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Up to 50% of patients initially treated for prostate cancer in a curative intent experience biochemical recurrence, possibly requiring adjuvant treatment. However, salvage treatment decisions, such as lymph node dissection or radiation therapy, are typically based on prostate specific antigen (PSA) recurrence. Importantly, common imaging modalities (e.g., computed tomography [CT], magnetic resonance imaging, and bone scan) are limited and the detection of recurrent disease is particularly challenging if PSA is low. Prostate specific membrane antigen (PSMA) positron-emission tomography/computed tomography (PET/CT) is a novel and promising imaging modality which aims to overcome the incapability of early identification of distant and regional metastases. Within this review, we summarize the current evidence related to PSMA-PET/CT in prostate cancer men diagnosed with biochemical recurrence after local treatment with curative intent. We discuss detection rates of PSMA-PET/CT stratified by PSA-levels and its impact on clinical decision making. Furthermore, we compare different imagefusion techniques such as PSMA-PET vs. F-/C-Choline-PET scans vs. PSMA-single photon emission computed tomography/CT. Finally, we touch upon the contemporary role of radio-guided-PSMA salvage lymphadenectomy.
After removal of a dental implant or extraction of a tooth in the upper jaw, the closure of an oroantral fistula (OAF) or oroantral communication (OAC) can be a difficult problem confronting the dentist and surgeon working in the oral and maxillofacial region. Oroantral communication (OAC) acts as a pathological pathway for bacteria and can cause infection of the antrum, which further obstructs the healing process as it is an unnatural communication between the oral cavity and the maxillary sinus. There are different ways to perform the surgical closure of the OAC. The decision-making in closure of oroantral communication and fistula is influenced by many factors. Consequently, it requires a combination of knowledge, experience, and information gathering. Previous narrative research has focused on assessments and comparisons of various surgical techniques for the closure of OAC/OAF. Thus, the decision-making process has not yet been described comprehensively.
The present study aims to illustrate all the factors that have to be considered in the management of OACs and OAFs that determine optimal treatment.
Die Steuerung biochemischer Prozesse oder die Verbesserung von Materialien erfordert zunächst ein tiefgründiges Verständnis über die zugrundeliegenden Systeme. Zur Untersuchung eignet sich Licht als ideales Werkzeug, da hiermit nützliche Informationen über die chemische Struktur, ihre Eigenschaften sowie den zusammenhängenden, schnellen Reaktionsabläufen erhalten werden können. Um die Aufklärung zu erleichtern können kleine, chemische Verbindungen eingeführt werden, welche beispielsweise ein Fluoreszenzmarker, eine photolabile Schutzgruppe oder eine photoschaltbare Verbindung sein können. Von jeweils einem Vertreter dieser Moleküle wurden unterschiedliche Studien durchgeführt, dessen Ergebnisse in dieser Arbeit in insgesamt drei Projekten zusammengefasst werden.
Zunächst wurde die Funktionalität der Helikase RhlB untersucht, die der Familie der DEAD-Box Proteine zugeordnet wird, und RNA-Duplexe in ihre Einzelstränge entwindet. Als RNA-Modellduplex diente JM2h, an dem ein RNA-Einzelstrang fluoreszenzmarkiert war (M2AP6). Die Einführung dieses Markers ermöglichte die Durchführung von statischen Fluoreszenzmessungen sowie von Mischexperimenten, die mit Hilfe der stopped-flow-Technik durchgeführt wurden. In den einleitenden Studien wurde die Helikase weggelassen, wodurch der Fokus auf den Fluoreszenzeigenschaften der RNA gelegt wurde. Die Ergebnisse hierzu zeigten, dass die Fluoreszenzintensität des Einzelstrangs durch Zugabe des komplementären Strangs deutlich abnimmt, wobei das Minimum bei einem äquimolaren Verhältnis erreicht wird. Die dazugehörigen stopped-flow-Messungen zeigten eine Beschleunigung der Hybridisierungsreaktion, wenn höhere Konzentrationen des Gegenstrangs in der Lösung vorhanden waren. Nach anschließender Zugabe der Helikase zur Lösung wurde ein Anstieg der Fluoreszenzintensität erwartet, der vom separierten Einzelstrang M2AP6 herrühren sollte. Dieser Anstieg wurde jedoch erst nach weiterer Zugabe von ATP beobachtet, der auf eine ATP-Abhängigkeit der Entwindungsreaktion von RhlB hindeutet. Diese Abhängigkeit wurde auch bereits für andere Helikasen der DEAD-Box Familie entdeckt. Die korrekte Funktionalität sowie die ATP-Abhängigkeit wurden in stopped-flow-Messungen verfiziert, bei denen der Fluoreszenzanstieg auch zeitaufgelöst betrachtet werden konnte. Für die spektralen Korrekturen der Fluoreszenzspektren wurde ein selbstgeschriebenes MATLAB-Programm namens FluCY verwendet (engl.: Fluorescence Correction & Quantum yield), welches eine schnelle und fehlerfreie Verarbeitung des Datensatzes ermöglichte.
Die zwei im folgenden beschriebenen Projekte handeln von photoaktivierbaren Molekülen. Zum einen photolabile Verbindungen, welche die Funktion z.B. eines Biomoleküls durch eine chemische Modifikation deaktivieren können. Durch eine lichtinduzierte Reaktion kommt es zur Abspaltung der Modifikation und die Funktion ist wiederhergestellt. In dieser Arbeit wurden verschiedene photolabile Schutzgruppen untersucht, die denselben Chromophor BIST (BIsStyryl-Thiophen) tragen. Durch die Einführung dieses Chromophors absorbierten sämtliche untersuchte Verbindungen sehr effizient sichtbares Licht (epsilon(445)=55.700 M^(-1) cm^(-1)), wodurch der photoinduzierte Bindungsbruch mit Wellenlängen durchgeführt werden, die bei einer biologischen Anwendungen keinen Schaden an der Zelle anrichten würden. Hieraufhin wurden in statischen und zeitaufgelösten Absorptionsmessungen Teilschritte der Freisetzungsreaktion untersucht, indem nach Photoanregung die Absorptionsänderungen auf verschiedenen Zeitskalen analysiert wurden. Die ultraschnelle Dynamik im Piko- bis Nanosekundenbereich (10^(-12)-10^(-9) s) wird durch eine spektral breite, positive Absorptionsänderng dominiert. Diese impliziert, dass die Deaktivierung über den Triplettpfad abläuft, der die vergleichsweise niedrigen Freisetzungsausbeuten erklärt (phi(u) < 5). Aufgrund des hohen Extinktionskoeffizienten reichen dennoch bereits niedrige Strahlungsdosen aus, um eine Freisetzung zu initiieren. Der geschwindigkeitsbestimmende Schritt dieser Reaktion ist dem Zerfall des aci-nitro Intermediats zugeordnet. Für ein sekundäres Amin, welches mit BIST geschützt wurde, ist eine Lebensdauer des Intermediats von 71 µs gefunden worden.
In einigen Fällen ist es erwünscht, eine vorliegende Aktivität nicht nur ein-, sondern auch ausschalten zu können, wofür photochrome Verbindungen (oder Photoschalter) verwendet werden. Die in dieser Arbeit untersuchte Verbindung ceCAM ist ein Alken-Photoschalter und vollführt bei Bestrahlung mit Licht eine cis/trans-Isomerisierung. ceCAM ist das Cyanoester-Derivat (ce) von Cumarin-substituierten Allylidenmalonat, von denen beide Konformere sehr effizient sichtbares Licht absorbieren trans: epsilon(489)=50.300 M^(-1) cm^(-1); cis: epsilon(437)=18.600 M^(-1) cm^(-1)). Andere photophysikalische Eigenschaften umfassen u.a. hohe thermische und photochemische Stabilität. Letztere wurde über ein Experiment nachgewiesen, bei dem die lichtinduzierte Isomerisierung alternierend durchgeführt wurde und selbst bei über 250 Zyklen keine signifikate Abnahme der Absorption beobachtet werden konnte. Des Weiteren konnte die Reaktion mit Quantenausbeuten von 39% (trans) und 42% (cis) induziert werden, wobei im photostationären Gleichgewicht auch hohe Isomerenverhältnisse mit bis zu 80% (trans) und 96% (cis) akkumuliert werden konnten. Die Geschwindigkeit der Reaktion wurde mit Hilfe der Ultakurzzeit-Spektroskopie untersucht. Die Dynamik im Zeitbereich von ps-ns zeigte, dass die trans/cis-Isomerisierung unterhalb von 0,5 ns und die umgekehrte Reaktion noch viel schneller (wenige ps) abgeschlossen ist. Durch die Untersuchungen in dieser Arbeit an den BIST-Verbindungen und ceCAM sind viele vorteilhafte, photophysikalische Eigenschaften charakterisiert worden, wodurch sie als verbesserte Alternative zu den bisher bekannten photolabilen Schutzgruppen oder Photoschaltern anzusehen sind.
5-lipoxygenase (5-LO) is the key enzyme in the biosynthesis of leukotrienes and specialized proresolving lipid mediators (SPM). It is mainly expressed in leukocytes and is part of the innate immune system. 5-LO can shuttle between the cytosol and the nucleus. Upon cell activation the protein translocates from soluble cellular compartments to the nuclear membrane. Besides FLAP which is required for cellular leukotriene and SPM formation, 5-LO interacts with other proteins like coactosin-like protein (CLP), Dicer, β-catenin and p53. In this review, the factors involved in the regulation of 5-LO expression, the role of 5-LO in the regulation of stem cell proliferation and differentiation and its biological functions apart from leukotriene and SPM formation are summarized.
Chirality is omnipresent in living nature. On the single molecule level, the response of a chiral species to a chiral probe depends on their respective handedness. A prominent example is the difference in the interaction of a chiral molecule with left or right circularly polarized light. In the present study, we show by Coulomb explosion imaging that circularly polarized light can also induce a chiral fragmentation of a planar and thus achiral molecule. The observed enantiomer strongly depends on the orientation of the molecule with respect to the light propagation direction and the helicity of the ionizing light. This finding might trigger new approaches to improve laser-driven enantioselective chemical synthesis.
CRFVoter : gene and protein related object recognition using a conglomerate of CRF-based tools
(2019)
Background: Gene and protein related objects are an important class of entities in biomedical research, whose identification and extraction from scientific articles is attracting increasing interest. In this work, we describe an approach to the BioCreative V.5 challenge regarding the recognition and classification of gene and protein related objects. For this purpose, we transform the task as posed by BioCreative V.5 into a sequence labeling problem. We present a series of sequence labeling systems that we used and adapted in our experiments for solving this task. Our experiments show how to optimize the hyperparameters of the classifiers involved. To this end, we utilize various algorithms for hyperparameter optimization. Finally, we present CRFVoter, a two-stage application of Conditional Random Field (CRF) that integrates the optimized sequence labelers from our study into one ensemble classifier.
Results: We analyze the impact of hyperparameter optimization regarding named entity recognition in biomedical research and show that this optimization results in a performance increase of up to 60%. In our evaluation, our ensemble classifier based on multiple sequence labelers, called CRFVoter, outperforms each individual extractor’s performance. For the blinded test set provided by the BioCreative organizers, CRFVoter achieves an F-score of 75%, a recall of 71% and a precision of 80%. For the GPRO type 1 evaluation, CRFVoter achieves an F-Score of 73%, a recall of 70% and achieved the best precision (77%) among all task participants.
Conclusion: CRFVoter is effective when multiple sequence labeling systems are to be used and performs better then the individual systems collected by it.
Congenitally blind individuals have been shown to activate the visual cortex during non-visual tasks. The neuronal mechanisms of such cross-modal activation are not fully understood. Here, we used an auditory working memory training paradigm in congenitally blind and in sighted adults. We hypothesized that the visual cortex gets integrated into auditory working memory networks, after these networks have been challenged by training. The spectral profile of functional networks was investigated which mediate cross-modal reorganization following visual deprivation. A training induced integration of visual cortex into task-related networks in congenitally blind individuals was expected to result in changes in long-range functional connectivity in the theta-, beta- and gamma band (imaginary coherency) between visual cortex and working memory networks. Magnetoencephalographic data were recorded in congenitally blind and sighted individuals during resting state as well as during a voice-based working memory task; the task was performed before and after working memory training with either auditory or tactile stimuli, or a control condition. Auditory working memory training strengthened theta-band (2.5-5 Hz) connectivity in the sighted and beta-band (17.5-22.5 Hz) connectivity in the blind. In sighted participants, theta-band connectivity increased between brain areas typically involved in auditory working memory (inferior frontal, superior temporal, insular cortex). In blind participants, beta-band networks largely emerged during the training, and connectivity increased between brain areas involved in auditory working memory and as predicted, the visual cortex. Our findings highlight long-range connectivity as a key mechanism of functional reorganization following congenital blindness, and provide new insights into the spectral characteristics of functional network connectivity.
We study how the informativeness of stock prices changes with the presence of high-frequency trading (HFT). Our estimate is based on the staggered start of HFT participation in a panel of international exchanges. With HFT presence, market prices are a less reliable predictor of future cash flows and investment, even more so for longer horizons. Further, firm-level idiosyncratic volatility decreases, and the holdings and trades by institutional investors deviate less from the market-capitalization weighted portfolio as a benchmark. Our results document that the informativeness of prices decreases subsequent to the start of HFT. These findings are consistent with theoretical models of HFTs' ability to anticipate informed order flow, resulting in decreased incentives to acquire fundamental information.
Purpose: Prisoners have a higher risk of suicide compared to non-incarcerated individuals. One aim of suicide prevention for prisoners is to identify risk factors in order to put stronger support mechanisms in place for the more vulnerable detainees. This study investigates the suicide risk (SR) in offence-related sub-populations in a representative German sample and differentiates between SR for adolescent and adult prisoners.
Methods: Conducting a national study with data from public German records on the entire prison population from 2000 to 2016 and suicide numbers in German prisons in the same period, SR was calculated for the total male prison population as well as for both subgroups, adolescent and adult male prisoners.
Results: In the study period, male prisoners spent 959.584 life years (LY) in German criminal detention. Among those, 524 prisoners died of suicide. SR was higher for detainees imprisoned for an offence resulting in extensive physical harm for another person, e.g. homicide (suicide rate = 134,8 suicides per 100.000 LY; OR = 2,47; CI95%: 1,98–3,08), bodily injury (suicide rate = 87,3; OR = 1,60; CI95%: 1,29–1,99), and sexual offences (suicide rate = 84,2; OR = 1,54; CI95%: 1,18–2,01) compared with the SR of the total prison population (suicide rate = 54.6). Age differences between offence-related SR were found for theft, with adolescents (suicide rate = 69,3; OR = 1,25; CI95%: 0,85–1,84) showing higher SR than adults (suicide rate = 38,2; OR = 0,7; CI95%: 0,54–0,92).
Conclusion: The index offence of detainees is associated with SR and age-related differences exist. Suicide prevention in prisons should take both into account to determine populations at risk.
We study the well-known resonance ψ(4040), corresponding to a 33S1 charm–anticharm vector state ψ(3S), within a QFT approach, in which the decay channels into DD, D∗D, D∗D∗, DsDs and D∗s Ds are considered. The spectral function shows sizable deviations from a Breit–Wigner shape (an enhancement, mostly generated by DD∗loops, occurs); moreover, besides the c ¯ c pole of ψ(4040), a second dynamically generated broad pole at 4 GeV emerges. Naively, it is tempting to identify this new pole with the unconfirmed state Y (4008). Yet, this state was not seen inthe reaction e+e− → ψ(4040) → DD∗, but in processes with π+π−J/ψ in the final state. A detailed study shows a related but different mechanism: a broad peak at 4GeV in the process e+e− → ψ(4040) → DD∗ → π+π−J/ψ appears when DD∗ loops are considered. Its existence in this reaction is not necessarily connected to the existence of a dynamically generated pole, but the underlying mechanism – the strong coupling of c ¯ c to DD∗ loops – can generate both of them. Thus, the controversial state Y (4008) may not be a genuine resonance, but a peak generated by the ψ(4040) and D∗D loops with π+π−J/ψ in the final state.
We investigate the well-known vector state ψ(4040) in the frame-work of a quantum field theoretical model. In particular, we study its spectral function and search for the pole(s) in the complex plane. Quite interestingly, the spectral function has a non-standard shape and two poles are present. The role of the meson-meson quantum loops (in particular DD* ones) is crucial and could also explain the not yet conformed “state” Y(4008).
As a first step, a simple and pedagogical recall of the η-η′ system is presented, in which the role of the axial anomaly, related to the heterochiral nature of the multiplet of (pseudo)scalar states, is underlined. As a consequence, η is close to the octet and η′ to the singlet configuration. On the contrary, for vector and tensor states, which belong to homochiral multiplets, no anomalous contribution to masses and mixing is present. Then, the isoscalar physical states are to a very good approximation nonstrange and strange, respectively. Finally, for pseudotensor states, which are part of an heterochiral multiplet (just as pseudoscalar ones), a sizable anomalous term is expected: η2(1645) roughly corresponds to the octet and η2(1870) to the singlet.
Charmonia with different transverse momentum pT usually comes from different mechanisms in the relativistic heavy ion collisions. This work tries to review the theoretical studies on quarkonium evolutions in the deconfined medium produced in p-Pb and Pb-Pb collisions. The charmonia with high pT are mainly from the initial hadronic collisions, and therefore sensitive to the initial energy density of the bulk medium. For those charmonia within 0.1 < pT < 5 GeV/c at the energies of Large Hadron Collisions (LHC), They are mainly produced by the recombination of charm and anti-charm quarks in the medium. In the extremely low pT ∼ 1/RA (RA is the nuclear radius), additional contribution from the coherent interactions between electromagnetic fields generated by one nucleus and the target nucleus plays a non-negligible role in the J/ψ production even in semi-central Pb-Pb collisions.
Background: Posttraumatic stress disorder (PTSD) after childhood abuse (CA) is often related to severe co-occurring psychopathology, such as symptoms of borderline personality disorder (BPD). The ICD-11 has included Complex PTSD as a new diagnosis, which is defined by PTSD symptoms plus disturbances in emotion regulation, self-concept, and interpersonal relationships. Unfortunately, the empirical database on psychosocial treatments for survivors of CA is quite limited. Furthermore, the few existing studies often have either excluded subjects with self-harm behaviour and suicidal ideation — which is common behaviour in subjects suffering from Complex PTSD. Thus, researchers are still trying to identify efficacious treatment programmes for this group of patients.
We have designed DBT-PTSD to meet the specific needs of patients with Complex PTSD. The treatment programme is based on the rules and principles of dialectical behavioural therapy (DBT), and adds interventions derived from cognitive behavioural therapy, acceptance and commitment therapy and compassion-focused therapy. DBT-PTSD can be provided as a comprehensive residential programme or as an outpatient programme. The effects of the residential programme were evaluated in a randomised controlled trial. Data revealed significant reduction of posttraumatic symptoms, with large between-group effect sizes when compared to a treatment-as-usual wait list condition (Cohen’s d = 1.5).
The first aim of this project on hand is to evaluate the efficacy of the outpatient DBT-PTSD programme. The second aim is to identify the major therapeutic variables mediating treatment efficacy. The third aim is to study neural mechanisms and treatment sensitivity of two frequent sequelae of PTSD after CA: intrusions and dissociation.
Methods: To address these questions, we include female patients who experienced CA and who fulfil DSM-5 criteria for PTSD plus borderline features, including criteria for severe emotion dysregulation. The study is funded by the German Federal Ministry of Education and Research, and started in 2014. Participants are randomised to outpatient psychotherapy with either DBT-PTSD or Cognitive Processing Therapy. Formal power analysis revealed a minimum of 180 patients to be recruited. The primary outcome is the change on the Clinician-Administered PTSD Scale for DSM-5.
Discussion: The expected results will be a major step forward in establishing empirically supported psychological treatments for survivors of CA suffering from Complex PTSD.
Trial registration: German Clinical Trials Register: registration number DRKS00005578, date of registration 19 December 2013.
Synthesis and SAR of the antistaphylococcal natural product nematophin from Xenorhabdus nematophila
(2019)
The repeated and improper use of antibiotics had led to an increased number of multiresistant bacteria. Therefore, new lead structures are needed. Here, the synthesis and an expanded structure–activity relationship of the simple and antistaphylococcal amide nematophin from Xenorhabdus nematophila and synthetic derivatives are described. Moreover, the synthesis of intrinsic fluorescent derivatives, incorporating azaindole moieties was achieved for the first time.
Background: While the incidence and aspects of pneumonia in ICU patients has been extensively discussed in the literature, studies on the occurrence of pneumonia in severely injured patients are rare. The aim of the present study is to elucidate factors associated with the occurrence of pneumonia in severely injured patients with thoracic trauma.
Setting: Level-I University Trauma Centres associated with the TraumaRegister DGU®.
Methods: A total of 1162 severely injured adult patients with thoracic trauma documented in the TraumaRegister DGU® (TR-DGU) were included in this study. Demographic data, injury severity, duration of mechanical ventilation (MV), duration of ICU stay, occurrence of pneumonia, bronchoalveolar lavage, aspiration, pathogen details, and incidences of mortality were evaluated. Statistical evaluation was performed using SPSS (Version 25.0, SPSS, Inc.) software.
Results: The overall incidence of pneumonia was 27.5%. Compared to patients without pneumonia, patients with pneumonia had sustained more severe injuries (mean ISS: 32.6 vs. 25.4), were older (mean age: 51.3 vs. 47.5) and spent longer periods under MV (mean: 368.9 h vs. 114.9 h). Age, sex (male), aspiration, and duration of MV were all independent predictors for pneumonia occurrence in a multivariate analysis. The cut-off point for duration of MV that best discriminated between patients who would and would not develop pneumonia during their hospital stay was 102 h. The extent of thoracic trauma (AISthorax), ISS, and presence of pulmonary comorbidities did not show significant associations to pneumonia incidence in our multivariate analysis. No significant difference in mortality between patients with and without pneumonia was observed.
Conclusions: Likelihood of pneumonia increases with age, aspiration, and duration of MV. These parameters were not found to be associated with differences in outcomes between patients with and without pneumonia. Future studies should focus on independent parameters to more clearly identify severely injured subgroups with a high risk of developing pneumonia.
Level of evidence: Level II - Retrospective medical record review.
Glioblastoma is one of the deadliest malignancies and is virtually incurable. Accumulating evidence indicates that a small population of cells with a stem-like phenotype is the major culprit of tumor recurrence. Enhanced DNA repair capacity and expression of stemness marker genes are the main characteristics of these cells. Elimination of this population might delay or prevent tumor recurrence following radiochemotherapy. The aim of this study was to analyze whether interference with the Hedgehog signaling (Hh) pathway or combined Hh/Notch blockade using small-molecule inhibitors can efficiently target these cancer stem cells and sensitize them to therapy. Using tumor sphere lines and primary patient-derived glioma cultures we demonstrate that the Hh pathway inhibitor GANT61 (GANT) and the arsenic trioxide (ATO)-mediated Hh/Notch inhibition are capable to synergistically induce cell death in combination with the natural anticancer agent (−)-Gossypol (Gos). Only ATO in combination with Gos also strongly decreased stemness marker expression and prevented sphere formation and recovery. These synergistic effects were associated with distinct proteomic changes indicating diminished DNA repair and markedly reduced stemness. Finally, using an organotypic brain slice transplantation model, we show that combined ATO/Gos treatment elicits strong growth inhibition or even complete elimination of tumors. Collectively, our data show for the first time that ATO and Gos, two drugs that can be used in the clinic, represent a promising targeted therapy approach for the synergistic elimination of glioma stem-like cells.
Current technologies used to generate CRISPR/Cas gene perturbation reagents are labor intense and require multiple ligation and cloning steps. Furthermore, increasing gRNA sequence diversity negatively affects gRNA distribution, leading to libraries of heterogeneous quality. Here, we present a rapid and cloning-free mutagenesis technology that can efficiently generate covalently-closed-circular-synthesized (3Cs) CRISPR/Cas gRNA reagents and that uncouples sequence diversity from sequence distribution. We demonstrate the fidelity and performance of 3Cs reagents by tailored targeting of all human deubiquitinating enzymes (DUBs) and identify their essentiality for cell fitness. To explore high-content screening, we aimed to generate the largest up-to-date gRNA library that can be used to interrogate the coding and noncoding human genome and simultaneously to identify genes, predicted promoter flanking regions, transcription factors and CTCF binding sites that are linked to doxorubicin resistance. Our 3Cs technology enables fast and robust generation of bias-free gene perturbation libraries with yet unmatched diversities and should be considered an alternative to established technologies.
The paper outlines a method for investigating the speed effect due to a time limit in testing. It is assumed that the time limit enables latent processing speed to influence responses by causing omissions in the case of insufficient speed. Because of processing speed as additional latent source, the customary confirmatory factor model is enlarged by a second latent variable representing latent processing speed. For distinguishing this effect from other method effects, the factor loadings are fixed according to the cumulative normal distribution. With the second latent variable added, confirmatory factor analysis of reasoning data (N=518) including omissions because of a time limit yielded good model fit and discriminated the speed effect from other possible effects due to the item difficulty, the homogeneity of an item subset and the item positions. Because of the crucial role of the cumulative normal distribution for fixing the factor loadings a check of the normality assumption is also reported.
Discovery of key whole-brain transitions and dynamics during human wakefulness and non-REM sleep
(2019)
The modern understanding of sleep is based on the classification of sleep into stages defined by their electroencephalography (EEG) signatures, but the underlying brain dynamics remain unclear. Here we aimed to move significantly beyond the current state-of-the-art description of sleep, and in particular to characterise the spatiotemporal complexity of whole-brain networks and state transitions during sleep. In order to obtain the most unbiased estimate of how whole-brain network states evolve through the human sleep cycle, we used a Markovian data-driven analysis of continuous neuroimaging data from 57 healthy participants falling asleep during simultaneous functional magnetic resonance imaging (fMRI) and EEG. This Hidden Markov Model (HMM) facilitated discovery of the dynamic choreography between different whole-brain networks across the wake-non-REM sleep cycle. Notably, our results reveal key trajectories to switch within and between EEG-based sleep stages, while highlighting the heterogeneities of stage N1 sleep and wakefulness before and after sleep.
Background: Peritonitis is responsible for thousands of deaths annually in Germany alone. Even source control (SC) and antibiotic treatment often fail to prevent severe sepsis or septic shock, and this situation has hardly improved in the past two decades. Most experimental immunomodulatory therapeutics for sepsis have been aimed at blocking or dampening a specific pro-inflammatory immunological mediator. However, the patient collective is large and heterogeneous. There are therefore grounds for investigating the possibility of developing personalized therapies by classifying patients into groups according to biomarkers. This study aims to combine an assessment of the efficacy of treatment with a preparation of human immunoglobulins G, A, and M (IgGAM) with individual status of various biomarkers (immunoglobulin level, procalcitonin, interleukin 6, antigen D-related human leucocyte antigen (HLA-DR), transcription factor NF-κB1, adrenomedullin, and pathogen spectrum).
Methods/design: A total of 200 patients with sepsis or septic shock will receive standard-of-care treatment (SoC). Of these, 133 patients (selected by 1:2 randomization) will in addition receive infusions of IgGAM for 5 days. All patients will be followed for approximately 90 days and assessed by the multiple-organ failure (MOF) score, by the EQ QLQ 5D quality-of-life scale, and by measurement of vital signs, biomarkers (as above), and survival.
Discussion: This study is intended to provide further information on the efficacy and safety of treatment with IgGAM and to offer the possibility of correlating these with the biomarkers to be studied. Specifically, it will test (at a descriptive level) the hypothesis that patients receiving IgGAM who have higher inflammation status (IL-6) and poorer immune status (low HLA-DR, low immunoglobulin levels) have a better outcome than patients who do not receive IgGAM. It is expected to provide information that will help to close the knowledge gap concerning the association between the effect of IgGAM and the presence of various biomarkers, thus possibly opening the way to a personalized medicine.
Trial registration: EudraCT, 2016–001788-34; ClinicalTrials.gov, NCT03334006. Registered on 17 Nov 2017.
Trial sponsor: RWTH Aachen University, represented by the Center for Translational & Clinical Research Aachen (contact Dr. S. Isfort).
Glaubt man Hermann Parzinger, entsteht in Berlin das würdige Zentrum einer Art Welthauptstadt: "Das Humboldt Forum: 'So viel Welt mit sich verbinden als möglich'"– das ist der Titel des 2011 herausgegebenen Folianten der Stiftung Preußischer Kulturbesitz, deren Präsident Parzinger ist. Die markigen Worte umreißen das Ziel des "wichtigsten Kulturprojekts in Deutschland zu Beginn des 21. Jahrhunderts", wie es im Untertitel heißt. "So viel Welt mit sich verbinden als möglich". Von wem stammt dieses werbewirksame Schlagwort? Und: Wie ist dieses Verbinden zu denken? [...] Mich interessiert hier und im Folgenden der erste Kontakt, der sich im Verb "ergreifen" ausdrückt. Offensichtlich setzt die Etablierung einer möglichst engen Verbindung von 'Mensch' und 'Welt' ein initiales Moment voraus, ein aktives Zupacken durch das Subjekt, das in der Folge die Fusion beider allererst ermöglicht. Das Ergreifen von "so viel Welt, als möglich" bildet das Fundament für humanistische Allgemeinbildung im Humboldt’schen Sinne: "[D]iese Aufgabe löst sich allein durch die Verknüpfung unsres Ich mit der Welt zu der allgemeinsten, regesten und freiesten Wechselwirkung." Angesichts der kontrovers geführten Kolonialismus-Debatte um das Humboldt-Forum ist es bemerkenswert, dass Parzingers Werbetext das Ergreifen tilgt, negiert er doch damit auch ein mögliches Gewaltmoment. Schließlich wurden Kolonien zuerst ergriffen, gewaltsam ein-genommen, bevor es zu einem zumindest einseitig produktiven Austausch von Waren, Kunst und dergleichen, zu einer "Verknüpfung" kommen konnte. Indem der Text die Kontaktanbahnung, das Ausgreifen verschweigt, kaschiert er damit auch das preußisch-imperiale Erbe. Wie sehr aber wirkt in jener Humboldt’schen Verbindung von Bildungssubjekt und Welt die initiale Gewalt fort, die an ihrem Anfang steht? Wie ist das Verhältnis von der "freiesten Wechselwirkung", also einer reziproken Interaktion, zum aggressiven, aktiven Ergreifen? Diese Fragen und der imperiale Wunsch, Berlin möge mit dem Humboldt-Forum nun zur "Angelegenheit der gesamten Welt werden", führen zu 'dem' Modell und Phantasma einer Welthauptstadt – zu Rom, genauer zum Rom Johann Wolfgang von Goethes.
In der Erinnerungskultur der Goethezeit spielt das haptische Erleben von Souvenirs eine entscheidende Rolle – im taktilen Umgang mit Andenken werden über Form, Materialität und Funktion Abwesende vergegenwärtigt, Erinnerungen und Gefühle evoziert. Nachvollziehbar wird die Kultivierung und Reflexion dieser Praktik der Erinnerungskultur in dem sehr gut überlieferten Nachlass von Johann Wolfgang von Goethe, der von der Klassik Stiftung Weimar bewahrt wird. Obwohl Goethe dem Tastsinn jegliche Erkenntnisfähigkeit abspricht und ihn als den niedersten der Sinne diskreditiert, werden das Berühren und Berührtwerden von Körpern und Dingen in seinen literarischen Werken sowie insbesondere in seinen privaten Korrespondenzen variantenreich verhandelt. Eingebettet in empfindsame Liebessemantik, assoziiert mit religiösen Praktiken und medizinischen Diskursen oder verknüpft mit erotischen Momenten ist die Berührung ein wiederkehrender Gegenstand expliziter und impliziter Auseinandersetzungen.
Für Aristoteles gleicht das Drama einem 'zóon', einem Lebewesen mit Anfang, Mitte und Ende. Gemeint sind Entstehung, Ausgestaltung und Abschluss der Handlungsstruktur, und zwar als 'psyché', als Seele, des Dramas. Aus einem Blickwinkel, der weniger am 'dráma' und mehr an den körperlichen Dimensionen des Theaters orientiert ist, ließe sich Aristoteles’ Vergleich auch zur Frage nach einer Organologie des Theaters und ihrer politischen und sinnesphysiologischen Implikationen wenden. Darum geht es mir im Folgenden – für ein unterschätztes Organ: für die Füße.
Air-sea feedbacks between the Mediterranean Sea and the atmosphere on various temporal and spatial scales play a major role in the Mediterranean regional climate system and beyond. The Mediterranean Sea is a source of moisture due to excess evaporation and, on a long-term average, is associated with a warming of the lower atmosphere in contact with the sea surface due to heat loss at the air-sea interface. The complex air-sea interactions and feedbacks in the Mediterranean basin strongly modulate the sea surface fluxes and favor several cyclogenetic activities under certain meteorological conditions. Examples of such cyclonic activities are medicanes (Mediterranean hurricanes) and Vb-cyclones. Medicanes are mesoscale, marine, and warm-core Mediterranean cyclones that exhibit some similarities to tropical cyclones, while Vb-cyclones are extra-tropical cyclones, that propagate from the Western Mediterranean Sea and travel across the Eastern European Alps into the Central European region. Extremely strong winds and heavy precipitation associated with these cyclones can lead to severe destruction and flooding. Changes in the intensity and frequency of these cyclones are also projected under changing future climate conditions, where the Mediterranean region has been identified as a hotspot in terms of rising temperatures.
The development of high-resolution regional climate models (RCMs) has progressed our understanding of the processes characterizing the Mediterranean climate. However, large uncertainties still exist regarding the estimates of air-sea fluxes, which, in turn, affect the simulation of the Mediterranean climate. Several factors can be attributed to such discrepancies, such as data quality, temporal and spatial resolution, and the misrepresentation of physical processes. To overcome some of these inconsistencies and deficiencies of the existing climate simulations, a new high-resolution atmosphere-ocean regional coupled model (AORCM) has been developed to simulate the air-sea feedback mechanisms. This coupled model incorporates the coupling of RCM COSMO-CLM (CCLM) and the regional ocean model NEMO-MED12 for the Mediterranean Sea (MED) as well as NEMO-NORDIC for the North- and Baltic Sea (NORDIC). Several experiments were performed using both the coupled and uncoupled models to investigate the impact of air-sea interactions and feedbacks on sea surface heat fluxes, wind speed, and on the formation of Mediterranean cyclones (i.e., medicanes and Vb-cyclones). These experiments were performed using different horizontal atmospheric grid resolutions to analyze the effect of resolution on sea surface heat fluxes, wind speed, and the development of medicanes.
The results of the present study indicate that a finer atmospheric grid resolution ([is as appreciated as]9 vs. [is as appreciated as]50 km) improved the wind speed simulations (particularly near coastal areas) and subsequently improved the simulations of the turbulent heat fluxes. Both parameters were better simulated in the coupled simulations than in the uncoupled simulations, but coupling introduced a warm SST bias in winter. Radiation fluxes were slightly better represented in coarse-grid simulations than in fine-grid simulations. However, the higher-resolution coupled model could reproduce the observed net outgoing total surface heat flux over the Mediterranean Sea. In addition to that sub diurnal SST variations have a strong effect on sub-daily heat fluxes and wind speed but minor effects at longer timescales. Regarding the impact of atmospheric grid resolution ([is as appreciated as]50, 25, and [is as appreciated as]9 km) and ocean coupling on medicanes, it was detected that the coupled model with a finer atmospheric grid ([is as appreciated as]9 km) was able to not only reproduce most medicane events, but also improved the track length, warm core, and wind speed compared to the uncoupled model. The coupled model with the coarse-grid ([is as appreciated as]50 and [is as appreciated as]25 km) did not show any improvement in simulating medicanes compared to the uncoupled model. The spectral nudging technique, applied on the wind components above 850 hPa in the interior domain to keep large-scale circulation close to the driving data (i.e., ERAInterim reanalysis), improved the accuracy of the times and locations of generated medicanes, but no improvement was found in the track length and intensity.
Concerning the role of the Mediterranean Sea coupling on Vb cyclones, the investigation showed that atmosphere-ocean coupling had an overall positive impact, although with a strong case-by-case variation, on the trajectories and intensity of Vb-cyclones as a result of the variation in moisture source for each event. In general, all model configurations could replicate Vbcyclones, their trajectories, and associated precipitation fields. The average structure of the precipitation field was best represented in the coupled simulations. Coupling of the North- and Baltic Seas also showed an improvement in some of the simulated Vb-cyclones.
The atmosphere-ocean coupling showed an overall positive impact on the simulation of sea surface heat fluxes and Mediterranean cyclones (medicanes and Vb-cyclones). Moreover, the representation of sea surface heat fluxes, wind speed, and medicane features was more realistic when using a finer atmospheric grid resolution (less than 10 km). The present study suggests that the combination of a finer atmospheric grid resolution together with atmosphere-ocean coupling is advantageous in simulating the Mediterranean climate system.
During the past 15 years there have been dramatic changes in the medical landscape, particularly in oncology and regenerative medicine. Cell therapies have played a substantial part in this progress. Cellular immunotherapies can use immune cells, such as T cells or natural killer cells that, after functional modification ex vivo, exert powerful anti-cancer effects when given to the patient. Innovative technologies, such as re-programming terminally differentiated cells into pluripotent stem cells or into other cell types and applying specific enzymes to more precisely edit the human genome, are paving the way towards more potent cell and gene therapies.
Mesenchymal stromal cells are promising cellular immunotherapeutics, which also have potential for use in tissue engineering strategies and other regenerative medicine applications. However, substantial gaps in our knowledge of their biology and therapeutic efficacy present major challenges to their sustainable implementation in the clinical routine.
In this article, progress in the field of cell therapeutics during the past 15 years will be briefly discussed, with a focus on mesenchymal stromal cells, highlighting the impact of this field on patient care.
Memory impairments are a major characteristic of schizophrenia (SZ). In the current study, we used an associative memory task to test the hypothesis that SZ patients and first-degree relatives have altered functional patterns in comparison to healthy controls. We analyzed the fMRI activation pattern during the presentation of a face-name task in 27 SZ patients, 23 first-degree relatives, and 27 healthy controls. In addition, we performed correlation analyses between individual psychopathology, accuracy and reaction time of the task and the beta scores of the functional brain activations. We observed a lower response accuracy and increased reaction time during the retrieval of face-name pairs in SZ patients compared with controls. Deficient performance was accompanied by abnormal functional activation patterns predominantly in DMN regions during encoding and retrieval. No significant correlation between individual psychopathology and neuronal activation during encoding or retrieval of face-name pairs was observed. Findings of first-degree relatives indicated slightly different functional pattern within brain networks in contrast to controls without significant differences in the behavioral task. Both the accuracy of memory performance as well as the functional activation pattern during retrieval revealed alterations in SZ patients, and, to a lesser degree, in relatives. The results are of potential relevance for integration within a comprehensive model of memory function in SZ. The development of a neurophysiological model of cognition in psychosis may help to clarify and improve therapeutic options to improve memory and functioning in the illness.
Numerous cell–cell and cell–matrix interactions within the bone marrow microenvironment enable the controlled lifelong self-renewal and progeny of hematopoietic stem and progenitor cells (HSPCs). On the cellular level, this highly mutual interaction is granted by cell adhesion molecules (CAMs) integrating differentiation, proliferation, and pro-survival signals from the surrounding microenvironment to the inner cell. However, cell–cell and cell–matrix interactions are also critically involved during malignant transformation of hematopoietic stem/progenitor cells. It has become increasingly apparent that leukemia-associated gene products, such as activated tyrosine kinases and fusion proteins resulting from chromosomal translocations, directly regulate the activation status of adhesion molecules, thereby directing the leukemic phenotype. These observations imply that interference with adhesion molecule function represents a promising treatment strategy to target pre-leukemic and leukemic lesions within the bone marrow niche. Focusing on myeloid leukemia, we provide a current overview of the mechanisms by which leukemogenic gene products hijack control of cellular adhesion to subsequently disturb normal hematopoiesis and promote leukemia development.
IKZF1 deletion (ΔIKZF1) is an important predictor of relapse in both childhood and adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Previously, we revealed that COBL is a hotspot for breakpoints in leukemia and could promote IKZF1 deletions. Through an international collaboration, we provide a detailed genetic and clinical picture of B-ALL with COBL rearrangements (COBL-r). Patients with B-ALL and IKZF1 deletion (n = 133) were included. IKZF1 ∆1-8 were associated with large alterations within chromosome 7: monosomy 7 (18%), isochromosome 7q (10%), 7p loss (19%), and interstitial deletions (53%). The latter included COBL-r, which were found in 12% of the IKZF1 ∆1-8 cohort. Patients with COBL-r are mostly classified as intermediate cytogenetic risk and frequently harbor ETV6, PAX5, CDKN2A/B deletions. Overall, 56% of breakpoints were located within COBL intron 5. Cryptic recombination signal sequence motifs were broadly distributed within the sequence of COBL, and no enrichment for the breakpoint cluster region was found. In summary, a diverse spectrum of alterations characterizes ΔIKZF1 and they also include deletion breakpoints within COBL. We confirmed that COBL is a hotspot associated with ΔIKZF1, but these rearrangements are not driven by RAG-mediated recombination.
Background: Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia.
Methods: This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to <18 years; AG2, 2 to <7 years; and AG3, 3 months to <2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7–28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL.
Results: The percentage of subjects meeting the PK target was <90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to <7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to <18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to <18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects’ underlying diseases.
Conclusion: The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation.
Trial registration: ClinicalTrials.gov identifier: NCT01716234
In this note, we first highlight different developments for banks under direct ECB supervision within the SSM that may prompt further investigation by supervisors. We find that banks that were weakly capitalized at the start of direct ECB supervision (1) still face elevated levels of non-performing loans, (2) are less cost-efficient and (3) reduced their share of subordinated debt financing over the last years. We then stress the importance of continuous and ongoing cost-benefit analysis regarding banking supervision in Europe. We also encourage processes to question existing supervisory practices to ensure a lean and efficient banking supervision. Finally, we underline the need of continuous and intensified coordination among regulatory bodies in the Banking Union since the efficacy of European bank supervision rests on its interplay with many different institutions.
This document was requested by the European Parliament's Committee on Economic and Monetary Affairs. It was originally published on the European Parliament’s webpage.
Nach der 2008 startenden Finanzmarktkrise sind Maßnahmen zur Regulierung und Stabilisierung der Finanzmärkte in das Zentrum der politischen und der gesellschaftlichen Aufmerksamkeit gerückt. Insbesondere die hohen fiskalischen Kosten der Staaten zur Stützung ihrer Bankensysteme sowie die volkswirtschaftlichen Kosten infolge des Einbruchs des Wirtschaftswachstums in den Jahren nach der Insolvenz der US Investmentbank Lehman Brothers hatten einen globalen Konsens über die Notwendigkeit neuer Regulierungsmaßnahmen zur Folge. Im Ergebnis wurden das internationale Regulierungswerk Basel III sowie weitere nationale Maßnahmen zur Stabilisierung des Finanzsektors neu konzipiert und in Europa im Wege einer in nationales Recht umzusetzenden Richtlinie (die Capital Require-ments Directive IV - CRD IV) sowie einer Verordnung (die Capital Requirements Regulation CRR, welche unmittelbar geltendes Recht darstellt) eingeführt.
Vor diesem Hintergrund analysiert das vorliegende interdisziplinäre Gutachten die Auswirkungen der Regulierungsmaßnahmen, die zwischen 2008 bis zu Beginn des Jahres 2018 umgesetzt wurden auf dem deutschen Finanzsektor.
In diesem explorativen Beitrag machen wir uns Gedanken über die Zukunft von Deutscher Bank und Commerzbank und entwickeln einen neuen Zugang zu dem Thema: Statt einer Fusion von DB und CB schlagen wir eine Teilfusion nur der Datenzentren vor – es entsteht auf diese Weise die Grundlage für eine Open Banking Plattform als „utility“, also als Betrieb im Eigentum der Nutzer, an der perspektivisch weitere Finanzinstitute teilnehmen können. Die über die Daten kooperierenden Institute bleiben mit Blick auf Produkte und Dienstleistungen unverändert Konkurrenten – „national champions“ entstehen auf diese Weise nicht. Aber es wird damit in Europa die Basis für einen erfolgversprechenden Wettbewerb mit den großen Datenplattformen aus USA und China (Facebook, Amazon, Alipay) gelegt, die früher oder später in den Finanzmarkt eindringen werden. Das von uns vorgeschlagene Modell einer offenen Datenplattform für Banken verhindert das Entstehen von „national champions“ und schützt damit auch das Kernanliegen der Bankenunion: Die Schaffung eines Finanzsystems, dessen Banken jede für sich ausscheiden können ohne eine systemische Krise auszulösen, und ohne den Steuerzahler zu einer Rettungsaktion zu zwingen