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We present the first systematic comparison of the charged-particle pseudorapidity densities for three widely different collision systems, pp, pPb, and PbPb, at the top energy of the Large Hadron Collider (√sNN=5.02TeV) measured over a wide pseudorapidity range (−3.5<η<5), the widest possible among the four experiments at that facility. The systematic uncertainties are minimised since the measurements are recorded by the same experimental apparatus (ALICE). The distributions for pPb and PbPb collisions are determined as a function of the centrality of the collisions, while results from pp collisions are reported for inelastic events with at least one charged particle at midrapidity. The charged-particle pseudorapidity densities are, under simple and robust assumptions, transformed to charged-particle rapidity densities. This allows for the calculation and the presentation of the evolution of the width of the rapidity distributions and of a lower bound on the Bjorken energy density, as a function of the number of participants in all three collision systems. We find a decreasing width of the particle production, and roughly a smooth ten fold increase in the energy density, as the system size grows, which is consistent with a gradually higher dense phase of matter.
Correlations between moments of different flow coefficients are measured in Pb–Pb collisions at √sNN=5.02TeV recorded with the ALICE detector. These new measurements are based on multiparticle mixed harmonic cumulants calculated using charged particles in the pseudorapidity region |η| <0.8with the transverse momentum range 0.2 <pT<5.0GeV/c. The centrality dependence of correlations between two flow coefficients as well as the correlations between three flow coefficients, both in terms of their second moments, are shown. In addition, a collection of mixed harmonic cumulants involving higher moments of v2and v3is measured for the first time, where the characteristic signature of negative, positive and negative signs of four-, six-and eight-particle cumulants are observed, respectively. The measurements are compared to the hydrodynamic calculations using iEBE-VISHNU with AMPT and TRENTo initial conditions. It is shown that the measurements carried out using the LHC Run 2 data in 2015 have the precision to explore the details of initial-state fluctuations and probe the nonlinear hydrodynamic response of v2and v3to their corresponding initial anisotropy coefficients ε2and ε3. These new studies on correlations between three flow coefficients as well as correlations between higher moments of two different flow coefficients will pave the way to tighten constraints on initial-state models and help to extract precise information on the dynamic evolution of the hot and dense matter created in heavy-ion collisions at the LHC.
Measurements of (anti)proton, (anti)deuteron, and (anti)3He production in the rapidity range −1<y<0 as a function of the transverse momentum and event multiplicity in p-Pb collisions at a center-of-mass energy per nucleon-nucleon pair sNN−−−√=8.16 TeV are presented. The coalescence parameters B2 and B3, measured as a function of the transverse momentum per nucleon and of the mean charged-particle multiplicity density, confirm a smooth evolution from low to high multiplicity across different collision systems and energies. The ratios between (anti)deuteron and (anti)3He yields and those of (anti)protons are also reported as a function of the mean charged-particle multiplicity density. A comparison with the predictions of the statistical hadronization and coalescence models for different collision systems and center-of-mass energies favors the coalescence description for the deuteron-to-proton yield ratio with respect to the canonical statistical model.
The measurement of the production of deuterons, tritons and 3He and their antiparticles in Pb-Pb collisions at √sNN = 5.02 TeV is presented in this article. The measurements are carried out at midrapidity (y|< 0.5) as a function of collision centrality using the ALICE detector. The pT-integrated yields, the coalescence parameters and the ratios to protons and antiprotons are reported and compared with nucleosynthesis models. The comparison of these results in different collision systems at different center-of-mass collision energies reveals a suppression of nucleus production in small systems. In the Statistical Hadronisation Model framework, this can be explained by a small correlation volume where the baryon number is conserved, as already shown in previous fluctuation analyses. However, a different size of the correlation volume is required to describe the proton yields in the same data sets. The coalescence model can describe this suppression by the fact that the wave functions of the nuclei are large and the fireball size starts to become comparable and even much smaller than the actual nucleus at low multiplicities.
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.
Resistance to CD19-directed immunotherapies in lymphoblastic leukemia has been attributed, among other factors, to several aberrant CD19 pre-mRNA splicing events, including recently reported excision of a cryptic intron embedded within CD19 exon 2. While “exitrons” are known to exist in hundreds of human transcripts, we discovered, using reporter assays and direct long-read RNA sequencing (dRNA-seq), that the CD19 exitron is an artifact of reverse transcription. Extending our analysis to publicly available datasets, we identified dozens of questionable exitrons, dubbed “falsitrons,” that appear only in cDNA-seq, but never in dRNA-seq. Our results highlight the importance of dRNA-seq for transcript isoform validation.
The teaching of professional roles in medical education is an interdisciplinary concern. However, surgeons require specific standards of professionalism for certain context-based situations. In addition to communication, studies require collaboration, leadership, error-/conflict-management, patient-safety and decision-making as essential competencies for surgeons. Standards for corresponding competencies are defined in special chapters of the German National Competency-based Learning Objectives for Undergraduate Medical Education (NKLM; chapter 8, 10). The current study asks whether these chapters are adequately taught in surgical curricula. Eight German faculties contributed to analysing mapping data considering surgical courses of undergraduate programs. All faculties used the MERlin mapping platform and agreed on procedures for data collection and processing. Sub-competency and objective coverage, as well as the achievement of the competency level were mapped. Overall counts of explicit citations were used for analysis. Collaboration within the medical team is a strongly represented topic. In contrast, interprofessional cooperation, particularly in healthcare sector issues is less represented. Patient safety and dealing with errors and complications is most emphasized for the Manager/Leader, while time management, career planning and leadership are not addressed. Overall, the involvement of surgery in teaching the competencies of the Collaborator and Manager/Leader is currently low. However, there are indications of a curricular development towards explicit teaching of these roles in surgery. Moreover, implicitly taught roles are numerous, which indicates a beginning awareness of professional roles.
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
(2021)
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
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.
Seed dispersal is hard to measure, and there is still a lack of knowledge about dispersal-related traits of plant species. Therefore, we developed D3, the Dispersal and Diaspore Database (available at
www.seed-dispersal.info), which aims at simplifying ecological and evolutionary analyses by providing and integrating various items related to seed dispersal: empirical studies, functional traits, image analyses and ranking indices (quantifying the adaptation to dispersal modes).
Currently, the database includes data for more than 5000 taxa and 33 items as well as digital images of diaspores (i.e. the dispersal units), seeds, fruits and infructescences. The included items cover common traits like diaspore mass, size, shape, terminal velocity and seed number per diaspore. Furthermore, we present newly or further developed items like ecomorphological categorizations of the diaspore and fruit as well as information from literature on prevailing dispersal modes. Finally, we introduce several items which are not covered in other databases yet: surface structure and form of the diaspore, the exposure of the diaspores in the infructescence and dispersal rankings. Dispersal rankings allow estimations of how well certain species are adapted to a specific dispersal mode in comparison to a larger species set. They are calculated as the percentile rank of an indicator of species’ dispersal potential in relation to a larger species set.
Especially for the new and further developed items we outline the basic concepts in detail, describe the measurement and categorization methods and show how to interpret and integrate these data for single species as well as for larger species sets. Thereby, we calculate baseline statistics of seed dispersal of the Central European flora. We found that diaspores of 72% of the taxa show specializations related to long-distance dispersal, i.e. most often elongated appendages or nutrient-rich tissues. Diaspore masses, sizes and terminal velocities vary over several orders of magnitude and can be approximated by lognormal distributions.