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Sonstige beteiligte Institutionen
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ResearcherID
- B-4606-2017 (1)
Background: Accurate assessment of hepatic fibrosis in patients with chronic HBeAg-negative Hepatitis B is of crucial importance not only to predict the long-term clinical course, but also to evaluate antiviral therapy indication. The aim of this study was to prospectively assess the utility of point shear wave elastography (pSWE) for longitudinal non-invasive fibrosis assessment in a large cohort of untreated patients with chronic HBeAg-negative hepatitis B virus (HBV) infection. Methods: 407 consecutive patients with HBeAg-negative HBV infection who underwent pSWE, transient elastography (TE) as well as laboratory fibrosis markers, including fibrosis index based on four factors (FIB-4), aspartate to platelet ratio index (APRI) and FibroTest, on the same day were prospectively followed up for six years. Patients were classified into one of the three groups: inactive carriers (IC; HBV-DNA <2000 IU/mL and ALT <40 U/L); grey zone group 1 (GZ-1; HBV DNA <2000 IU/mL and ALT >40 U/L); grey zone group 2 (GZ-2; HBV-DNA >2000 IU/mL and ALT <40 U/L). Results: pSWE results were significantly correlated with TE (r = 0.29, p < 0.001) and APRI (r = 0.17; p = 0.005). Median pSWE values did not differ between IC, GZ-1 and GZ-2 patients (p = 0.82, p = 0.17, p = 0.34). During six years of follow-up, median pSWE and TE values did not differ significantly over time (TE: p = 0.27; pSWE: p = 0.05). Conclusion: Our data indicate that pSWE could be useful for non-invasive fibrosis assessment and follow-up in patients with HBeAg-negative chronic HBV infection.
The helical distribution of the electronic density in chiral molecules, such as DNA and bacteriorhodopsin, has been suggested to induce a spin–orbit coupling interaction that may lead to the so-called chirality-induced spin selectivity (CISS) effect. Key ingredients for the theoretical modelling are, in this context, the helically shaped potential of the molecule and, concomitantly, a Rashba-like spin–orbit coupling due to the appearance of a magnetic field in the electron reference frame. Symmetries of these models clearly play a crucial role in explaining the observed effect, but a thorough analysis has been largely ignored in the literature. In this work, we present a study of these symmetries and how they can be exploited to enhance chiral-induced spin selectivity in helical molecular systems.
Oligodendrocytes provide metabolic and functional support to neuronal cells, rendering them key players in the functioning of the central nervous system. Oligodendrocytes need to be newly formed from a pool of oligodendrocyte precursor cells (OPCs). The differentiation of OPCs into mature and myelinating cells is a multistep process, tightly controlled by spatiotemporal activation and repression of specific growth and transcription factors. While oligodendrocyte turnover is rather slow under physiological conditions, a disruption in this balanced differentiation process, for example in case of a differentiation block, could have devastating consequences during ageing and in pathological conditions, such as multiple sclerosis. Over the recent years, increasing evidence has shown that epigenetic mechanisms, such as DNA methylation, histone modifications, and microRNAs, are major contributors to OPC differentiation. In this review, we discuss how these epigenetic mechanisms orchestrate and influence oligodendrocyte maturation. These insights are a crucial starting point for studies that aim to identify the contribution of epigenetics in demyelinating diseases and may thus provide new therapeutic targets to induce myelin repair in the long run.
Projected climate changes for the 21st century may cause great uncertainties on the hydrology of a river basin. This study explored the impacts of climate change on the water balance and hydrological regime of the Jhelum River Basin using the Soil and Water Assessment Tool (SWAT). Two downscaling methods (SDSM, Statistical Downscaling Model and LARS-WG, Long Ashton Research Station Weather Generator), three Global Circulation Models (GCMs), and two representative concentration pathways (RCP4.5 and RCP8.5) for three future periods (2030s, 2050s, and 2090s) were used to assess the climate change impacts on flow regimes. The results exhibited that both downscaling methods suggested an increase in annual streamflow over the river basin. There is generally an increasing trend of winter and autumn discharge, whereas it is complicated for summer and spring to conclude if the trend is increasing or decreasing depending on the downscaling methods. Therefore, the uncertainty associated with the downscaling of climate simulation needs to consider, for the best estimate, the impact of climate change, with its uncertainty, on a particular basin. The study also resulted that water yield and evapotranspiration in the eastern part of the basin (sub-basins at high elevation) would be most affected by climate change. The outcomes of this study would be useful for providing guidance in water management and planning for the river basin under climate change.
Defeat of the antibiotic resistance of pathogenic bacteria is one great challenge today and for the future. In the last century many classes of effective antibacterials have been developed, so that upcoming resistances could be met with novel drugs of various compound classes. Meanwhile, there is a certain lack of research of the pharmaceutical companies, and thus there are missing developments of novel antibiotics. Gram-positive bacteria are the most important cause of clinical infections. The number of novel antibacterials in clinical trials is strongly restricted. There is an urgent need to find novel antibacterials. We used synthetic chemistry to build completely novel hybrid molecules of substituted indoles and benzothiophene. In a simple one-pot reaction, two novel types of thienocarbazoles were yielded. Both indole substituted compound classes have been evaluated as completely novel antibacterials against the Staphylococcus and Enterococcus species. The evaluated partly promising activities depend on the indole substituent type. First lead compounds have been evaluated within in vivo studies. They confirmed the in vitro results for the new classes of small-molecule antibacterials.
Background: Cancer patients are increasingly treated with alpha-particle-emitting radiopharmaceuticals. At the subcellular level, alpha particles induce densely spaced ionizations and molecular damage. Induction of DNA lesions, especially clustered DNA double-strand breaks (DSBs), threatens a cell's survival. Currently, it is under debate to what extent the spatial topology of the damaged chromatin regions and the repair protein arrangements are contributing. Methods: Super-resolution light microscopy (SMLM) in combination with cluster analysis of single molecule signal-point density regions of DSB repair markers was applied to investigate the nano-structure of DNA damage foci tracks of Ra-223 in-solution irradiated leukocytes. Results: Alpha-damaged chromatin tracks were efficiently outlined by γ-H2AX that formed large (super) foci composed of numerous 60–80 nm-sized nano-foci. Alpha damage tracks contained 60–70% of all γ-H2AX point signals in a nucleus, while less than 30% of 53BP1, MRE11 or p-ATM signals were located inside γ-H2AX damage tracks. MRE11 and p-ATM protein fluorescent tags formed focal nano-clusters of about 20 nm peak size. There were, on average, 12 (±9) MRE11 nanoclusters in a typical γ-H2AX-marked alpha track, suggesting a minimal number of MRE11-processed DSBs per track. Our SMLM data suggest regularly arranged nano-structures during DNA repair in the damaged chromatin domain.
Approaches to mimic the complexity of the skeletal mesenchymal stem/stromal cell niche in vitro
(2019)
Mesenchymal stem/stromal cells (MSCs) are an essential element of most modern tissue engineering and regenerative medicine approaches due to their multipotency and immunoregulatory functions. Despite the prospective value of MSCs for the clinics, the stem cells community is questioning their developmental origin, in vivo localization, identification, and regenerative potential after several years of far-reaching research in the field. Although several major progresses have been made in mimicking the complexity of the MSC niche in vitro, there is need for comprehensive studies of fundamental mechanisms triggered by microenvironmental cues before moving to regenerative medicine cell therapy applications. The present comprehensive review extensively discusses the microenvironmental cues that influence MSC phenotype and function in health and disease – including cellular, chemical and physical interactions. The most recent and relevant illustrative examples of novel bioengineering approaches to mimic biological, chemical, and mechanical microenvironmental signals present in the native MSC niche are summarized, with special emphasis on the forefront techniques to achieve bio-chemical complexity and dynamic cultures. In particular, the skeletal MSC niche and applications focusing on the bone regenerative potential of MSC are addressed. The aim of the review was to recognize the limitations of the current MSC niche in vitro models and to identify potential opportunities to fill the bridge between fundamental science and clinical application of MSCs.
Schutzfaktoren bei Kindern vor dem Übergang in die Sekundarstufe – Ergebnisse aus der STRESSStudie
(2019)
Der Übergang in die Sekundarstufe stellt für Kinder ein normativ kritisches Lebensereignis dar, das unterschiedlich bewertet und bewältigt wird. Der vorliegende Beitrag befasst sich mit der Frage, welche Schutzfaktoren dazu beitragen, dass Kinder dem Übergang mit Gefühlen der Vorfreude begegnen und sie dieses Ereignis problemorientiert bewältigen. Untersucht werden 596 ViertklässlerInnen aus Bayern und Hessen vor dem Übergang in die Sekundarstufe. In Anlehnung an die kognitiv-transaktionale Theorie von Lazarus und Folkman (1984) werden die Zusammenhänge von primärer Bewertung als Herausforderung und problemorientierter Stressbewältigung unter Berücksichtigung von personalen (akademisches Selbstkonzept, Selbstwirksamkeit) und sozialen Schutzfaktoren (Familienzusammenhalt, allgemeines förderndes Elternverhalten) analysiert. Mithilfe von Strukturgleichungsmodellen lassen sich Mediationseffekte der Schutzfaktoren nachweisen. Insbesondere das akademische Selbstkonzept und ein förderliches Familienumfeld erweisen sich als bedeutsame protektive Faktoren in der Phase vor dem Übergang.
Background
Limited data is available to guide the choice of the conditioning regimen for patients with acute myeloid leukemia (AML) undergoing transplant with persistent disease.
Methods
We retrospectively compared outcome of fludarabine-treosulfan (FT), thiotepa-busulfan-fludarabine (TBF), and sequential fludarabine, intermediate dose Ara-C, amsacrine, total body irradiation/busulfan, cyclophosphamide (FLAMSA) conditioning in patients with refractory or relapsed AML.
Results
Complete remission rates at day 100 were 92%, 80%, and 88% for FT, TBF, and FLAMSA, respectively (p=0.13). Non-relapse mortality, incidence of relapse, acute (a) and chronic (c) graft-versus-host disease (GVHD) rates did not differ between the three groups. Overall survival at 2years was 37% for FT, 24% for TBF, and 34% for FLAMSA (p=0.10). Independent prognostic factors for survival were Karnofsky performance score and patient CMV serology (p=0.01; p=0.02), while survival was not affected by age at transplant. The use of anti-thymocyte globulin (ATG) was associated with reduced risk of grade III-IV aGVHD (p=0.02) and cGVHD (p=0.006), with no influence on relapse.
Conclusions
In conclusion, FT, TBF, and FLAMSA regimens provided similar outcome in patients undergoing transplant with active AML. Survival was determined by patient characteristics as Karnofsky performance score and CMV serology, however was not affected by age at transplant. ATG appears able to reduce the incidence of acute and chronic GVHD without influencing relapse risk.
Background
Causality between hepatitis B virus (HBV) infection and diffuse large B-cell lymphoma (DLBCL) was reported in various studies. However, the implication of different virological serum markers of HBV infection in patients with both HBV infection and DLBCL is not fully understood. The aim of this study was to investigate the impact of HBV markers on overall survival (OS) and progression-free survival (PFS) in patients with both HBV infection and DLBCL.
Methods
In this study, patients (n = 40) diagnosed with both HBV infection and DLBCL were identified between 2000 and 2017. Six patients with hepatitis C virus (HCV) and/or human immunodeficiency virus (HIV) co-infection were excluded from this study. We retrospectively analyzed patients’ demographic characteristics, treatment, and the prognostic impact of different HBV markers at first diagnosis of DLBCL (HBsAg, anti-HBs, HBeAg, anti-HBe, and HBV-DNA) on OS and PFS.
Results
The majority of patients (n = 21, 62%) had advanced disease stage (III/IV) at diagnosis. In the first-line therapy, 24 patients (70%) were treated with R-CHOP regimen (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisolone). HBeAg positive patients had a trend toward inferior OS and PFS compared with HBeAg negative patients. Anti-HBe positive patients had a statistically significant better OS and PFS compared with anti-HBe negative group (both P < .0001). Viremia with HBV-DNA ≥ 2 × 107 IU/L had a significant negative impact on OS and PFS (both P < .0001).
Conclusion
High activity of viral replication is associated with a poor survival outcome of patients with both HBV infection and DLBCL.
The identification of biomarker signatures is important for cancer diagnosis and prognosis. However, the detection of clinical reliable signatures is influenced by limited data availability, which may restrict statistical power. Moreover, methods for integration of large sample cohorts and signature identification are limited. We present a step-by-step computational protocol for functional gene expression analysis and the identification of diagnostic and prognostic signatures by combining meta-analysis with machine learning and survival analysis. The novelty of the toolbox lies in its all-in-one functionality, generic design, and modularity. It is exemplified for lung cancer, including a comprehensive evaluation using different validation strategies. However, the protocol is not restricted to specific disease types and can therefore be used by a broad community. The accompanying R package vignette runs in ~1 h and describes the workflow in detail for use by researchers with limited bioinformatics training.
Die Erkennung handschriftlicher Artefakte wie Unterstreichungen in Buchdrucken ermöglicht Rückschlüsse auf das Rezeptionsverhalten und die Provenienzgeschichte und wird auch für eine OCR benötigt. Dabei soll zwischen handschriftlichen Unterstreichungen und waagerechten Linien im Druck (z. B. Trennlinien usw.) unterschieden werden, da letztere nicht ausgezeichnet werden sollen. Im Beitrag wird ein Ansatz basierend auf einem auf Unterstreichungen trainierten Neuronalen Netz gemäß der U-Net Architektur vorgestellt, dessen Ergebnisse in einem zweiten Schritt mit heuristischen Regeln nachbearbeitet werden. Die Evaluationen zeigen, dass Unterstreichungen sehr gut erkannt werden, wenn bei der Binarisierung der Scans nicht zu viele Pixel der Unterstreichung wegen geringem Kontrast verloren gehen. Zukünftig sollen die Worte oberhalb der Unterstreichung mit OCR transkribiert werden und auch andere Artefakte wie handschriftliche Notizen in alten Drucken erkannt werden.
The gastrointestinal tract is abundantly colonized by microbes, yet the translocation of oral species to the intestine is considered a rare aberrant event, and a hallmark of disease. By studying salivary and fecal microbial strain populations of 310 species in 470 individuals from five countries, we found that transmission to, and subsequent colonization of, the large intestine by oral microbes is common and extensive among healthy individuals. We found evidence for a vast majority of oral species to be transferable, with increased levels of transmission in colorectal cancer and rheumatoid arthritis patients and, more generally, for species described as opportunistic pathogens. This establishes the oral cavity as an endogenous reservoir for gut microbial strains, and oral-fecal transmission as an important process that shapes the gastrointestinal microbiome in health and disease.
Biofabrication aims to fabricate biologically functional products through bioprinting or bioassembly (Groll et al 2016 Biofabrication 8 013001). In biofabrication processes, cells are positioned at defined coordinates in three-dimensional space using automated and computer controlled techniques (Moroni et al 2018 Trends Biotechnol. 36 384–402), usually with the aid of biomaterials that are either (i) directly processed with the cells as suspensions/dispersions, (ii) deposited simultaneously in a separate printing process, or (iii) used as a transient support material. Materials that are suited for biofabrication are often referred to as bioinks and have become an important area of research within the field. In view of this special issue on bioinks, we aim herein to briefly summarize the historic evolution of this term within the field of biofabrication. Furthermore, we propose a simple but general definition of bioinks, and clarify its distinction from biomaterial inks.
Von keinem anderen Gedicht ist im Briefwechsel zwischen Benn und Oelze häufiger die Rede als von den in der Forschung bislang wenig beachteten „Rosen“. Tatsächlich handelt es sich bei dem Text aus dem Jahr 1946 um Benns Erstling nach der Schreibpause, die sich an das Kriegsende und den Suizid seiner zweiten Frau anschließt. Benn schwankt den „Rosen“ gegenüber offenbar selbst zwischen einer biographisch bedingten Anhänglichkeit und offen geäußerten ästhetischen Bedenken. Der Beitrag zeichnet das jahrelange, geradezu dramatische Hin und Her über Publikation oder Nichtpublikation, Widmen und Nichtwidmen zwischen Benn, Oelze und auch deren Ehefrauen Charlotte Oelze und Ilse Benn nach.
Two different chromophores, namely a dipolar and an octupolar system, were prepared and their linear and nonlinear optical properties as well as their bioimaging capabilities were compared. Both contain triphenylamine as the donor and a triarylborane as the acceptor, the latter modified with cationic trimethylammonio groups to provide solubility in aqueous media. The octupolar system exhibits a much higher two‐photon brightness, and also better cell viability and enhanced selectivity for lysosomes compared with the dipolar chromophore. Furthermore, both dyes were applied in two‐photon excited fluorescence (TPEF) live‐cell imaging.
Cyclic (amino)(aryl)carbenes (cAArCs) based on the isoindoline core were successfully generated in situ by α‐elimination of 3‐alkoxyisoindolines at high temperatures or by deprotonation of isoindol‐2‐ium chlorides with sodium or copper(I) acetates at low temperatures. 3‐Alkoxy‐isoindolines 2 a,b‐OR (R=Me, Et, iPr) have been prepared in high yields by the addition of a solution of 2‐aryl‐1,1‐diphenylisoindol‐2‐ium triflate (1 a,b‐OTf; a: aryl=Dipp=2,6‐diisopropylphenyl; b: Mesityl‐, Mes=2,4,6‐trimethylphenyl) to the corresponding alcohol (ROH) with NEt3 at room temperature. Furthermore, the reaction of 2 a,b‐OMe in diethyl ether with a tenfold excess of hydrochloric acid led to the isolation of the isoindol‐2‐ium chlorides 1 a,b‐Cl in high yields. The thermally generated cAArC reacts with sulfur to form the thioamide 3 a. Without any additional trapping reagent, in situ generation of 1,1‐diphenylisoidolin‐3‐ylidenes does not lead to the isolation of these compounds, but to the reaction products of the insertion of the carbene carbon atom into an ortho C−H bond of a phenyl substituent, followed by ring‐expansion reaction; namely, anthracene derivatives 9‐N(H)aryl‐10‐Ph‐C14H8 4 a,b (a: Dipp; b: Mes). These compounds are conveniently synthesized by deprotonation of the isoindol‐2‐ium chlorides with sodium acetate in high yields. Deprotonation of 1 a‐Cl with copper(I) acetate at low temperatures afforded a mixture of 4 a and the corresponding cAArC copper(I) chloride 5 a, and allowed the isolation and structural characterization of the first example of a cAArC copper complex of general formula [(cAArC)CuCl].
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can present with different histopathological growth patterns. The impact of these histopathological growth patterns on relapse characteristics is unknown. We therefore analyzed paired biopsies obtained at initial diagnosis and relapse from 33 NLPHL patients who had received first‐line treatment within German Hodgkin Study Group (GHSG) trial protocols, and from a second cohort of 41 relapsed NLPHL patients who had been treated outside GHSG studies. Among the 33 GHSG patients, 21 patients presented with a typical growth pattern at initial diagnosis, whereas 12 patients had a variant histology. The histopathological growth patterns at initial diagnosis and at relapse were consistent in 67% of cases. A variant histology at initial diagnosis was associated with a shorter median time to lymphoma recurrence (2.8 vs 5.2 years; P = .0219). A similar tendency towards a shorter median time to lymphoma recurrence was observed for patients presenting with a variant histology at relapse, irrespective of the growth pattern at initial diagnosis. Results obtained from the 41 NLPHL patients who had been treated outside GHSG studies were comparable (median time to lymphoma recurrence for variant histology vs typical growth pattern at initial diagnosis: 1.5 vs 7.0 years). In conclusion, the histopathological growth pattern remains consistent at relapse in the majority of NLPHL cases, and has major impact on the time of relapse.
Nonalcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein-Barr virus-induced G protein-coupled receptor 2 (EBI2) and its oxysterol ligand 7 alpha,25-dihydroxycholesterol (7 alpha,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in the livers of NASH patients by LC-MS and tested the role of the EBI2-7 alpha,25-diHC system in a murine feeding model of NASH. Free oxysterol profiling in livers from NASH patients revealed a pronounced increase in 24- and 7-hydroxylated oxysterols in NASH compared with controls. Levels of 24- and 7-hydroxylated oxysterols correlated with histological NASH activity. Histological analysis of murine liver samples demonstrated ballooning and liver inflammation. No significant genotype-related differences were observed in Ebi2(-/-) mice and mice with defects in the 7 alpha,25-diHC synthesizing enzymes CH25H and CYP7B1 compared with wild-type littermate controls, arguing against an essential role of these genes in NASH pathogenesis. Elevated 24- and 7-hydroxylated oxysterol levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by the enhanced level of 7 alpha-hydroxycholest-4-en-3-one and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH.
Understanding the mechanisms of early invasion and epithelial defense in opportunistic mold infections is crucial for the evaluation of diagnostic biomarkers and novel treatment strategies. Recent studies revealed unique characteristics of the immunopathology of mucormycoses. We therefore adapted an alveolar Transwell® A549/HPAEC bilayer model for the assessment of epithelial barrier integrity and cytokine response to Rhizopus arrhizus, Rhizomucor pusillus, and Cunninghamella bertholletiae. Hyphal penetration of the alveolar barrier was validated by 18S ribosomal DNA detection in the endothelial compartment. Addition of dendritic cells (moDCs) to the alveolar compartment led to reduced fungal invasion and strongly enhanced pro-inflammatory cytokine response, whereas epithelial CCL2 and CCL5 release was reduced. Despite their phenotypic heterogeneity, the studied Mucorales species elicited the release of similar cytokine patterns by epithelial and dendritic cells. There were significantly elevated lactate dehydrogenase concentrations in the alveolar compartment and epithelial barrier permeability for dextran blue of different molecular weights in Mucorales-infected samples compared to Aspergillus fumigatus infection. Addition of monocyte-derived dendritic cells further aggravated LDH release and epithelial barrier permeability, highlighting the influence of the inflammatory response in mucormycosis-associated tissue damage. An important focus of this study was the evaluation of the reproducibility of readout parameters in independent experimental runs. Our results revealed consistently low coefficients of variation for cytokine concentrations and transcriptional levels of cytokine genes and cell integrity markers. As additional means of model validation, we confirmed that our bilayer model captures key principles of Mucorales biology such as accelerated growth in a hyperglycemic or ketoacidotic environment or reduced epithelial barrier invasion upon epithelial growth factor receptor blockade by gefitinib. Our findings indicate that the Transwell® bilayer model provides a reliable and reproducible tool for assessing host response in mucormycosis.
Translation efficiency can be affected by mRNA stability and secondary structures, including G-quadruplex structures (G4s). The highly conserved DEAH-box helicase DHX36/RHAU resolves G4s on DNA and RNA in vitro, however a systems-wide analysis of DHX36 targets and function is lacking. We map globally DHX36 binding to RNA in human cell lines and find it preferentially interacting with G-rich and G4-forming sequences on more than 4500 mRNAs. While DHX36 knockout (KO) results in a significant increase in target mRNA abundance, ribosome occupancy and protein output from these targets decrease, suggesting that they were rendered translationally incompetent. Considering that DHX36 targets, harboring G4s, preferentially localize in stress granules, and that DHX36 KO results in increased SG formation and protein kinase R (PKR/EIF2AK2) phosphorylation, we speculate that DHX36 is involved in resolution of rG4 induced cellular stress.
Animals, just like humans, can freely move. They do so for various important reasons, such as finding food and escaping predators. Observing these behaviors can inform us about the underlying cognitive processes. In addition, while humans can convey complicated information easily through speaking, animals need to move their bodies to communicate. This has prompted many creative solutions by animal neuroscientists to enable studying the brain during movement. In this review, we first summarize how animal researchers record from the brain while an animal is moving, by describing the most common neural recording techniques in animals and how they were adapted to record during movement. We further discuss the challenge of controlling or monitoring sensory input during free movement.
However, not only is free movement a necessity to reflect the outcome of certain internal cognitive processes in animals, it is also a fascinating field of research since certain crucial behavioral patterns can only be observed and studied during free movement. Therefore, in a second part of the review, we focus on some key findings in animal research that specifically address the interaction between free movement and brain activity. First, focusing on walking as a fundamental form of free movement, we discuss how important such intentional movements are for understanding processes as diverse as spatial navigation, active sensing, and complex motor planning. Second, we propose the idea of regarding free movement as the expression of a behavioral state. This view can help to understand the general influence of movement on brain function.
Together, the technological advancements towards recording from the brain during movement, and the scientific questions asked about the brain engaged in movement, make animal research highly valuable to research into the human “moving brain”.
Hepatic activation of protein kinase C (PKC) isoforms by diacylglycerol (DAG) promotes insulin resistance and contributes to the development of type 2 diabetes (T2D). The closely related protein kinase D (PKD) isoforms act as effectors for DAG and PKC. Here, we showed that PKD3 was the predominant PKD isoform expressed in hepatocytes and was activated by lipid overload. PKD3 suppressed the activity of downstream insulin effectors including the kinase AKT and mechanistic target of rapamycin complex 1 and 2 (mTORC1 and mTORC2). Hepatic deletion of PKD3 in mice improved insulin-induced glucose tolerance. However, increased insulin signaling in the absence of PKD3 promoted lipogenesis mediated by SREBP (sterol regulatory element-binding protein) and consequently increased triglyceride and cholesterol content in the livers of PKD3-deficient mice fed a high-fat diet. Conversely, hepatic-specific overexpression of a constitutively active PKD3 mutant suppressed insulin-induced signaling and caused insulin resistance. Our results indicate that PKD3 provides feedback on hepatic lipid production and suppresses insulin signaling. Therefore, manipulation of PKD3 activity could be used to decrease hepatic lipid content or improve hepatic insulin sensitivity.
Background
To evaluate optimal therapy and potential risk factors.
Methods
Data of DSRCT patients <40 years treated in prospective CWS trials 1997-2015 were analyzed.
Results
Median age of 60 patients was 14.5 years. Male:female ratio was 4:1. Tumors were abdominal/retroperitoneal in 56/60 (93%). 6/60 (10%) presented with a localized mass, 16/60 (27%) regionally disseminated nodes, and 38/60 (63%) with extraperitoneal metastases. At diagnosis, 23/60 (38%) patients had effusions, 4/60 (7%) a thrombosis, and 37/54 (69%) elevated CRP. 40/60 (67%) patients underwent tumor resection, 21/60 (35%) macroscopically complete. 37/60 (62%) received chemotherapy according to CEVAIE (ifosfamide, vincristine, actinomycin D, carboplatin, epirubicin, etoposide), 15/60 (25%) VAIA (ifosfamide, vincristine, adriamycin, actinomycin D) and, 5/60 (8%) P6 (cyclophosphamide, doxorubicin, vincristine, ifosfamide, etoposide). Nine received high-dose chemotherapy, 6 received regional hyperthermia, and 20 received radiotherapy. Among 25 patients achieving complete remission, 18 (72%) received metronomic therapies. Three-year event-free (EFS) and overall survival (OS) were 11% (±8 confidence interval [CI] 95%) and 30% (±12 CI 95%), respectively, for all patients and 26.7% (±18.0 CI 95%) and 56.9% (±20.4 CI 95%) for 25 patients achieving remission. Extra-abdominal site, localized disease, no effusion or ascites only, absence of thrombosis, normal CRP, complete tumor resection, and chemotherapy with VAIA correlated with EFS in univariate analysis. In multivariate analysis, significant factors were no thrombosis and chemotherapy with VAIA. In patients achieving complete remission, metronomic therapy with cyclophosphamide/vinblastine correlated with prolonged time to relapse.
Conclusion
Pleural effusions, venous thrombosis, and CRP elevation were identified as potential risk factors. The VAIA scheme showed best outcome. Maintenance therapy should be investigated further.
Aim: European temperate forests have lost dead wood and the associated biodiversity owing to intensive management over centuries. Nowadays, some of these forests are being restored by enrichment with dead wood, but mostly only at stand scales. Here, we investigated effects of a seminal dead-wood enrichment strategy on saproxylic organisms at the landscape scale.
Location: Temperate European beech forest in southern Germany.
Methods: In a before-after control-impact design, we compared assemblages and gamma diversities of saproxylic organisms in strictly protected old-growth forest areas (reserves) and historically moderately and intensively managed forest areas before and a decade after starting a landscape-wide strategy of dead-wood enrichment.
Results: Before enrichment with dead wood, the gamma diversity of saproxylic organisms in historically intensively managed forest stands was significantly lower than in reserves and historically moderately managed forest stands; this difference disappeared after 10 years of dead-wood enrichment. The species composition of beetles in forest stands of the three historical management intensities differed before the enrichment strategy, but a decade thereafter, the species compositions of previously intensively logged and forest reserve plots were similar. However, the differences in fungal species composition between historical management categories before and after 10 years of enrichment persisted.
Main conclusions: Our results demonstrate that intentional enrichment of dead wood at the landscape scale is a powerful tool for rapidly restoring saproxylic beetle communities and for restoring wood-inhabiting fungal communities, which need longer than a decade for complete restoration. We propose that a strategy of area-wide active restoration combined with some permanent strict refuges is a promising means of promoting the biodiversity of age-long intensively managed Central European beech forests.
Kinesins play an important role in many physiological functions including intracellular vesicle transport and mitosis. The emerging role of kinesins in different cancers led us to investigate the expression and functional role of kinesins in meningioma. Therefore, we re-analyzed our previous microarray dataset of benign, atypical, and anaplastic meningiomas (n = 62) and got evidence for differential expression of five kinesins (KIFC1, KIF4A, KIF11, KIF14 and KIF20A). Further validation in an extended study sample (n = 208) revealed a significant upregulation of these genes in WHO°I to °III meningiomas (WHO°I n = 61, WHO°II n = 88, and WHO°III n = 59), which was most pronounced in clinically more aggressive tumors of the same WHO grade. Immunohistochemical staining confirmed a WHO grade-associated upregulated protein expression in meningioma tissues. Furthermore, high mRNA expression levels of KIFC1, KIF11, KIF14 and KIF20A were associated with shorter progression-free survival. On a functional level, knockdown of kinesins in Ben-Men-1 cells and in the newly established anaplastic meningioma cell line NCH93 resulted in a significantly inhibited tumor cell proliferation upon siRNA-mediated downregulation of KIF11 in both cell lines by up to 95% and 71%, respectively. Taken together, in this study we were able to identify the prognostic and functional role of several kinesin family members of which KIF11 exhibits the most promising properties as a novel prognostic marker and therapeutic target, which may offer new treatment options for aggressive meningiomas.
The functional role of the respiratory epithelium is to generate a physical barrier. In addition, the epithelium supports the innate and acquired immune system through various cytokines and chemokines. However, epithelial cells are also involved in the pathogenesis of various respiratory diseases, some of which are mediated by increased permeability of the mucosal membrane or disturbed mucociliary transport. In addition, it has been shown that epithelial cells are involved in the development of inflammatory respiratory diseases. The following review article focuses on the aspects of epithelial mis-differentiation, in particular with respect to nasal mucosal barrier function, epithelial immunogenicity, nasal epithelial-mesenchymal transition and nasal microbiome.
Combining Distributed Consensus with Robust H-infinity-Control for Satellite Formation Flying
(2019)
Control methods that guarantee stability in the presence of uncertainties are mandatory in space applications. Further, distributed control approaches are beneficial in terms of scalability and to achieve common goals, especially in multi-agent setups like formation control. This paper presents a combination of robust H-infinity control and distributed control using the consensus approach by deriving a distributed consensus-based generalized plant description that can be used in H-infinity synthesis. Special focus was set towards space applications, namely satellite formation flying. The presented results show the applicability of the developed distributed robust control method to a simple, though realistic space scenario, namely a spaceborne distributed telescope. By using this approach, an arbitrary number of satellites/agents can be controlled towards an arbitrary formation geometry. Because of the combination with robust H-infinity control, the presented method satisfies the high stability and robustness demands as found e.g., in space applications.
Der vorliegende Beitrag beschreibt die praxis- und theorieorientierte Entwicklung und Evaluation eines medienpädagogischen Unterrichtskonzepts für die Sekundarstufe I zur Förderung der Medienkritikfähigkeit im Kontext zeitgenössischer Propaganda. Auf der Basis einer Analyse theoretischer und empirischer Grundlagen zum Propagandabegriff und zur Medienkritikfähigkeit und unter besonderer Berücksichtigung des Ansatzes einer handlungs- und entwicklungsorientierten Didaktik wird ein medienpädagogisches Unterrichtskonzept entwickelt. Ausgehend von einem weitgefassten Propagandabegriff sind im Rahmen des Unterrichtskonzepts der Vergleich und die kritische Beurteilung unterschiedlicher Formen aktueller und historischer Propaganda sowie die Gestaltung eigener Medienbeiträge in Form von „Counter Narratives“ bedeutsame Vorgehensweisen. Die quasi-experimentelle Evaluation des Unterrichtskonzepts in der Sekundarstufe I eines Gymnasiums ist als „mixed-methods-design“ konzipiert und bestätigt die Wirksamkeit der Intervention in Bezug auf die Förderung der Medienkritikfähigkeit.
Chimeric Antigen Receptor Library Screening Using a Novel NF-kappa B/NFAT Reporter Cell Platform
(2019)
Chimeric antigen receptor (CAR)-T cell immunotherapy is under intense preclinical and clinical investigation, and it involves a rapidly increasing portfolio of novel target antigens and CAR designs. We established a platform that enables rapid and high-throughput CAR-screening campaigns with reporter cells derived from the T cell lymphoma line Jurkat. Reporter cells were equipped with nuclear factor kappa B (NF kappa B) and nuclear factor of activated T cells (NFAT) reporter genes that generate a duplex output of enhanced CFP (ECFP) and EGFP, respectively. As a proof of concept, we modified reporter cells with CD19-specific and ROR1-specific CARs, and we detected high-level reporter signals that allowed distinguishing functional from non-functional CAR constructs. The reporter data were highly reproducible, and the time required for completing each testing campaign was substantially shorter with reporter cells (6 days) compared to primary CAR-T cells (21 days). We challenged the reporter platform to a large-scale screening campaign on a ROR1-CAR library, and we showed that reporter cells retrieved a functional CAR variant that was present with a frequency of only 6 in 1.05 x 10(6). The data illustrate the potential to implement this reporter platform into the preclinical development path of novel CAR-T cell products and to inform and accelerate the selection of lead CAR candidates for clinical translation.
Bulb, leaf, scape and flower samples of British bluebells (Hyacinthoides non-scripta) were collected regularly for one growth period. Methanolic extracts of freeze-dried and ground samples showed antitrypanosomal activity, giving more than 50% inhibition, for 20 out of 41 samples. High-resolution mass spectrometry was used in the dereplication of the methanolic extracts of the different plant parts. The results revealed differences in the chemical profile with bulb samples being distinctly different from all aerial parts. High molecular weight metabolites were more abundant in the flowers, shoots and leaves compared to smaller molecular weight ones in the bulbs. The anti-trypanosomal activity of the extracts was linked to the accumulation of high molecular weight compounds, which were matched with saponin glycosides, while triterpenoids and steroids occurred in the inactive extracts. Dereplication studies were employed to identify the significant metabolites via chemotaxonomic filtration and considering their previously reported bioactivities. Molecular networking was implemented to look for similarities in fragmentation patterns between the isolated saponin glycoside at m/z 1445.64 [M + formic-H](-) equivalent to C64H104O33 and the putatively found active metabolite at m/z 1283.58 [M + formic-H](-) corresponding to scillanoside L-1. A combination of metabolomics and bioactivity-guided approaches resulted in the isolation of a norlanostane-type saponin glycoside with antitrypanosoma I activity of 98.9% inhibition at 20 mu M.
Deregulation of the HECT-type ubiquitin ligase E6AP (UBE3A) is implicated in human papilloma virus-induced cervical tumorigenesis and several neurodevelopmental disorders. Yet the structural underpinnings of activity and specificity in this crucial ligase are incompletely understood. Here, we unravel the determinants of ubiquitin recognition by the catalytic domain of E6AP and assign them to particular steps in the catalytic cycle. We identify a functionally critical interface that is specifically required during the initial formation of a thioester-linked intermediate between the C terminus of ubiquitin and the ligase-active site. This interface resembles the one utilized by NEDD4-type enzymes, indicating that it is widely conserved across HECT ligases, independent of their linkage specificities. Moreover, we uncover surface regions in ubiquitin and E6AP, both in the N- and C-terminal portions of the catalytic domain, that are important for the subsequent reaction step of isopeptide bond formation between two ubiquitin molecules. We decipher key elements of linkage specificity, including the C-terminal tail of E6AP and a hydrophilic surface region of ubiquitin in proximity to the acceptor site Lys-48. Intriguingly, mutation of Glu-51, a single residue within this region, permits formation of alternative chain types, thus pointing to a key role of ubiquitin in conferring linkage specificity to E6AP. We speculate that substrate-assisted catalysis, as described previously for certain RING-associated ubiquitin-conjugating enzymes, constitutes a common principle during linkage-specific ubiquitin chain assembly by diverse classes of ubiquitination enzymes, including HECT ligases.
Graft-versus-host disease (GVHD) is a major cause of transplant-related mortality (TRM) after allogeneic haematopoietic stem cell transplantation (HSCT) and presents a challenge in haploidentical HSCT. GVHD may be prevented by ex vivo graft T-cell depletion or in vivo depletion of proliferating lymphocytes. However, both approaches pose significant risks, particularly infections and relapse, compromising survival. A photodepletion strategy to eliminate alloreactive T cells from mismatched donor lymphocyte infusions (enabling administration without immunosuppression), was used to develop ATIR101, an adjunctive therapy for use after haploidentical HSCT. In this phase I dose-finding study, 19 adults (median age: 54 years) with high-risk haematological malignancies were treated with T-cell-depleted human leucocyte antigen-haploidentical myeloablative HSCT followed by ATIR101 at doses of 1 x 10(4)-5 x 10(6) CD3(+) cells/kg (median 31 days post-transplant). No patient received post-transplant immunosuppression or developed grade III/IV acute GVHD, demonstrating the feasibility of ATIR101 infusion for evaluation in two subsequent phase 2 studies. Additionally, we report long-term follow -up of patients treated with ATIR101 in this study. At 1 year, all 9 patients receiving doses of 0 center dot 3-2 x 10(6) CD3(+) cells/kg ATIR101 remained free of serious infections and after more than 8 years, TRM was 0%, relapse-related mortality was 33% and overall survival was 67% in these patients.
Previous magnetic resonance imaging (MRI) studies revealed structural-functional brain reorganization 12 months after gastric-bypass surgery, encompassing cortical and subcortical regions of all brain lobes as well as the cerebellum. Changes in the mean of cluster-wise gray/white matter density (GMD/WMD) were correlated with the individual loss of body mass index (BMI), rendering the BMI a potential marker of widespread surgery-induced brain plasticity. Here, we investigated voxel-by-voxel associations between surgery-induced changes in adiposity, metabolism and inflammation and markers of functional and structural neural plasticity. We re-visited the data of patients who underwent functional and structural MRI, 6 months (n = 27) and 12 months after surgery (n = 22), and computed voxel-wise regression analyses. Only the surgery-induced weight loss was significantly associated with brain plasticity, and this only for GMD changes. After 6 months, weight loss overlapped with altered GMD in the hypothalamus, the brain's homeostatic control site, the lateral orbitofrontal cortex, assumed to host reward and gustatory processes, as well as abdominal representations in somatosensory cortex. After 12 months, weight loss scaled with GMD changes in right cerebellar lobule VII, involved in language-related/cognitive processes, and, by trend, with the striatum, assumed to underpin (food) reward. These findings suggest time-dependent and weight-loss related gray matter plasticity in brain regions involved in the control of eating, sensory processing and cognitive functioning.
2D electrophysiology is often used to determine the electrical properties of neurons, while in the brain, neurons form extensive 3D networks. Thus, performing electrophysiology in a 3D environment provides a closer situation to the physiological condition and serves as a useful tool for various applications in the field of neuroscience. In this study, we established 3D electrophysiology within a fiber-reinforced matrix to enable fast readouts from transfected cells, which are often used as model systems for 2D electrophysiology. Using melt electrowriting (MEW) of scaffolds to reinforce Matrigel, we performed 3D electrophysiology on a glycine receptor-transfected Ltk-11 mouse fibroblast cell line. The glycine receptor is an inhibitory ion channel associated when mutated with impaired neuromotor behaviour. The average thickness of the MEW scaffold was 141.4 ± 5.7µm, using 9.7 ± 0.2µm diameter fibers, and square pore spacings of 100 µm, 200 µm and 400 µm. We demonstrate, for the first time, the electrophysiological characterization of glycine receptor-transfected cells with respect to agonist efficacy and potency in a 3D matrix. With the MEW scaffold reinforcement not interfering with the electrophysiology measurement, this approach can now be further adapted and developed for different kinds of neuronal cultures to study and understand pathological mechanisms under disease conditions.
Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r(g) approximate to 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We (h(SNP)(2)) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and estimated the variance in therapy outcomes that could be explained by common genetic variants learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h(SNP)(2) could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.
Aims
The aim of this study was to determine whether the Joint European Societies guidelines on secondary cardiovascular prevention are followed in everyday practice.
Design
A cross-sectional ESC-EORP survey (EUROASPIRE V) at 131 centres in 81 regions in 27 countries.
Methods
Patients (<80 years old) with verified coronary artery events or interventions were interviewed and examined ≥6 months later.
Results
A total of 8261 patients (females 26%) were interviewed. Nineteen per cent smoked and 55% of them were persistent smokers, 38% were obese (body mass index ≥30 kg/m2), 59% were centrally obese (waist circumference: men ≥102 cm; women ≥88 cm) while 66% were physically active <30 min 5 times/week. Forty-two per cent had a blood pressure ≥140/90 mmHg (≥140/85 if diabetic), 71% had low-density lipoprotein cholesterol ≥1.8 mmol/L (≥70 mg/dL) and 29% reported having diabetes. Cardioprotective medication was: anti-platelets 93%, beta-blockers 81%, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers 75% and statins 80%.
Conclusion
A large majority of coronary patients have unhealthy lifestyles in terms of smoking, diet and sedentary behaviour, which adversely impacts major cardiovascular risk factors. A majority did not achieve their blood pressure, low-density lipoprotein cholesterol and glucose targets. Cardiovascular prevention requires modern preventive cardiology programmes delivered by interdisciplinary teams of healthcare professionals addressing all aspects of lifestyle and risk factor management, in order to reduce the risk of recurrent cardiovascular events.
Background
The oral mucosa has an important role in maintaining barrier integrity at the gateway to the gastrointestinal and respiratory tracts. Smoking is a strong environmental risk factor for the common oral inflammatory disease periodontitis and oral cancer. Cigarette smoke affects gene methylation and expression in various tissues. This is the first epigenome-wide association study (EWAS) that aimed to identify biologically active methylation marks of the oral masticatory mucosa that are associated with smoking.
Results
Ex vivo biopsies of 18 current smokers and 21 never smokers were analysed with the Infinium Methylation EPICBeadChip and combined with whole transcriptome RNA sequencing (RNA-Seq; 16 mio reads per sample) of the same samples. We analysed the associations of CpG methylation values with cigarette smoking and smoke pack year (SPY) levels in an analysis of covariance (ANCOVA). Nine CpGs were significantly associated with smoking status, with three CpGs mapping to the genetic region of CYP1B1 (cytochrome P450 family 1 subfamily B member 1;best p=5.5x10(-8)) and two mapping to AHRR (aryl-hydrocarbon receptor repressor; best p=5.9x10(-9)). In the SPY analysis, 61 CpG sites at 52 loci showed significant associations of the quantity of smoking with changes in methylation values. Here, the most significant association located to the gene CYP1B1, with p=4.0x10(-10). RNA-Seq data showed significantly increased expression of CYP1B1 in smokers compared to non-smokers (p=2.2x10(-14)), together with 13 significantly upregulated transcripts. Six transcripts were significantly downregulated. No differential expression was observed for AHRR. In vitro studies with gingival fibroblasts showed that cigarette smoke extract directly upregulated the expression of CYP1B1.
Conclusion
This study validated the established role of CYP1B1 and AHRR in xenobiotic metabolism of tobacco smoke and highlights the importance of epigenetic regulation for these genes. For the first time, we give evidence of this role for the oral masticatory mucosa.
Osmotic stimulus or stress results in vasopressin release. Animal and human in vitro studies have shown that inflammatory parameters, such as interle ukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha), increase in parallel in the central nervous system and bronchial, corneal or intestinal epithelial cell lines in response to osmotic stimulus. Whether osmotic stimulus directly causes a systemic inflammatory response in humans is unknown. We therefore investigated the influence of osmotic stimulus on circulatory markers of systemic inflammation in healthy volunteers. In this prospective cohort study, 44 healthy volunteers underwent a standardized test protocol with an osmotic stimulus leading into the hyperosmotic/hypernatremic range (serum sodium >= 150 mmol/L) by hypertonic saline infusion. Copeptin - a marker indicating vasopressin activity - serum sodium and osmolality, plasma IL-8 and TNF-alpha were measured at baseline and directly after osmotic stimulus. Median (range) serum sodium increased from 141 mmol/L (136, 147) to 151 mmol/L (145, 154) (P < 0.01), serum osmolality increased from 295 mmol/L (281, 306) to 315 mmol/L (304, 325) (P < 0.01). Median (range) copeptin increased from 4.3 pg/L (1.1, 21.4) to 28.8 pg/L (19.9, 43.4) (P < 0.01). Median (range) IL-8 levels showed a trend to decrease from 0.79 pg/mL (0.37, 1.6) to 0.7 pg/mL (0.4, 1.9) (P < 0.09) and TNF-alpha levels decreased from 0.53 pg/mL (0.11, 1.1) to 0.45 pg/mL (0.1 2, 0.97) (P < 0.036). Contrary to data obtained in vitro, circulating proinflammatory cytokines tend to or decrease in human plasma after osmotic stimulus. In this study, osmotic stimulus does not increase circulating markers of systemic inflammation.
Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3
(2019)
The underlying genetic mechanisms and early pathological events of children with primary cardiomyopathy (CMP) are insufficiently characterized. In this study, we aimed to characterize the mutational spectrum of primary CMP in a large cohort of patients ≤18 years referred to a tertiary center. Eighty unrelated index patients with pediatric primary CMP underwent genetic testing with a panel‐based next‐generation sequencing approach of 89 genes. At least one pathogenic or probably pathogenic variant was identified in 30/80 (38%) index patients. In all CMP subgroups, patients carried most frequently variants of interest in sarcomere genes suggesting them as a major contributor in pediatric primary CMP. In MYH7, MYBPC3, and TNNI3, we identified 18 pathogenic/probably pathogenic variants (MYH7 n = 7, MYBPC3 n = 6, TNNI3 n = 5, including one homozygous (TNNI3 c.24+2T>A) truncating variant. Protein and transcript level analysis on heart biopsies from individuals with homozygous mutation of TNNI3 revealed that the TNNI3 protein is absent and associated with upregulation of the fetal isoform TNNI1. The present study further supports the clinical importance of sarcomeric mutation—not only in adult—but also in pediatric primary CMP. TNNI3 is the third most important disease gene in this cohort and complete loss of TNNI3 leads to severe pediatric CMP.
Invasive aspergillosis (IA) is a severe complication in immunocompromised patients. Early diagnosis is crucial to decrease its high mortality, yet the diagnostic gold standard (histopathology and culture) is time‐consuming and cannot offer early confirmation of IA. Detection of IA by polymerase chain reaction (PCR) shows promising potential. Various studies have analysed its diagnostic performance in different clinical settings, especially addressing optimal specimen selection. However, direct comparison of different types of specimens in individual patients though essential, is rarely reported. We systematically assessed the diagnostic performance of an Aspergillus‐specific nested PCR by investigating specimens from the site of infection and comparing it with concurrent blood samples in individual patients (pts) with IA. In a retrospective multicenter analysis PCR was performed on clinical specimens (n = 138) of immunocompromised high‐risk pts (n = 133) from the site of infection together with concurrent blood samples. 38 pts were classified as proven/probable, 67 as possible and 28 as no IA according to 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus definitions. A considerably superior performance of PCR from the site of infection was observed particularly in pts during antifungal prophylaxis (AFP)/antifungal therapy (AFT). Besides a specificity of 85%, sensitivity varied markedly in BAL (64%), CSF (100%), tissue samples (67%) as opposed to concurrent blood samples (8%). Our results further emphasise the need for investigating clinical samples from the site of infection in case of suspected IA to further establish or rule out the diagnosis.
Aberrant methylation of DNA is supposed to be a major and early driver of colonic adenoma development, which may result in colorectal cancer (CRC). Although gene methylation assays are used already for CRC screening, differential epigenetic alterations of recurring and nonrecurring colorectal adenomas have yet not been systematically investigated. Here, we collected a sample set of formalin‐fixed paraffin‐embedded colorectal low‐grade adenomas (n = 72) consisting of primary adenomas without and with recurrence (n = 59), recurrent adenomas (n = 10), and normal mucosa specimens (n = 3). We aimed to unveil differentially methylated CpG positions (DMPs) across the methylome comparing not only primary adenomas without recurrence vs primary adenomas with recurrence but also primary adenomas vs recurrent adenomas using the Illumina Human Methylation 450K BeadChip array. Unsupervised hierarchical clustering exhibited a significant association of methylation patterns with histological adenoma subtypes. No significant DMPs were identified comparing primary adenomas with and without recurrence. Despite that, a total of 5094 DMPs (false discovery rate <0.05; fold change >10%) were identified in the comparisons of recurrent adenomas vs primary adenomas with recurrence (674; 98% hypermethylated), recurrent adenomas vs primary adenomas with and without recurrence (241; 99% hypermethylated) and colorectal adenomas vs normal mucosa (4179; 46% hypermethylated). DMPs in cytosine‐phosphate‐guanine (CpG) islands were frequently hypermethylated, whereas open sea‐ and shelf‐regions exhibited hypomethylation. Gene ontology analysis revealed enrichment of genes associated with the immune system, inflammatory processes, and cancer pathways. In conclusion, our methylation data could assist in establishing a more robust and reproducible histological adenoma classification, which is a prerequisite for improving surveillance guidelines.
The synthetic compound dendritic polyglycerol sulfate (dPGS) is a pleiotropic acting molecule but shows a high binding affinity to immunological active molecules as L‐/P‐selectin or complement proteins leading to well described anti‐inflammatory properties in various mouse models. In order to make a comprehensive evaluation of the direct effect on the innate immune system, macrophage polarization is analyzed in the presence of dPGS on a phenotypic but also metabolic level. dPGS administered macrophages show a significant increase of MCP1 production paralleled by a reduction of IL‐10 secretion. Metabolic analysis reveals that dPGS could potently enhance the glycolysis and mitochondrial respiration in M0 macrophages as well as decrease the mitochondrial respiration of M2 macrophages. In summary the data indicate that dPGS polarizes macrophages into a pro‐inflammatory phenotype in a metabolic pathway‐dependent manner.
Aims
Volume overload (VO) and pressure overload (PO) induce differential cardiac remodelling responses including distinct signalling pathways. Extracellular signal‐regulated kinases 1 and 2 (ERK1/2), key signalling components in the mitogen‐activated protein kinase (MAPK) pathways, modulate cardiac remodelling during pressure overload (PO). This study aimed to assess their role in VO‐induced cardiac remodelling as this was unknown.
Methods and results
Aortocaval fistula (Shunt) surgery was performed in mice to induce cardiac VO. Two weeks of Shunt caused a significant reduction of cardiac ERK1/2 activation in wild type (WT) mice as indicated by decreased phosphorylation of the TEY (Thr‐Glu‐Tyr) motif (−28% as compared with Sham controls, P < 0.05). Phosphorylation of other MAPKs was unaffected. For further assessment, transgenic mice with cardiomyocyte‐specific ERK2 overexpression (ERK2tg) were studied. At baseline, cardiac ERK1/2 phosphorylation in ERK2tg mice remained unchanged compared with WT littermates, and no overt cardiac phenotype was observed; however, cardiac expression of the atrial natriuretic peptide was increased on messenger RNA (3.6‐fold, P < 0.05) and protein level (3.1‐fold, P < 0.05). Following Shunt, left ventricular dilation and hypertrophy were similar in ERK2tg mice and WT littermates. Left ventricular function was maintained, and changes in gene expression indicated reactivation of the foetal gene program in both genotypes. No differences in cardiac fibrosis and kinase activation was found amongst all experimental groups, whereas apoptosis was similarly increased through Shunt in ERK2tg and WT mice.
Conclusions
VO‐induced eccentric hypertrophy is associated with reduced cardiac ERK1/2 activation in vivo. Cardiomyocyte‐specific overexpression of ERK2, however, does not alter cardiac remodelling during VO. Future studies need to define the pathophysiological relevance of decreased ERK1/2 signalling during VO.
Background
Deep brain stimulation (DBS) is an effective evidence‐based therapy for dystonia. However, no unequivocal predictors of therapy responses exist. We investigated whether patients optimally responding to DBS present distinct brain network organization and structural patterns.
Methods
From a German multicenter cohort of 82 dystonia patients with segmental and generalized dystonia who received DBS implantation in the globus pallidus internus, we classified patients based on the clinical response 3 years after DBS. Patients were assigned to the superior‐outcome group or moderate‐outcome group, depending on whether they had above or below 70% motor improvement, respectively. Fifty‐one patients met MRI‐quality and treatment response requirements (mean age, 51.3 ± 13.2 years; 25 female) and were included in further analysis. From preoperative MRI we assessed cortical thickness and structural covariance, which were then fed into network analysis using graph theory. We designed a support vector machine to classify subjects for the clinical response based on individual gray‐matter fingerprints.
Results
The moderate‐outcome group showed cortical atrophy mainly in the sensorimotor and visuomotor areas and disturbed network topology in these regions. The structural integrity of the cortical mantle explained about 45% of the DBS stimulation amplitude for optimal response in individual subjects. Classification analyses achieved up to 88% of accuracy using individual gray‐matter atrophy patterns to predict DBS outcomes.
Conclusions
The analysis of cortical integrity, informed by group‐level network properties, could be developed into independent predictors to identify dystonia patients who benefit from DBS.
Das Forschungsgebiet der Perowskit‐Halbleiter entwickelt sich rasant. Ein Vorteil besteht darin, dass sich damit Solarzellen und optoelektronische Bauelemente von der Fotodiode bis zum Laser einfach aus einer Lösung herstellen lassen. Damit ist zum Beispiel die Herstellung durch Drucken einer „Solarzellentinte“ möglich. Der geringe Energiebedarf durch niedrige Prozesstemperaturen verkürzt zudem die Energierückgewinnungszeit drastisch im Vergleich zu konventionellen Solarzellen. Obwohl noch eine junge Technologie, erreichen Perowskit‐Solarzellen bereits heute Wirkungsgrade bis etwa 25 % und sind damit auf Augenhöhe mit konventionellen Dünnschichttechnologien. Ein weiterer Vorteil besteht darin, dass sich die Bandlücke durch chemische Modifikation einfach an Anwendungen anpassen lässt. Zu den Herausforderungen der Forschung zählen noch die geringe Lebensdauer und chemische Langzeitstabilität sowie die Suche nach ungiftigen Ersatzstoffen für das Blei. Kommerzielle Anwendungen sind bereits absehbar.
The detection of toxic gases, such as NH\(_{3}\) and CO, in the environment is of high interest in chemical, electronic, and automotive industry as even small amounts can display a health risk for workers. Sensors for the real‐time monitoring of these gases should be simple, robust, reversible, highly sensitive, inexpensive and show a fast response. The indicator supraparticles presented herein can fulfill all of these requirements. They consist of silica nanoparticles, which are assembled to supraparticles upon spray‐drying. Sensing molecules such as Reichardt's dye and a binuclear rhodium complex are loaded onto the microparticles to target NH\(_{3}\) and CO detection, respectively. The spray‐drying technique affords high flexibility in primary nanoparticle size selection and thus, easy adjustment of the porosity and specific surface area of the obtained micrometer‐sized supraparticles. This ultimately enables the fine‐tuning of the sensor sensitivity and response. For the application of the indicator supraparticles in a gas detection device, they can be immobilized on a coating. Due to their microscale size, they are large enough to poke out of thin coating layers, thus guaranteeing their gas accessibility, while being small enough to be applicable to flexible substrates.
Hierin wird die inhärente geometrische Isomerie eines PtII Komplexes als neues Werkzeug zur Kontrolle von supramolekularen Assemblierungsprozessen ausgenutzt. Bestrahlung mit UV‐Licht sowie die sorgfältige Auswahl des verwendeten Lösungsmittels, der Temperatur und Konzentration führen zu einer regelbaren Koordinationsisomerie. Dies ermöglicht ein vollständig reversibles Schalten zwischen zwei definierten aggregierten Spezies (1D Fasern ↔ 2D Lamellen) mit unterschiedlichem photoresponsivem Verhalten. Unsere Erkenntnisse erweitern nicht nur die Reichweite von Koordinationsisomerie, sondern eröffnen auch aufregende Möglichkeiten zur Entwicklung neuartiger stimuliresponsiver Materialien.
This article exemplifies Gunter Grimm’s concept of productive reception by analyzing César Fernández García’s young adult novel La última bruja de Trasmoz (2009) and the episode Tiempo de hechizos (2017) of the TV series El ministerio del tiempo as two modern works which artistically and creatively deal with Gustavo Adolfo Bécquer’s Cartas desde mi celda (1864). The study is based on the core assumption that the choice of genre greatly influences the treatment of motives such as the perception of nature and the idea of dreams, as well as the image of the witch. While Bécquer’s letters, which focus on the rural people’s superstition, present the witch of Aragonese folklore, the modern examples portray two of her fantastic counterparts: the novel depicts its magical protagonist as an evil supernatural being, whereas the TV episode of the science fiction series shows the witch as a time traveller and a victim.
When it comes to linguistic norms in France, one standard will be immediately evoked – le bon usage. This version of traditional French is taught at school and has been serving as a model ever since the French Revolution. Yet – and maybe as a counter-reaction to such strict and prescriptive norm – there exists a multitude of alternative forms, especially with regard to the lexis, which are marked by different registers or styles. Thus, the French language is characterized by lexical doublets in the transition area between standard and familier. A varied terminology in the description of styles in dictionaries as well as a stigmatisation of the nonstandard lead to speaker insecurities and to a general devaluation of the parallel vocabulary. What are the consequences of this in speech behaviour? Is there a remarkable difference between speech behaviour and prescriptive norm? Do speakers show any sign of linguistic insecurity when using nonstandard structures? The research issue will be addressed by means of a qualitative analysis of videoblogs from French YouTubers.
This article is dedicated to the analysis of the body, which is staged as sick and painful. El último cuerpo de Úrsula by Peruvian author Patricia de Souza is characterized by the connection between body, pain perception and eroticism. Illness and paralysis play a fundamental role in the narrative because they cause the recomposition of the ego, which leads the protagonist, Úrsula Res, to perceive and reflect the fragmentation of her identity and the increasing distance from her body. Through approaches to pain and disability, the expressiveness of the narrativized eroticism of this text, based on an obedient relationship to the body, is revealed.
This article focuses on selected Latin American female rap artists (Anita Tijoux, Rebeca Lane, and the duo Krudas Cubensi), and the way they perform feminism, autobiography and testimony through their lyrics and performances. The analysis concentrates on the synergies between the texts themselves, the official music videos shared on YouTube and the background music. It aims to demonstrate that only such a synergistic approach to rap allows a profound understanding of its particularities and its contributions to feminist discourses and spaces for feminist testimony in the current rise of both right-wing politics and feminist movements on the continent.
This article explores the construction of Catalan masculinity and Catalan identity in literature on the Spanish-Moroccan War of 1859/60. During the war, an immense amount of patriotic literature in Catalan language was published in Catalonia, in which the authors glorified the deeds of the Catalan general Joan Prim i Prats and of the Catalan volunteers who fought in the war. The article aims to illustrate, on the basis of the analysis of poems, theatre plays, patriotic songs, reports and chronicles written by Catalan authors, the importance of the First Spanish-Moroccan War for the development of Catalan identity. It attempts as well to demonstrate that the authors used the literature about the war to diffuse a specific Catalan ideal of masculinity and to stylize General Prim and the volunteers into national heroes, who embodied the strength of the Catalan cultural nation, since the Catalan community needed new idols after a long time of political and cultural decline caused by the centralist policies of the Spanish state. The Catalan ideal of masculinity was utilized to differentiate the Catalans from the other Spaniards whose masculinity was considered to be in decadence by the other European nations.
This contribution deals with the phonetic heterogeneity of spoken Spanish in Andalusia in the sector of public auditory media, specifically in the program ¡Anda Levanta! of Canal Fiesta Radio. First, we take into consideration Article 10 of the Statute of the Autonomy of Andalusia, which enhances the protection, promotion, study, and prestige of the Andalusian modalities and its respective variety (cf. Parlamento de Andalucía 2007: 13). Second, we refer to the Libro de Estilo, a mandatory guide for presenters of public audiovisual media in Andalusia since 2014. The results of the qualitative analysis indicate divergences between the presenters and their audience with regard to their use of phonetic characteristics typical of the Andalusian varieties: where the presenters tend to avoid the salient aspects of the varieties, the audience employs a range of phonetic characteristics typical for Andalusian varieties, including some of the characteristics that are considered less prestigious.
Investigations focusing on the social criticism in La Regenta (1884-1885) by Leopoldo Alas «Clarín» have constantly referred to the unmasking of society’s hypocrisy and provincialism through the implementation of satire and irony in the novel. This observation, though, has to be defined more clearly. Vetustan society, specifically the bourgeoisie, is characterized primarily by the incessant exhibition of supposed wisdom and intelligentsia in public to generate social prestige and power. By analyzing the narrative strategies which are related to the composition of the secondary characters, the role of two specific public venues (Casino and Theatre of Vetusta) and the (de)construction of P. Ronzal, P. Guimarán and S. Bermúdez in the novel, this article illustrates how false wisdom and pseudo-intelligentsia become central motifs regarding social criticism in La Regenta.
Die Zeitschrift promptus – Würzburger Beiträge zur Romanistik richtet sich an alle NachwuchswissenschaftlerInnen im Bereich der romanistischen Sprach- und Literaturwissenschaft sowie der Fachdidaktik. Das Ziel der Zeitschrift ist die Förderung der romanistischen Forschung im Allgemeinen und des wissenschaftlichen Nachwuchses der Romanistik im Besonderen. Sie versteht sich damit als Impulsgeber für junge romanistische Forschung, ohne sich dabei thematisch zu beschränken.
The electron‐precise binary boron subhalide species [B\(_2\)X\(_6\)]\(^{2−}\) X=F, Br, I) were synthesized and their structures confirmed by X‐ray crystallography. The existence of the previously claimed [B\(_2\)Cl\(_6\)]\(^{2−}\), which had been questioned, was also confirmed by X‐ray crystallography. The dianions are isoelectronic to hexahaloethanes, are subhalide analogues of the well‐known tetrahaloborate anions (BX\(_4\)\(^−\)), and are rare examples of molecular electron‐precise binary boron species beyond B\(_2\)X\(_4\), BX\(_3\), and [BX\(_4\)]\(^−\).
Die elektronenpräzisen binären Borsubhalogenide [B\(_2\)X\(_6\)]\(^{2−}\) (X=F, Br, I) wurden synthetisiert und strukturell im Festkörper untersucht. Zudem konnte die vermutete Existenz von [B\(_2\)Cl\(_6\)]\(^{2−}\) mittels Röntgendiffraktometrie nachgewiesen werden. Diese Dianionen sind isoelektronisch zu den Hexahalogeniden des Ethans und können als Homologe des Tetrahalogenborat‐Anions BX\(_4\)\(^−\) betrachtet werden. Darüber hinaus gehören sie zu den seltenen Beispielen von elektronenpräzisen binären Borverbindungen (B\(_2\)X\(_4\), BX\(_3\), [BX\(_4\)]\(^−\)).
Detaillierte Einblicke in die Struktur von mit Wirkstoffen beladenen Polymermizellen sind rar, aber wichtig um gezielt optimierte Transportsysteme entwickeln zu können. Wir konnten beobachten, dass eine Erhöhung der Curcumin‐Beladung von Triblockcopolymeren auf Basis von Poly(2‐oxazolinen) und Poly(2‐oxazinen) schlechtere Auflösungseigenschaften nach sich zieht. Mitthilfe von Festkörper‐NMR‐Spektroskopie und komplementären Techniken ist es möglich, ein ladungsabhängiges Strukturmodell auf molekularer Ebene zu erstellen, das eine Erklärung für die beobachteten Unterschiede liefert. Dabei belegen die Änderungen der chemischen Verschiebungen und Kreuzsignale in 2D‐NMR‐Experimenten die Beteiligung des hydrophoben Polymerblocks an der Koordination der Curcumin‐Moleküle, während bei höherer Beladung auch eine zunehmende Wechselwirkung mit dem hydrophilen Polymerblock beobachtet wird. Letztere könnte elementar für die Stabilisierung von ultrahochbeladenen Polymermizellen sowie das Design von verbesserten Wirkstofftransportsystemen sein.
Eine effiziente, einstufige Synthese von 1,1,1‐Trialkylalkanen durch die sequenzielle, dehydrierende Borylierung und zweifache Hydroborierung von terminalen Alkinen mit Pinakolboran (HBpin) wurde unter Verwendung des kostengünstigen und einfach zugänglichen Kupfersalzes Cu(OAc)2 als Katalysator realisiert. Das Verfahren zeichnet sich durch ein breites Substratspektrum, eine außerordentliche Selektivität und eine hohe Toleranz gegenüber funktionellen Gruppen aus. Zudem kann die Reaktion ohne Ausbeuteverlust im Gramm‐Maßstab durchgeführt werden. Die somit erhaltenen 1,1,1‐Trialkylalkane können Anwendungen in der Herstellung von synthetisch wertvollen und bislang schwer zugänglichen α‐Vinylboronaten und zyklischen Boryl‐Verbindungen finden. Verschiedene Alkylgruppen können stufenweise über eine basenvermittelte deborylierende Alkylierung eingeführt werden, um racemische, tertiäre Alkylboronate herzustellen, die einfach in nützliche tertiäre Alkohole umgewandelt werden können.
The membrane protein EsaA is a conserved component of the type VIIb secretion system. Limited proteolysis of purified EsaA from Staphylococcus aureus USA300 identified a stable 48 kDa fragment, which was mapped by fingerprint mass spectrometry to an uncharacterized extracellular segment of EsaA. Analysis by circular dichroism spectroscopy showed that this fragment folds into a single stable domain made of mostly α‐helices with a melting point of 34.5°C. Size‐exclusion chromatography combined with multi‐angle light scattering indicated the formation of a dimer of the purified extracellular domain. Octahedral crystals were grown in 0.2 M ammonium citrate tribasic pH 7.0, 16% PEG 3350 using the hanging‐drop vapor‐diffusion method. Diffraction data were analyzed to 4.0 Å resolution, showing that the crystals belonged to the enantiomorphic tetragonal space groups P41212 or P43212, with unit‐cell parameters a = 197.5, b = 197.5, c = 368.3 Å, α = β = γ = 90°.
Here, we present the unique case of a 51‐year‐old German patient with multiple myeloma excreting Ascaris lumbricoides in his stool five weeks after allogeneic hematopoietic stem cell transplantation. Stool analysis remained negative for the presence of eggs, and there was no eosinophilia in the peripheral blood at any time around stem cell transplantation. The patient was commenced on a three‐day treatment with mebendazole, which was well tolerated. No serious interactions with the concomitant post‐transplant medication or negative effects on the hematopoiesis were observed, and the myeloma still is in complete remission. To our knowledge, this is the first report on excretion of A lumbricoides in the context of allogeneic stem cell transplantation. The case is remarkable with view to the fact that the parasite has supposedly survived all courses of myeloma treatment including autologous and allogeneic conditioning. Parasitosis with A lumbricoides has a worldwide prevalence of about a billion and is extremely rare in northern Europe. Possibly the patient got infected during a trip to Egypt years before multiple myeloma was diagnosed.
Combined MEK‐BRAF inhibition is a well‐established treatment strategy in BRAF‐mutated cancer, most prominently in malignant melanoma with durable responses being achieved through this targeted therapy. However, a subset of patients face primary unresponsiveness despite presence of the activating mutation at position V600E, and others acquire resistance under treatment. Underlying resistance mechanisms are largely unknown, and diagnostic tests to predict tumor response to BRAF‐MEK inhibitor treatment are unavailable.
Multiple myeloma represents the second most common hematologic malignancy, and point mutations in BRAF are detectable in about 10% of patients. Targeted inhibition has been successfully applied, with mixed responses observed in a substantial subset of patients mirroring the widespread spatial heterogeneity in this genomically complex disease. Central nervous system (CNS) involvement is an extremely rare, extramedullary form of multiple myeloma that can be diagnosed in less than 1% of patients. It is considered an ultimate high‐risk feature, associated with unfavorable cytogenetics, and, even with intense treatment applied, survival is short, reaching less than 12 months in most cases. Here we not only describe the first patient with an extramedullary CNS relapse responding to targeted dabrafenib and trametinib treatment, we furthermore provide evidence that a point mutation within the capicua transcriptional repressor (CIC) gene mediated the acquired resistance in this patient.
The steric and electronic properties of aryl substituents in monoaryl borohydrides (Li[ArBH\(_3\)]) and dihydroboranes were systematically varied and their reactions with [Ru(PCy\(_3\))\(_2\)HCl(H\(_2\))] (Cy: cyclohexyl) were studied, resulting in bis(σ)‐borane or terminal borylene complexes of ruthenium. These variations allowed for the investigation of the factors involved in the activation of dihydroboranes in the synthesis of terminal borylene complexes. The complexes were studied by multinuclear NMR spectroscopy, mass spectrometry, X‐ray diffraction analysis, and density functional theory (DFT) calculations. The experimental and computational results suggest that the ortho‐substitution of the aryl groups is necessary for the formation of terminal borylene complexes.
Viruses and intracellular bacterial pathogens (IBPs) have in common the need of suitable host cells for efficient replication and proliferation during infection. In human infections, the cell types which both groups of pathogens are using as hosts are indeed quite similar and include phagocytic immune cells, especially monocytes/macrophages (MOs/MPs) and dendritic cells (DCs), as well as nonprofessional phagocytes, like epithelial cells, fibroblasts and endothelial cells. These terminally differentiated cells are normally in a metabolically quiescent state when they are encountered by these pathogens during infection. This metabolic state of the host cells does not meet the extensive need for nutrients required for efficient intracellular replication of viruses and especially IBPs which, in contrast to the viral pathogens, have to perform their own specific intracellular metabolism to survive and efficiently replicate in their host cell niches. For this goal, viruses and IBPs have to reprogram the host cell metabolism in a pathogen-specific manner to increase the supply of nutrients, energy, and metabolites which have to be provided to the pathogen to allow its replication. In viral infections, this appears to be often achieved by the interaction of specific viral factors with central metabolic regulators, including oncogenes and tumor suppressors, or by the introduction of virus-specific oncogenes. Less is so far known on the mechanisms leading to metabolic reprogramming of the host cell by IBPs. However, the still scant data suggest that similar mechanisms may also determine the reprogramming of the host cell metabolism in IBP infections. In this review, we summarize and compare the present knowledge on this important, yet still poorly understood aspect of pathogenesis of human viral and especially IBP infections.
Sacha inchi oil is a premier raw material with highly nutritional and functional features for the foodstuff, pharmaceutical, beauty, and personal care industries. One of the most important facts about this oil is the huge chemical content of unsaturated and polyunsaturated fatty acids. However, the current available information on the characterization of the triglyceride composition and the advance physicochemical parameters relevant to emulsion development is limited. Therefore, this research focused on providing a detailed description of the lipid composition using high-resolution tandem mass spectrometry and thorough physicochemical characterization to find the value of the required hydrophilic–lipophilic balance (HLB). For this, a study in the interfacial tension was evaluated, followed by the assessment of different parameters such as creaming index, droplet size, viscosity, zeta potential, pH, and electrical conductivity for a series emulsified at thermal stress condition. The results show that fatty acids are arranged into glycerolipids and the required HLB to achieve the maximum physical stability is around 8.
Active Galactic Nuclei emit radiation over the whole electromagnetic spectrum up to TeV energies. Blazars are one subtype with their jets pointing towards the observer. One of their typical features is extreme variability on timescales, from minutes to years. The fractional variability is an often used parameter for investigating the degree of variability of a light curve. Different detection methods and sensitivities of the instruments result in differently binned data and light curves with gaps. As they can influence the physics interpretation of the broadband variability, the effects of these differences on the fractional variability need to be studied. In this paper, we study the systematic effects of completeness in time coverage and the sampling rate. Using public data from instruments monitoring blazars in various energy ranges, we study the variability of the bright TeV blazars Mrk 421 and Mrk 501 over the electromagnetic spectrum, taking into account the systematic effects, and compare our findings with previous results. Especially in the TeV range, the fractional variability is higher than in previous studies, which can be explained by the much longer (seven years compared to few weeks) and more complete data sample.
The photophysical properties (absorption, fluorescence and phosphorescence) of a series of triarylboranes of the form 4-D-C\(_6\)H\(_4\)-B(Ar)\(_2\) (D=\(^t\)Bu or NPh\(_2\); Ar=mesityl (Mes) or 2,4,6-tris(trifluoromethylphenyl (Fmes)) were analyzed theoretically using state-of-the-art DFT and TD-DFT methods. Simulated emission spectra and computed decay rate constants are in very good agreement with the experimental data. Unrestricted electronic computations including vibronic contributions explain the unusual optical behavior of 4-\(^t\)Bu-C\(_6\)H\(_4\)-B(Fmes)\(_2\) 2, which shows both fluorescence and phosphorescence at nearly identical energies (at 77 K in a frozen glass). Analysis of the main normal modes responsible for the phosphorescence vibrational fine structure indicates that the bulky tert-butyl group tethered to the phenyl ring is strongly involved. Interestingly, in THF solvent, the computed energies of the singlet and triplet excited states are very similar for compound 2 only, which may explain why 2 shows phosphorescence in contrast to the other members of the series.
A series of photoactivatable CO‐releasing molecules (PhotoCORMs) was prepared from manganese pentacarbonyl bromide and 1H‐benzimidazol‐2‐ylmethyl‐(N‐phenyl)amine ligands (L) bearing different electron‐donating and electron‐withdrawing groups R = H, 4‐CH\(_3\), 4‐OCH\(_3\), 4‐Cl, 4‐NO\(_2\), 2‐, 3‐, and 4‐COOCH\(_3\) on the phenyl substituent to give octahedral manganese(I) complexes of the general formula [MnBr(CO)\(_3\)(L)]. Aerated DMSO solutions of the compounds are stable in the dark for 16 h with no CO release. However, the compounds rapidly release CO upon illumination at 412–525 nm, depending on the substitution pattern. Its influence on the photophysical and photochemical properties was systematically explored using UV/Vis spectroscopy and CO release measurements with a commercial gas sensor system. In the nitro‐substituted compound, the electronically excited state switched from benzimidazole‐ to phenyl‐centered, leading to a markedly different photochemical behavior of this visible‐light activated PhotoCORM.
It is one of the primary goals of medical care to secure good quality of life (QoL) while prolonging survival. This is a major challenge in severe medical conditions with a prognosis such as amyotrophic lateral sclerosis (ALS). Further, the definition of QoL and the question whether survival in this severe condition is compatible with a good QoL is a matter of subjective and culture-specific debate. Some people without neurodegenerative conditions believe that physical decline is incompatible with satisfactory QoL. Current data provide extensive evidence that psychosocial adaptation in ALS is possible, indicated by a satisfactory QoL. Thus, there is no fatalistic link of loss of QoL when physical health declines. There are intrinsic and extrinsic factors that have been shown to successfully facilitate and secure QoL in ALS which will be reviewed in the following article following the four ethical principles (1) Beneficence, (2) Non-maleficence, (3) Autonomy and (4) Justice, which are regarded as key elements of patient centered medical care according to Beauchamp and Childress. This is a JPND-funded work to summarize findings of the project NEEDSinALS (www.NEEDSinALS.com) which highlights subjective perspectives and preferences in medical decision making in ALS.
The opportunistic fungal pathogen Aspergillus fumigatus can cause severe infections, particularly in immunocompromised individuals. Upon infection, A. fumigatus faces the powerful and directly acting immune defense of the human host. The mechanisms on how A. fumigatus evades innate immune attack and complement are still poorly understood. Here, we identify A. fumigatus enolase, AfEno1, which was also characterized as fungal allergen, as a surface ligand for human plasma complement regulators. AfEno1 binds factor H, factor-H-like protein 1 (FHL-1), C4b binding protein (C4BP), and plasminogen. Factor H attaches to AfEno1 via two regions, via short conserved repeats (SCRs) 6–7 and 19–20, and FHL-1 contacts AfEno1 via SCRs 6–7. Both regulators when bound to AfEno1 retain cofactor activity and assist in C3b inactivation. Similarly, the classical pathway regulator C4BP binds to AfEno1 and bound to AfEno1; C4BP assists in C4b inactivation. Plasminogen which binds to AfEno1 via lysine residues is accessible for the tissue-type plasminogen activator (tPA), and active plasmin cleaves the chromogenic substrate S2251, degrades fibrinogen, and inactivates C3 and C3b. Plasmin attached to swollen A. fumigatus conidia damages human A549 lung epithelial cells, reduces the cellular metabolic activity, and induces cell retraction, which results in exposure of the extracellular matrix. Thus, A. fumigatus AfEno1 is a moonlighting protein and virulence factor which recruits several human regulators. The attached human regulators allow the fungal pathogen to control complement at the level of C3 and to damage endothelial cell layers and tissue components.
Brushite cements have been clinically used for irregular bone defect filling applications, and various strategies have been previously reported to modify and improve their physicochemical properties such as strength and injectability. However, strategies to address other limitations of brushite cements such as low radiopacity or acidity without negatively impacting mechanical strength have not yet been reported. In this study, we report the effect of substituting the beta-tricalcium phosphate reactant in brushite cement with baghdadite (Ca\(_3\)ZrSi\(_2\)O\(_9\)), a bioactive zirconium-doped calcium silicate ceramic, at various concentrations (0, 5, 10, 20, 30, 50, and 100 wt%) on the properties of the final brushite cement product. X-ray diffraction profiles indicate the dissolution of baghdadite during the cement reaction, without affecting the crystal structure of the precipitated brushite. EDX analysis shows that calcium is homogeneously distributed within the cement matrix, while zirconium and silicon form cluster-like aggregates with sizes ranging from few microns to more than 50 µm. X-ray images and µ-CT analysis indicate enhanced radiopacity with increased incorporation of baghdadite into brushite cement, with nearly a doubling of the aluminium equivalent thickness at 50 wt% baghdadite substitution. At the same time, compressive strength of brushite cement increased from 12.9 ± 3.1 MPa to 21.1 ± 4.1 MPa with 10 wt% baghdadite substitution. Culture medium conditioned with powdered brushite cement approached closer to physiological pH values when the cement is incorporated with increasing amounts of baghdadite (pH = 6.47 for pure brushite, pH = 7.02 for brushite with 20 wt% baghdadite substitution). Baghdadite substitution also influenced the ionic content in the culture medium, and subsequently affected the proliferative activity of primary human osteoblasts in vitro. This study indicates that baghdadite is a beneficial additive to enhance the radiopacity, mechanical performance and cytocompatibility of brushite cement
To facilitate true regeneration, a vascular graft should direct the evolution of a neovessel to obtain the function of a native vessel. For this, scaffolds have to permit the formation of an intraluminal endothelial cell monolayer, mimicking the tunica intima. In addition, when attempting to mimic a tunica media‐like outer layer, the stacking and orientation of vascular smooth muscle cells (vSMCs) should be recapitulated. An integral scaffold design that facilitates this has so far remained a challenge. A hybrid fabrication approach is introduced by combining solution electrospinning and melt electrowriting. This allows a tissue‐structure mimetic, hierarchically bilayered tubular scaffold, comprising an inner layer of randomly oriented dense fiber mesh and an outer layer of microfibers with controlled orientation. The scaffold supports the organization of a continuous luminal endothelial monolayer and oriented layers of vSM‐like cells in the media, thus facilitating control over specific and tissue‐mimetic cellular differentiation and support of the phenotypic morphology in the respective layers. Neither soluble factors nor a surface bioactivation of the scaffold is needed with this approach, demonstrating that heterotypic scaffold design can direct physiological tissue‐like cell organization and differentiation.
Die sogenannte „Rückkehr der Wölfe" stellt viele Menschen in Europa und in Deutschland vor besondere Herausforderungen. Viele Menschen in ländlichen Milieus, die in besonderem Maße von den Effekten dieser Rückkehr betroffen sind, reagieren ablehnend auf die tierlichen Rückkehrer*innen. Dies hängt nicht zuletzt mit traumatischen Erlebnissen zusammen, die manche Tierhaltende durch das Beutegreifverhalten mancher Wölfe auf ihre Tiere erleiden. Der vorliegende Beitrag liest die Rückkehr der Wölfe als Teil der dramatischen Veränderungen der Welt im beginnenden 21. Jahrhundert. Mit diesen Veränderungen verbunden sind im gesamten Globalen Norden tiefgreifende Verhaltens- und Einstellungsänderungen, auch gegenüber anderen als menschlichen Lebewesen. Die Wölfe sind Teil dieses Prozesses. Sie zeigen in besonderem Maße, wie die Fluidität gewohnter Ordnungen und Grenzziehungen, etwa die der Zugehörigkeit zu menschlichen Haushalten oder die Einteilung der Lebensräume in rurale und urbane, wilde und zivilisierte, zur ethischen Herausforderung wird. Obgleich der Prozess der Aushandlung des Zusammenlebens offen und höchst widersprüchlich verläuft, zeigen sich in der Diskussion auch neue Einsichten in die Verbundenheit menschlicher Akteur*innen mit anderen Lebewesen. Damit sind wesentliche Voraussetzungen gegeben für die Entwicklung neuer Haltungen und Wertsetzungen, die dem engen Austausch zwischen Menschen und anderen Lebewesen gerecht werden.
Autosomal recessive congenital ichthyosis (ARCI) belongs to a heterogeneous group of disorders of keratinization. To date, 10 genes have been identified to be causative for ARCI. NIPAL4 (Nipa‐Like Domain‐Containing 4) is the second most commonly mutated gene in ARCI. In this study, we present a large cohort of 101 families affected with ARCI carrying mutations in NIPAL4. We identified 16 novel mutations and increase the total number of pathogenic mutations in NIPAL4 to 34. Ultrastructural analysis of biopsies from six patients showed morphological abnormalities consistent with an ARCI EM type III. One patient with a homozygous splice site mutation, which leads to a loss of NIPAL4 mRNA, showed additional ultrastructural aberrations together with a more severe clinical phenotype. Our study gives insights into the frequency of mutations, a potential hot spot for mutations, and genotype–phenotype correlations.
This paper deals with the interrelation between the concept of linguistic insecurity described by Labov (1966) and the irregular formation of Spanish superlatives based on Latin roots such as paupérrimo, celebérrimo etc. instead of the analogue formation pobrísimo or celebrísimo. After a brief overview on the frequency of these forms and their alleged regular equivalents in Spanish corpora, a closer look is taken on the speakers’ internal and external aspects of linguistic (in)security. Finally, it is shown by an acceptability test that there are forms on -érrim*, which are not exclusively restricted to the norma culta in Spanish.
The reactivity of a diruthenium tetrahydride complex towards three selected dihydroboranes was investigated. The use of [DurBH\(_{2}\)] (Dur=2,3,5,6‐Me\(_{4}\)C\(_{6}\)H) and [(Me\(_{3}\)Si)\(_{2}\)NBH\(_{2}\)] led to the formation of bridging borylene complexes of the form [(Cp\(^{*}\)RuH)\(_{2}\)BR] (Cp\(^{*}\)=C\(_{5}\)Me\(_{5}\); 1 a: R=Dur; 1 b: R=N(SiMe\(_{3}\))\(_{2}\)) through oxidative addition of the B−H bonds with concomitant hydrogen liberation. Employing the more electron‐deficient dihydroborane [3,5‐(CF\(_{3}\))\(_{2}\)‐C\(_{6}\)H\(_{3}\)BH\(_{2}\)] led to the formation of an anionic complex bearing a tetraarylated chain of four boron atoms, namely Li(THF)\(_{4}\)[(Cp\(^{*}\)Ru)\(_{2}\)B\(_{4}\)H\(_{5}\)(3,5‐(CF\(_{3}\))\(_{2}\)C\(_{6}\)H\(_{3}\))\(_{4}\)] (4), through an unusual, incomplete threefold dehydrocoupling process. A comparative theoretical investigation of the bonding in a simplified model of 4 and the analogous complex nido‐[1,2(Cp\(^{*}\)Ru)\(_{2}\)(μ‐H)B\(_{4}\)H\(_{9}\)] (I) indicates that there appear to be no classical σ‐bonds between the boron atoms in complex I, whereas in the case of 4 the B\(_{4}\) chain better resembles a network of three B−B σ bonds, the central bond being significantly weaker than the other two.
Stereospecific Synthesis and Photophysical Properties of Propeller-Shaped C\(_{90}\)H\(_{48}\) PAH
(2019)
Herein, we have synthesized an enantiomerically pure propeller‐shaped PAH, C\(_{90}\)H\(_{48}\), possessing three [7]helicene and three [5]helicene subunits. This compound can be obtained in gram quantities in a straightforward manner. The photophysical and chiroptical properties were investigated using UV/Vis absorption and emission, optical rotation and circular dichroism spectroscopy, supported by DFT calculations. The nonlinear optical properties were investigated by two‐photon absorption measurements using linearly and circularly polarized light. The extremely twisted structure and packing of the homochiral compound were investigated by single‐crystal X‐ray diffraction analysis.
Up to three polychlorinated pyridyldiphenylmethyl radicals bridged by a triphenylamine carrying electron withdrawing (CN), neutral (Me), or donating (OMe) groups were synthesized and analogous radicals bridged by tris(2,6‐dimethylphenyl)borane were prepared for comparison. All compounds were as stable as common closed‐shell organic compounds and showed significant fluorescence upon excitation. Electronic, magnetic, absorption, and emission properties were examined in detail, and experimental results were interpreted using DFT calculations. Oxidation potentials, absorption and emission energies could be tuned depending on the electron density of the bridges. The triphenylamine bridges mediated intramolecular weak antiferromagnetic interactions between the radical spins, and the energy difference between the high spin and low spin states was determined by temperature dependent ESR spectroscopy and DFT calculations. The fluorescent properties of all radicals were examined in detail and revealed no difference for high and low spin states which facilitates application of these dyes in two‐photon absorption spectroscopy and OLED devices.
The reaction products of the picolyl radicals at high temperature were characterized by mass‐selective threshold photoelectron spectroscopy in the gas phase. Aminomethylpyridines were pyrolyzed to initially produce picolyl radicals (m /z =92). At higher temperatures further thermal reaction products are generated in the pyrolysis reactor. All compounds were identified by mass‐selected threshold photoelectron spectroscopy and several hitherto unexplored reactive molecules were characterized. The mechanism for several dissociation pathways was outlined in computations. The spectrum of m /z =91, resulting from hydrogen loss of picolyl, shows four isomers, two ethynyl pyrroles with adiabatic ionization energies (IE\(_{ad}\)) of 7.99 eV (2‐ethynyl‐1H ‐pyrrole) and 8.12 eV (3‐ethynyl‐1H ‐pyrrole), and two cyclopentadiene carbonitriles with IE′s of 9.14 eV (cyclopenta‐1,3‐diene‐1‐carbonitrile) and 9.25 eV (cyclopenta‐1,4‐diene‐1‐carbonitrile). A second consecutive hydrogen loss forms the cyanocyclopentadienyl radical with IE′s of 9.07 eV (T\(_0\)) and 9.21 eV (S\(_1\)). This compound dissociates further to acetylene and the cyanopropynyl radical (IE=9.35 eV). Furthermore, the cyclopentadienyl radical, penta‐1,3‐diyne, cyclopentadiene and propargyl were identified in the spectra. Computations indicate that dissociation of picolyl proceeds initially via a resonance‐stabilized seven‐membered ring.
While polysulfones constitute a class of well‐established, highly valuable applied materials, knowledge about polymers based on the related sulfoximine group is very limited. We have employed functionalized diaryl sulfoximines and a p ‐phenylene bisborane as building blocks for unprecedented BN‐ and BO‐doped alternating inorganic–organic hybrid copolymers. While the former were accessed by a facile silicon/boron exchange protocol, the synthesis of polymers with main‐chain B–O linkages was achieved by salt elimination.
Two different chromophores, namely a dipolar and an octupolar system, were prepared and their linear and nonlinear optical properties as well as their bioimaging capabilities were compared. Both contain triphenylamine as the donor and a triarylborane as the acceptor, the latter modified with cationic trimethylammonio groups to provide solubility in aqueous media. The octupolar system exhibits a much higher two‐photon brightness, and also better cell viability and enhanced selectivity for lysosomes compared with the dipolar chromophore. Furthermore, both dyes were applied in two‐photon excited fluorescence (TPEF) live‐cell imaging.
Research on facial emotion expression has mostly focused on emotion recognition, assuming that a small number of discrete emotions is elicited and expressed via prototypical facial muscle configurations as captured in still photographs. These are expected to be recognized by observers, presumably via template matching. In contrast, appraisal theories of emotion propose a more dynamic approach, suggesting that specific elements of facial expressions are directly produced by the result of certain appraisals and predicting the facial patterns to be expected for certain appraisal configurations. This approach has recently been extended to emotion perception, claiming that observers first infer individual appraisals and only then make categorical emotion judgments based on the estimated appraisal patterns, using inference rules. Here, we report two related studies to empirically investigate the facial action unit configurations that are used by actors to convey specific emotions in short affect bursts and to examine to what extent observers can infer a person's emotions from the predicted facial expression configurations. The results show that (1) professional actors use many of the predicted facial action unit patterns to enact systematically specified appraisal outcomes in a realistic scenario setting, and (2) naïve observers infer the respective emotions based on highly similar facial movement configurations with a degree of accuracy comparable to earlier research findings. Based on estimates of underlying appraisal criteria for the different emotions we conclude that the patterns of facial action units identified in this research correspond largely to prior predictions and encourage further research on appraisal-driven expression and inference.
Research with adults in laboratory settings has shown that distributed rereading is a beneficial learning strategy but its effects depend on time of test. When learning outcomes are measured immediately after rereading, distributed rereading yields no benefits or even detrimental effects on learning, but the beneficial effects emerge two days later. In a preregistered experiment, the effects of distributed rereading were investigated in a classroom setting with school students. Seventh-graders (N = 191) reread a text either immediately or after 1 week. Learning outcomes were measured after 4 min or 1 week. Participants in the distributed rereading condition reread the text more slowly, predicted their learning success to be lower, and reported a lower on-task focus. At the shorter retention interval, massed rereading outperformed distributed rereading in terms of learning outcomes. Contrary to students in the massed condition, students in the distributed condition showed no forgetting from the short to the long retention interval. As a result, they performed equally well as the students in the massed condition at the longer retention interval. Our results indicate that distributed rereading makes learning more demanding and difficult and leads to higher effort during rereading. Its effects on learning depend on time of test, but no beneficial effects were found, not even at the delayed test.
The mold Fusarium is a ubiquitous fungus causing plant, animal and human infections. In humans, Fusarium spp. are the major cause of eye infections in patients wearing contact lenses or after local trauma. Systemic infections by Fusarium spp. mainly occur in immunosuppressed patients and can disseminate throughout the human body. Due to high levels of resistance to antifungals a fast identification of the causative agent is an urgent need. By using a probe-based real-time PCR assay specific for the genus Fusarium we analysed several different clinical specimens detecting Fusarium spp. commonly found in clinical samples in Germany. Also, a large collection of lung fluid samples of haematological patients was analysed (n = 243). In these, two samples (0.8%) were reproducibly positive, but only one could be confirmed by sequencing. For this case of probable invasive fungal disease (IFD) culture was positive for Fusarium species. Here we describe a rapid, probe-based real-time PCR assay to specifically detect DNA from a broad range of Fusarium species and its application to clinically relevant specimens.
Human A3 adenosine receptor hA3AR has been implicated in gastrointestinal cancer, where its cellular expression has been found increased, thus suggesting its potential as a molecular target for novel anticancer compounds. Observation made in our previous work indicated the importance of the carbonyl group of amide in the indolylpyrimidylpiperazine (IPP) for its human A2A adenosine receptor (hA2AAR) subtype binding selectivity over the other AR subtypes. Taking this observation into account, we structurally modified an indolylpyrimidylpiperazine (IPP) scaffold, 1 (a non-selective adenosine receptors’ ligand) into a modified IPP (mIPP) scaffold by switching the position of the carbonyl group, resulting in the formation of both ketone and tertiary amine groups in the new scaffold. Results showed that such modification diminished the A2A activity and instead conferred hA3AR agonistic activity. Among the new mIPP derivatives (3–6), compound 4 showed potential as a hA3AR partial agonist, with an Emax of 30% and EC50 of 2.89 ± 0.55 μM. In the cytotoxicity assays, compound 4 also exhibited higher cytotoxicity against both colorectal and liver cancer cells as compared to normal cells. Overall, this new series of compounds provide a promising starting point for further development of potent and selective hA3AR partial agonists for the treatment of gastrointestinal cancers.
The normal function of the heart relies on a series of complex metabolic processes orchestrating the proper generation and use of energy. In this context, mitochondria serve a crucial role as a platform for energy transduction by supplying ATP to the varying demand of cardiomyocytes, involving an intricate network of pathways regulating the metabolic flux of substrates. The failure of these processes results in structural and functional deficiencies of the cardiac muscle, including inherited cardiomyopathies. These genetic diseases are characterized by cardiac structural and functional anomalies in the absence of abnormal conditions that can explain the observed myocardial abnormality, and are frequently associated with heart failure. Since their original description, major advances have been achieved in the genetic and phenotype knowledge, highlighting the involvement of metabolic abnormalities in their pathogenesis. This review provides a brief overview of the role of mitochondria in the energy metabolism in the heart and focuses on metabolic abnormalities, mitochondrial dysfunction, and storage diseases associated with inherited cardiomyopathies.
Mineral bone cements were actually not developed for their application as bone-bonding agents, but as bone void fillers. In particular, calcium phosphate cements (CPC) are considered to be unsuitable for that application, particularly under moist conditions. Here, we showed the ex vivo ability of different magnesium phosphate cements (MPC) to adhere on bovine cortical bone substrates. The cements were obtained from a mixture of farringtonite (Mg\(_3\)(PO\(_4\))\(_2\)) with different amounts of phytic acid (C\(_6\)H\(_{18}\)O\(_{24}\)P\(_6\), inositol hexaphosphate, IP6), whereas cement setting occurred by a chelation reaction between Mg\(^{2+}\) ions and IP6. We were able to show that cements with 25% IP6 and a powder-to-liquid ratio (PLR) of 2.0 g/mL resulted in shear strengths of 0.81 ± 0.12 MPa on bone even after 7 d storage in aqueous conditions. The samples showed a mixed adhesive–cohesive failure with cement residues on the bone surface as indicated by scanning electron microscopy and energy-dispersive X-ray analysis. The presented material demonstrated appropriate bonding characteristics, which could enable a broadening of the mineral bone cements’ application field to bone adhesives
The limiting behaviour of a one‐dimensional discrete system is studied by means of Γ‐convergence. We consider a toy model of a chain of atoms. The interaction potentials are of Lennard‐Jones type and periodically or stochastically distributed. The energy of the system is considered in the discrete to continuum limit, i.e. as the number of atoms tends to infinity. During that limit, a homogenization process takes place. The limiting functional is discussed, especially with regard to fracture. Secondly, we consider a rescaled version of the problem, which yields a limiting energy of Griffith's type consisting of a quadratic integral term and a jump contribution. The periodic case can be found in [8], the stochastic case in [6,7].
In recent years, the midlatitudes are characterized by more intense heatwaves in summer and sometimes severe cold spells in winter that might emanate from changes in atmospheric circulation, including synoptic‐scale and planetary wave activity in the midlatitudes. In this study, we investigate the heat and momentum exchange between the mean flow and atmospheric waves in the North Atlantic sector and adjacent continents by means of the physically consistent Eliassen–Palm flux diagnostics applied to reanalysis and forced climate model data. In the long‐term mean, momentum is transferred from the mean flow to atmospheric waves in the northwest Atlantic region, where cyclogenesis prevails. Further downstream over Europe, eddy fluxes return momentum to the mean flow, sustaining the jet stream against friction. A global climate model is able to reproduce this pattern with high accuracy. Atmospheric variability related to atmospheric wave activity is much more expressed at the intraseasonal rather than the interannual time‐scale. Over the last 40 years, reanalyses reveal a northward shift of the jet stream and a weakening of intraseasonal weather variability related to synoptic‐scale and planetary wave activity. This pertains to the winter and summer seasons, especially over central Europe, and correlates with changes in the North Atlantic Oscillation as well as regional temperature and precipitation. A very similar phenomenon is found in a climate model simulation with business‐as‐usual scenario, suggesting an anthropogenic trigger in the weakening of intraseasonal weather variability in the midlatitudes.
Detailed insight into the internal structure of drug‐loaded polymeric micelles is scarce, but important for developing optimized delivery systems. We observed that an increase in the curcumin loading of triblock copolymers based on poly(2‐oxazolines) and poly(2‐oxazines) results in poorer dissolution properties. Using solid‐state NMR spectroscopy and complementary tools we propose a loading‐dependent structural model on the molecular level that provides an explanation for these pronounced differences. Changes in the chemical shifts and cross‐peaks in 2D NMR experiments give evidence for the involvement of the hydrophobic polymer block in the curcumin coordination at low loadings, while at higher loadings an increase in the interaction with the hydrophilic polymer blocks is observed. The involvement of the hydrophilic compartment may be critical for ultrahigh‐loaded polymer micelles and can help to rationalize specific polymer modifications to improve the performance of similar drug delivery systems.
A new strategy is demonstrated for the synthesis of warped, negatively curved, all‐sp\(^2\)‐carbon π‐scaffolds. Multifold C−C coupling reactions are used to transform a polyaromatic borinic acid into a saddle‐shaped polyaromatic hydrocarbon (2 ) bearing two heptagonal rings. Notably, this Schwarzite substructure is synthesized in only two steps from an unfunctionalized alkene. A highly warped structure of 2 was revealed by X‐ray crystallographic studies and pronounced flexibility of this π‐scaffold was ascertained by experimental and computational studies. Compound 2 exhibits excellent solubility, visible range absorption and fluorescence, and readily undergoes two reversible one‐electron oxidations at mild potentials.
Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14–20 mg L\(^{-1}\)) even after many months of treatment due to low water solubility, bioavailability, and unfavorable pharmacokinetic profile. Here a novel MT nanoformulation with very high MT concentrations in physiological aqueous media is reported. The MT‐loaded nanoformulations are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X‐ray diffraction which confirms the amorphous nature of the drug. The polymer itself does not show any cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI‐H295 both in monolayers and tumor cell spheroids, micellar MT is demonstrated to exhibit comparable efficacy to its ethanol solution. It is postulated that this formulation will be suitable for i.v. application and rapid attainment of therapeutic plasma concentrations. In conclusion, the micellar formulation is considered a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity toward ACC in vitro.
A convenient and efficient one‐step synthesis of 1,1,1‐triborylalkanes was achieved via sequential dehydrogenative borylation and double hydroborations of terminal alkynes with HBpin (HBpin=pinacolborane) catalyzed by inexpensive and readily available Cu(OAc)\(_2\). This process proceeds under mild conditions, furnishing 1,1,1‐tris(boronates) with wide substrate scope, excellent selectivity, and good functional‐group tolerance, and is applicable to gram‐scale synthesis without loss of yield. The 1,1,1‐triborylalkanes can be used in the preparation of α‐vinylboronates and borylated cyclic compounds, which are valuable but previously rare compounds. Different alkyl groups can be introduced stepwise via base‐mediated deborylative alkylation to produce racemic tertiary alkyl boronates, which can be readily transformed into useful tertiary alcohols.
Artificial light at night (ALAN) is increasing exponentially worldwide, accelerated by the transition to new efficient lighting technologies. However, ALAN and resulting light pollution can cause unintended physiological consequences. In vertebrates, production of melatonin—the “hormone of darkness” and a key player in circadian regulation—can be suppressed by ALAN. In this paper, we provide an overview of research on melatonin and ALAN in vertebrates. We discuss how ALAN disrupts natural photic environments, its effect on melatonin and circadian rhythms, and different photoreceptor systems across vertebrate taxa. We then present the results of a systematic review in which we identified studies on melatonin under typical light-polluted conditions in fishes, amphibians, reptiles, birds, and mammals, including humans. Melatonin is suppressed by extremely low light intensities in many vertebrates, ranging from 0.01–0.03 lx for fishes and rodents to 6 lx for sensitive humans. Even lower, wavelength-dependent intensities are implied by some studies and require rigorous testing in ecological contexts. In many studies, melatonin suppression occurs at the minimum light levels tested, and, in better-studied groups, melatonin suppression is reported to occur at lower light levels. We identify major research gaps and conclude that, for most groups, crucial information is lacking. No studies were identified for amphibians and reptiles and long-term impacts of low-level ALAN exposure are unknown. Given the high sensitivity of vertebrate melatonin production to ALAN and the paucity of available information, it is crucial to research impacts of ALAN further in order to inform effective mitigation strategies for human health and the wellbeing and fitness of vertebrates in natural ecosystems.
Quinolone antibiotics present an attractive oral treatment option in patients with cystic fibrosis (CF). Prior studies have reported comparable clearances and volumes of distribution in patients with CF and healthy volunteers for primarily renally cleared quinolones. We aimed to provide the first pharmacokinetic comparison for pefloxacin as a predominantly nonrenally cleared quinolone and its two metabolites between both subject groups. Eight patients with CF (fat-free mass [FFM]: 36.3 ± 6.9 kg, average ± SD) and ten healthy volunteers (FFM: 51.7 ± 9.9 kg) received 400 mg pefloxacin as a 30 min intravenous infusion and orally in a randomized, two-way crossover study. All plasma and urine data were simultaneously modelled. Bioavailability was complete in both subject groups. Pefloxacin excretion into urine was approximately 74% higher in patients with CF compared to that in healthy volunteers, whereas the urinary excretion of metabolites was only slightly higher in patients with CF. After accounting for body size and composition via allometric scaling by FFM, pharmacokinetic parameter estimates in patients with CF divided by those in healthy volunteers were 0.912 for total clearance, 0.861 for nonrenal clearance, 1.53 for renal clearance, and 0.916 for volume of distribution. Nonrenal clearance accounted for approximately 90% of total pefloxacin clearance. Overall, bioavailability and disposition were comparable between both subject groups.