driven by the interplay of the different spin and isospin channels. This pioneering study demonstrates the feasibility of a femtoscopic measurement in the p-Σ0 channel and with the expected larger data samples in LHC Run 3 and Run 4, the p-Σ0 interaction will be constrained with high precision.
Mid-rapidity production of π±, K± and (p¯)p measured by the ALICE experiment at the LHC, in Pb-Pb and inelastic pp collisions at sNN−−−√ = 5.02 TeV, is presented. The invariant yields are measured over a wide transverse momentum (pT) range from hundreds of MeV/c up to 20 GeV/c. The results in Pb-Pb collisions are presented as a function of the collision centrality, in the range 0−90%. The comparison of the pT-integrated particle ratios, i.e. proton-to-pion (p/π) and kaon-to-pion (K/π) ratios, with similar measurements in Pb-Pb collisions at sNN−−−√ = 2.76 TeV show no significant energy dependence. Blast-wave fits of the pT spectra indicate that in the most central collisions radial flow is slightly larger at 5.02 TeV with respect to 2.76 TeV. Particle ratios (p/π, K/π) as a function of pT show pronounced maxima at pT ≈ 3 GeV/c in central Pb-Pb collisions. At high pT, particle ratios at 5.02 TeV are similar to those measured in pp collisions at the same energy and in Pb-Pb collisions at sNN−−−√ = 2.76 TeV. Using the pp reference spectra measured at the same collision energy of 5.02 TeV, the nuclear modification factors for the different particle species are derived. Within uncertainties, the nuclear modification factor is particle species independent for high pT and compatible with measurements at sNN−−−√ = 2.76 TeV. The results are compared to state-of-the-art model calculations, which are found to describe the observed trends satisfactorily.