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Serum levels of the lipid mediator sphingosine-1-phosphate (S1P) are reduced in septic patients and are inversely associated with disease severity. We show that serum S1P is reduced in human sepsis and in murine models of sepsis. We then investigated whether pharmacological or genetic approaches that alter serum S1P may attenuate cardiac dysfunction and whether S1P signaling might serve as a novel theragnostic tool in sepsis. Mice were challenged with lipopolysaccharide and peptidoglycan (LPS/PepG). LPS/PepG resulted in an impaired systolic contractility and reduced serum S1P. Administration of the immunomodulator FTY720 increased serum S1P, improved impaired systolic contractility and activated the phosphoinositide 3-kinase (PI3K)-pathway in the heart. Cardioprotective effects of FTY720 were abolished following administration of a S1P receptor 2 (S1P2) antagonist or a PI3K inhibitor. Sphingosine kinase-2 deficient mice had higher endogenous S1P levels and the LPS/PepG-induced impaired systolic contractility was attenuated in comparison with wild-type mice. Cardioprotective effects of FTY720 were confirmed in polymicrobial sepsis. We show here for the first time that the impaired left ventricular systolic contractility in experimental sepsis is attenuated by FTY720. Mechanistically, our results indicate that activation of S1P2 by increased serum S1P and the subsequent activation of the PI3K-Akt survival pathway significantly contributes to the observed cardioprotective effect of FTY720.
In our previous work we showed that NGAL, a protein involved in the regulation of proliferation and differentiation, is overexpressed in human breast cancer (BC) and predicts poor prognosis. In neoadjuvant chemotherapy (NACT) pathological complete response (pCR) is a predictor for outcome. The aim of this study was to evaluate NGAL as a predictor of response to NACT and to validate NGAL as a prognostic factor for clinical outcome in patients with primary BC. Immunohistochemistry was performed on tissue microarrays from 652 core biopsies from BC patients, who underwent NACT in the GeparTrio trial. NGAL expression and intensity was evaluated separately. NGAL was detected in 42.2% of the breast carcinomas in the cytoplasm. NGAL expression correlated with negative hormone receptor (HR) status, but not with other baseline parameters. NGAL expression did not correlate with pCR in the full population, however, NGAL expression and staining intensity were significantly associated with higher pCR rates in patients with positive HR status. In addition, strong NGAL expression correlated with higher pCR rates in node negative patients, patients with histological grade 1 or 2 tumors and a tumor size <40 mm. In univariate survival analysis, positive NGAL expression and strong staining intensity correlated with decreased disease-free survival (DFS) in the entire cohort and different subgroups, including HR positive patients. Similar correlations were found for intense staining and decreased overall survival (OS). In multivariate analysis, NGAL expression remained an independent prognostic factor for DFS. The results show that in low-risk subgroups, NGAL was found to be a predictive marker for pCR after NACT. Furthermore, NGAL could be validated as an independent prognostic factor for decreased DFS in primary human BC.
Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium
(2017)
Chordomas are rare bone tumors with few therapeutic options. Here we show, using whole-exome and genome sequencing within a precision oncology program, that advanced chordomas (n = 11) may be characterized by genomic patterns indicative of defective homologous recombination (HR) DNA repair and alterations affecting HR-related genes, including, for example, deletions and pathogenic germline variants of BRCA2, NBN, and CHEK2. A mutational signature associated with HR deficiency was significantly enriched in 72.7% of samples and co-occurred with genomic instability. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib, which is preferentially toxic to HR-incompetent cells, led to prolonged clinical benefit in a patient with refractory chordoma, and whole-genome analysis at progression revealed a PARP1 p.T910A mutation predicted to disrupt the autoinhibitory PARP1 helical domain. These findings uncover a therapeutic opportunity in chordoma that warrants further exploration, and provide insight into the mechanisms underlying PARP inhibitor resistance.
In psychiatry, there has been a growing focus on identifying at-risk populations. For schizophrenia, these efforts have led to the development of early recognition and intervention measures. Despite a similar disease burden, the populations at risk of bipolar disorder have not been sufficiently characterized. Within the BipoLife consortium, we used magnetic resonance imaging (MRI) data from a multicenter study to assess structural gray matter alterations in N = 263 help-seeking individuals from seven study sites. We defined the risk using the EPIbipolar assessment tool as no-risk, low-risk, and high-risk and used a region-of-interest approach (ROI) based on the results of two large-scale multicenter studies of bipolar disorder by the ENIGMA working group. We detected significant differences in the thickness of the left pars opercularis (Cohen’s d = 0.47, p = 0.024) between groups. The cortex was significantly thinner in high-risk individuals compared to those in the no-risk group (p = 0.011). We detected no differences in the hippocampal volume. Exploratory analyses revealed no significant differences in other cortical or subcortical regions. The thinner cortex in help-seeking individuals at risk of bipolar disorder is in line with previous findings in patients with the established disorder and corresponds to the region of the highest effect size in the ENIGMA study of cortical alterations. Structural alterations in prefrontal cortex might be a trait marker of bipolar risk. This is the largest structural MRI study of help-seeking individuals at increased risk of bipolar disorder.
There are special challenges in implementing parenteral nutrition (PN) in paediatric patients, which arises from the wide range of patients, ranging from extremely premature infants up to teenagers weighing up to and over 100 kg, and their varying substrate requirements. Age and maturity-related changes of the metabolism and fluid and nutrient requirements must be taken into consideration along with the clinical situation during which PN is applied. The indication, the procedure as well as the intake of fluid and substrates are very different to that known in PN-practice in adult patients, e.g. the fluid, nutrient and energy needs of premature infants and newborns per kg body weight are markedly higher than of older paediatric and adult patients. Premature infants <35 weeks of pregnancy and most sick term infants usually require full or partial PN. In neonates the actual amount of PN administered must be calculated (not estimated). Enteral nutrition should be gradually introduced and should replace PN as quickly as possible in order to minimise any side-effects from exposure to PN. Inadequate substrate intake in early infancy can cause long-term detrimental effects in terms of metabolic programming of the risk of illness in later life. If energy and nutrient demands in children and adolescents cannot be met through enteral nutrition, partial or total PN should be considered within 7 days or less depending on the nutritional state and clinical conditions.
Wie sieht eigentlich die eigene didaktische Praxis der Politikdidaktik an Hochschulen
aus? Im vorliegenden Text wird diese Frage am Beispiel eines Einführungsmoduls
diskutiert.
Zentraler Anspruch Frankfurter Politikdidaktik ist eine kritische Subjektorientierung,
die sich vor allem auf einen emphatischen, aber auch auf einen kritischen
Subjektbegriff gründet. Dieser findet sich in verschiedenen, an der Praxis orientierten
Formen wieder: in Form der Reflexion subjektiver Theorien der Studierenden,
in Form einer grundsätzlichen und konkreten Begründungspflicht politischer Bildung
und damit auch einhergehend einer Metakommunikation, im Verständnis der
Kritik politischer Bildung in jeweils konkreten Verhältnissen (Seminar wie Unterricht),
in der Betrachtung von Macht und Herrschaft in Form des pädagogischen
Widerspruchs von Autonomie und Leitung und auch in Form der Gegenstandsanalyse
einer kritischen Problemorientierung und kategorialen Bildung.
Methodisch sind reflexive und praktische Zugänge zu den genannten Bereichen
politischer Bildung prägend. Wirksame Bildungsprozesse müssen sich auf
subjektive Theorien beziehen und müssen ihre eigene, konkrete Bildungspraxis
einbeziehen. Subjektive Theorien werden in einem theoretischen Teil des Moduls
eruiert und reflektiert. Eine Projektphase im zweiten Teil stellt die Bedingungen
zur Verfügung, diese subjektiven Theorie durch (hoffentlich alternatives) praktisches
Handeln und seine Reflexion zu verändern. Ziel ist, die biografisch von Praxis
geprägten und stets handlungsleitenden subjektiven Theorien durch intellektuelle,
aber auch durch praktisch-körperliche Bildungserfahrungen so zu bearbeiten,
sodass sich ein professioneller Habitus entwickeln kann.
In the upcoming years, the internet of things (IoT)will enrich daily life. The combination of artificial intelligence(AI) and highly interoperable systems will bring context-sensitive multi-domain services to reality. This paper describesa concept for an AI-based smart living platform with open-HAB, a smart home middleware, and Web of Things (WoT) askey components of our approach. The platform concept con-siders different stakeholders, i.e. the housing industry, serviceproviders, and tenants. These activities are part of the Fore-Sight project, an AI-driven, context-sensitive smart living plat-form.
The formation of secondary particles in the atmosphere accounts for more than half of global cloud condensation nuclei. Experiments at the CERN CLOUD (Cosmics Leaving OUtdoor Droplets) chamber have underlined the importance of ions for new particle formation, but quantifying their effect in the atmosphere remains challenging. By using a novel instrument setup consisting of two nano-particle counters, one of them equipped with an ion filter, we were able to further investigate the ion-related mechanisms of new particle formation. In autumn 2015, we carried out experiments at CLOUD on four systems of different chemical compositions involving monoterpenes, sulfuric acid, nitrogen oxides, and ammonia. We measured the influence of ions on the nucleation rates under precisely controlled and atmospherically relevant conditions. Our results indicate that ions enhance the nucleation process when the charge is necessary to stabilize newly formed clusters, i.e. in conditions where neutral clusters are unstable. For charged clusters that were formed by ion-induced nucleation, we were able to measure, for the first time, their progressive neutralization due to recombination with oppositely charged ions. A large fraction of the clusters carried a charge at 1.2 nm diameter. However, depending on particle growth rates and ion concentrations, charged clusters were largely neutralized by ion–ion recombination before they grew to 2.2 nm. At this size, more than 90 % of particles were neutral. In other words, particles may originate from ion-induced nucleation, although they are neutral upon detection at diameters larger than 2.2 nm. Observations at Hyytiälä, Finland, showed lower ion concentrations and a lower contribution of ion-induced nucleation than measured at CLOUD under similar conditions. Although this can be partly explained by the observation that ion-induced fractions decrease towards lower ion concentrations, further investigations are needed to resolve the origin of the discrepancy.
Nucleation and growth of aerosol particles from atmospheric vapors constitutes a major source of global cloud condensation nuclei (CCN). The fraction of newly formed particles that reaches CCN sizes is highly sensitive to particle growth rates, especially for particle sizes <10 nm, where coagulation losses to larger aerosol particles are greatest. Recent results show that some oxidation products from biogenic volatile organic compounds are major contributors to particle formation and initial growth. However, whether oxidized organics contribute to particle growth over the broad span of tropospheric temperatures remains an open question, and quantitative mass balance for organic growth has yet to be demonstrated at any temperature. Here, in experiments performed under atmospheric conditions in the Cosmics Leaving Outdoor Droplets (CLOUD) chamber at the European Organization for Nuclear Research (CERN), we show that rapid growth of organic particles occurs over the range from −25 ∘C to 25 ∘C. The lower extent of autoxidation at reduced temperatures is compensated by the decreased volatility of all oxidized molecules. This is confirmed by particle-phase composition measurements, showing enhanced uptake of relatively less oxygenated products at cold temperatures. We can reproduce the measured growth rates using an aerosol growth model based entirely on the experimentally measured gas-phase spectra of oxidized organic molecules obtained from two complementary mass spectrometers. We show that the growth rates are sensitive to particle curvature, explaining widespread atmospheric observations that particle growth rates increase in the single-digit-nanometer size range. Our results demonstrate that organic vapors can contribute to particle growth over a wide range of tropospheric temperatures from molecular cluster sizes onward.