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This paper analyzes the mental development of the main character Salvador in the Spanish movie Los girasoles ciegos (2008) by José Luis Cuerda, based on the camera perspective and focalization, as well as the three-instance model according to Sigmund Freud. For this purpose, screen captures from the movie are examined to see how Salvador’s loss of control is pictured. This is applied to Freud’s three-instance model to prove the takeover of the Id. Throughout the whole movie, the inner conflict between his Ego and Id, i.e. his life as a deacon versus his life as a soldier, is present. The whole process of the breakdown of his mental state is revealed through the camera perspective and visual focalization.
The present article aims to examine images of the Mediterranean Sea in Jean-Daniel Pollet’s essay film Méditerranée (1963), with a particular focus on its representation as a multifaceted space of cultural memory. After some preliminary observations on the relation between the essay film as a genre and images of the Mediterranean, I shall, on the one hand, have a look at the semantic processes through which the film builds up a recognizable image of the Great Sea. On the other hand, however, I will argue that, at the same time, Méditerranée calls this signifying process into question by representing the sea as a space of cultural memory understood as a space of becoming and of deferral of meaning.
To this day, Lorca’s most popular plays, the Trilogía dramática de la tierra española, are considered to be among the most widely read texts of twentieth century Spanish literature. By combining elements from Antiquity with classic and modern features of Spanish theatre and placing them in new functional contexts, the author succeeds in creating an innovative theatre of sociocritical nature in times of political repression. This article analyses several of these innovations and aims to demonstrate the influence Lorca’s Tragedias rurales still have on today’s literature and culture. Simon Stone’s play Yerma (2017) and the Netflix series Las Chicas del Cable (2017-2020) are approached here with this purpose.
This article deals with discursive and argumentative strategies used by Brazilian President Jair Bolsonaro to bring science in discredit during the 2020’s COVID-19-pandemic. Based on official statements and Tweets launched over the crisis the Discourse-Historical Approach is applied to make strategies brought into play by Bolsonaro visible. While the President declares scientific advice such as distancing and quarantine as ineffective, he recommends the use of hydroxychloroquine as well as old fashioned prayers for staying safe and healthy. He evokes that there are «fake news» and «partners of paralysis», to which he responds by demasking and bringing the one and only truth towards «the people». The analysis points out that Bolsonaro is downplaying the virus and the risk of transmission and puts the economy ahead of health. His supporters as a consequence tend to ignore the
WHO recommendations how to behave during the pandemic.
The present article examines the narrative modes in which Lebanese author Amin Maalouf investigates his roots in Origines a hybrid work which stands in contrast with his previous essays and fictions as to its (auto)biographical dimension. Resembling what Dominique Viart and Bruno Vercier in their analysis of predominant themes and narrative strategies in contemporary French literature name «récit de filiation», Maalouf’s quest for his familial past explores the concept of intergenerational transmission of memory. However, despite this individual postmemorial approach, Maalouf’s intimate writing is intrinsically linked with the complex history of the Ottoman Empire and therefore with collective narratives of war, diasporic identities, and migration relating to the present time or the recent past.
France, Italy, and Spain are three Romance-speaking countries which – at least in Europe – have been affected to a very high degree by the consequences of the Corona pandemic. This paper examines discursive strategies on social media (Twitter and Facebook) by the three heads of government/state of the aforementioned countries – namely Emmanuel Macron (France), Giuseppe Conte (Italy), and Pedro Sánchez (Spain)- from a corpuslinguistic point of view. For this purpose, a corpus was created which contains all Twitter and Facebook messages posted by these heads of government/state from the beginning of February until the end of April 2020. By applying corpus-linguistic methods we find that all three politicians consciously use social media to sensitize, inform, and – in view of a dramatic pandemic situation – unite their respective populations behind them.
With her famous suggestion to «give her [the woman] a room of her own and five hundred a year, let her speak her mind» from 1929, Virginia Woolf verbalized a core issue of female
writing by hinting at the socioeconomic circumstances and domestic obligations of most women – valid at her times, but still today. Both Elena Ferrante and Annie Ernaux discuss, in their respective novels, the topics of being women in the particular sociocultural landscape (in Italy and, respectively, in France) after World War II and up to these days, the themes of marriage and motherhood, employment and especially (female) authorship. This article aims to show in a close reading of both Ferrante and Ernaux that the two writers play with the literary form of the (auto-)biography on a diegetic, but also extradiegetic level, while formulating at the same time a collective work that embraces the experience of womanhood but circumvents the hazard of a merely subjective and sensitive writing, as female writing has sometimes been claimed to be.
This article examines so-called colonial discourses in Belgium on the former Sub-Saharan colony owned by the Belgian King, Leopold II., which today is known as the Democratic Republic of Congo (DR Congo) or the Congo-Kinshasa. After having introduced the colonial history of the DR Congo from the 15th century until 1910, an empirical analysis of the colonial discourses in Belgium from the 1890s until today will be illustrated in conjunction with Belgium’s linguistic-cultural division and the age-related divergence. Belgian colonial discourse is characterized by a historical misrepresentation by the political authorities while especially social forces have pled for a critical examination of their own colonial history in Belgium since the year 2000.
Die Zeitschrift promptus – Würzburger Beiträge zur Romanistik erscheint einmal jährlich und wird durch den gemeinnützigen Verein promptus e.V. herausgegeben.
Sie richtet sich an alle Nachwuchswissenschaftler im Bereich der romanistischen Sprach- und Literaturwissenschaft sowie der Fachdidaktik und bietet diesen die Möglichkeit, in einem frühen Stadium ihrer akademischen Laufbahn qualitativ hochwertige Arbeiten zu publizieren. Zudem versteht sich die Zeitschrift als Impulsgeber für junge romanistische Forschung, ohne sich dabei thematisch zu beschränken.
Increasing natural pest control in agricultural fields is an important aim of ecological intensification. Combined effects of landscape context and local placement of agri‐environmental schemes (AES) on natural pest control and within‐field distance functions of natural pest control agents have rarely been addressed but might affect the distribution of biocontrol providers. Importantly, it is currently unknown whether ecosystem services provided by adjacent AES are consistent for different crop types during crop rotation.
In this study, we assessed whether crop rotation from oilseed rape to cereals altered within‐field distance functions of ground‐dwelling predators from adjacent agri‐environmental fields along a gradient in landscape context. Additionally, we recorded crop pests, predation rates, parasitoids as well as crop yields on a total of 30 study sites.
Distance functions varied between trophic levels: Carabid richness decreased while densities of carabid beetles, staphylinid beetles as well as crop yields increased towards the field centres. Distance functions of parasitoids and pests were modulated by the amount of semi‐natural habitat in the surrounding landscape, while the effects of adjacent AES were limited.
Distance decay functions found for ground‐dwelling predators in oilseed rape in the previous year were not always present in cereals. Increasing distance to the field edge also increased effects of crop rotation on carabid beetle assemblages, indicating a source habitat function of field edges.
Synthesis and applications. Distance functions of natural pest control are not universal and the effects of agri‐environmental schemes (AES) in different adjacent crops during crop rotation vary and depend on ecological contrasts. A network of semi‐natural habitats and spatially optimized AES habitats can benefit pest control in agricultural landscapes, but constraints as a result of crop type need to be addressed by annually targeted, spatially shifting agri‐environment schemes for different crops.
The limited proliferative capacity of neuroprogenitor cells (NPCs) within the periventricular germinal niches (PGNs) located caudal of the subventricular zone (SVZ) of the lateral ventricles together with their high proliferation capacity after isolation strongly implicates cell‐extrinsic humoral factors restricting NPC proliferation in the hypothalamic and midbrain PGNs. We comparatively examined the effects of norepinephrine (NE) as an endogenous candidate regulator of PGN neurogenesis in the SVZ as well as the periventricular hypothalamus and the periaqueductal midbrain. Histological and neurochemical analyses revealed that the pattern of NE innervation of the adult PGNs is inversely associated with their in vivo NPC proliferation capacity with low NE levels coupled to high NPC proliferation in the SVZ but high NE levels coupled to low NPC proliferation in hypothalamic and midbrain PGNs. Intraventricular infusion of NE decreased NPC proliferation and neurogenesis in the SVZ‐olfactory bulb system, while pharmacological NE inhibition increased NPC proliferation and early neurogenesis events in the caudal PGNs. Neurotoxic ablation of NE neurons using the Dsp4‐fluoxetine protocol confirmed its inhibitory effects on NPC proliferation. Contrarily, NE depletion largely impairs NPC proliferation within the hippocampus in the same animals. Our data indicate that norepinephrine has opposite effects on the two fundamental neurogenic niches of the adult brain with norepinephrine being a negative regulator of adult periventricular neurogenesis. This knowledge might ultimately lead to new therapeutic approaches to influence neurogenesis in hypothalamus‐related metabolic diseases or to stimulate endogenous regenerative potential in neurodegenerative processes such as Parkinson's disease.
We report the direct imidization of naphthalene and perylene dicarboxylic anhydrides/esters with bulky ortho,ortho‐diaryl‐ and ortho,ortho‐dialkynylaniline derivatives. This imidization method uses n‐butyllithium as a strong base to increase the reactivity of bulky amine derivatives, proceeds under mild reaction conditions, requires only stoichiometric amounts of reactants and gives straightforward access to new sterically crowded rylene dicarboximides. Mechanistic investigations suggest an isoimide as intermediary product, which was converted to the corresponding imide upon addition of an aqueous base. Single‐crystal X‐ray diffraction analyses reveal dimeric packing motifs for monoimides, while two‐side shielded bisimides crystallize in isolated molecules without close π–π‐interactions. Spectroscopic investigations disclose the influence of the bulky substituents on the optical properties in the solid state.
During deployment, soldiers face situations in which they are not only exposed to violence but also have to perpetrate it themselves. This study investigates the role of soldiers' levels of posttraumatic stress disorder (PTSD) symptoms and appetitive aggression, that is, a lust for violence, for their engaging in violence during deployment. Furthermore, factors during deployment influencing the level of PTSD symptoms and appetitive aggression after deployment were examined for a better comprehension of the maintenance of violence. Semi‐structured interviews were conducted with 468 Burundian soldiers before and after a 1‐year deployment to Somalia. To predict violent acts during deployment (perideployment) as well as appetitive aggression and PTSD symptom severity after deployment (postdeployment), structural equation modeling was utilized. Results showed that the number of violent acts perideployment was predicted by the level of appetitive aggression and by the severity of PTSD hyperarousal symptoms predeployment. In addition to its association with the predeployment level, appetitive aggression postdeployment was predicted by violent acts and trauma exposure perideployment as well as positively associated with unit support. PTSD symptom severity postdeployment was predicted by the severity of PTSD avoidance symptoms predeployment and trauma exposure perideployment, and negatively associated with unit support. This prospective study reveals the importance of appetitive aggression and PTSD hyperarousal symptoms for the engagement in violent acts during deployment, while simultaneously demonstrating how these phenomena may develop in mutually reinforcing cycles in a war setting.
Single crystals of three at bay area tetraphenoxy‐substituted perylene bisimide dyes are grown by vacuum sublimation. X‐ray analysis reveals the self‐assembly of these highly twisted perylene bisimides (PBIs) in the solid state via imide–imide hydrogen bonding into hydrogen‐bonded PBI chains. The crystallographic insights disclose that the conformation and sterical congestion imparted by the phenoxy substituents can be controlled by ortho‐substituents. Accordingly, whilst sterically less demanding methyl and isopropyl substituents afford double‐stranded PBI chains of complementary P and M atropo‐enantiomers, single hydrogen‐bonded chains of homochiral PBIs are observed for the sterically more demanding ortho‐phenyl substituents. Investigation of the absorption and fluorescence properties of microcrystals and thin films of these PBIs allow for an unambiguous interpretation of these exciton systems. Thus, the J‐aggregates of the double‐stranded crystals exhibit a much larger (negative) exciton coupling than the single‐stranded one, which in contrast has the higher solid‐state fluorescence quantum yield.
Cataglyphis ants are known for their outstanding navigational abilities. They return to their inconspicuous nest after far‐reaching foraging trips using path integration, and whenever available, learn and memorize visual features of panoramic sceneries. To achieve this, the ants combine directional visual information from celestial cues and panoramic scenes with distance information from an intrinsic odometer. The largely vision‐based navigation in Cataglyphis requires sophisticated neuronal networks to process the broad repertoire of visual stimuli. Although Cataglyphis ants have been subjected to many neuroethological studies, little is known about the general neuronal organization of their central brain and the visual pathways beyond major circuits. Here, we provide a comprehensive, three‐dimensional neuronal map of synapse‐rich neuropils in the brain of Cataglyphis nodus including major connecting fiber systems. In addition, we examined neuronal tracts underlying the processing of visual information in more detail. This study revealed a total of 33 brain neuropils and 30 neuronal fiber tracts including six distinct tracts between the optic lobes and the cerebrum. We also discuss the importance of comparative studies on insect brain architecture for a profound understanding of neuronal networks and their function.
The COVID‐19 pandemic caused by SARS‐CoV‐2 has far‐reaching direct and indirect medical consequences. These include both the course and treatment of diseases. It is becoming increasingly clear that infections with SARS‐CoV‐2 can cause considerable immunological alterations, which particularly also affect pathogenetically and/or therapeutically relevant factors.
Against this background we summarize here the current state of knowledge on the interaction of SARS‐CoV‐2/COVID‐19 with mediators of the acute phase of inflammation (TNF, IL‐1, IL‐6), type 1 and type 17 immune responses (IL‐12, IL‐23, IL‐17, IL‐36), type 2 immune reactions (IL‐4, IL‐13, IL‐5, IL‐31, IgE), B‐cell immunity, checkpoint regulators (PD‐1, PD‐L1, CTLA4), and orally druggable signaling pathways (JAK, PDE4, calcineurin). In addition, we discuss in this context non‐specific immune modulation by glucocorticosteroids, methotrexate, antimalarial drugs, azathioprine, dapsone, mycophenolate mofetil and fumaric acid esters, as well as neutrophil granulocyte‐mediated innate immune mechanisms.
From these recent findings we derive possible implications for the therapeutic modulation of said immunological mechanisms in connection with SARS‐CoV‐2/COVID‐19. Although, of course, the greatest care should be taken with patients with immunologically mediated diseases or immunomodulating therapies, it appears that many treatments can also be carried out during the COVID‐19 pandemic; some even appear to alleviate COVID‐19.
Although the clinical presentations of patients with pityriasis lichenoides et varioliformis acuta (PLEVA) may vary, bullae are not usually part of the clinical spectrum. To date, only two other cases of a bullous variant of PLEVA with evidence of autoantibodies against hemidesmosomal antigens have been reported. The term PLEVA pemphigoides was suggested for this unique clinical, pathological and serological combination of both PLEVA and bullous pemphigoid.
Die \(\pi\)-Koordination von Aren- und anionischen Heteroarenliganden ist ein allgegenwärtiges Strukturmotiv in der metallorganischen Chemie der d- und f-Block-Elemente. Im Gegensatz dazu sind vergleichbare \(\pi\)-Wechselwirkungen neutraler Heteroarene, darunter auch solche neutraler, aromatischer Borheterocyclen, für den f-Block weit weniger verbreitet, was z. T. mit einer geringeren Effektivität der Metall-zu-Ligand-Rückbindung in Zusammenhang gebracht werden kann. Für die Actinoide sind π-Komplexe mit neutralen Heteroarenliganden sogar gänzlich unbekannt. Durch Ausnutzung der außergewöhnlichen \(\pi\)-Donorstärke eines 1,4-Diborabenzols ist es uns nun gelungen, eine Reihe stabiler π-Halbsandwichkomplexe des Thoriums(IV) und des Urans(IV) über einen erstaunlich einfachen Zugang zu generieren: Umsetzung eines 1,4-Diborabenzols mit ThCl\(_{4}\)(dme)\(_{2}\) bzw. UCl\(_{4}\) in Gegenwart einer Lewis-Base. Hierdurch konnten die ersten Beispiele für Actinoidkomplexe mit einem neutralen Borheterocyclus als Sandwich-artigem Liganden erhalten werden. Laut experimentellen und theoretischen Studien ist die starke Actinoid-Heteroaren-Wechselwirkung in diesen Molekülen im Wesentlichen von elektrostatischer Natur. Der kovalente Hauptbeitrag wird hingegen von der Ligand-zu-Metall-\(\pi\)-Wechselwirkung geleistet, während \(\pi\)/δ-Rückbindungsanteile kaum eine Rolle spielen.
Introduction
For both students and teachers, it is challenging to learn and teach a correct crown preparation. The purpose of this study was the design, feasibility and evaluation of a 3D printed tooth model with internal preparation for dental education in crown preparation and to analyse the quality of the prepared printed teeth in comparison with prepared standard model teeth.
Materials and methods
A printable tooth was designed and printed by a stereolithographic printer. 38 fourth‐year dental students in the first clinical course in prosthodontics were trained in a voluntary course using printed teeth. Different aspects of the printed tooth were evaluated by a questionnaire using German school grades (1 best to 5 worst). The quality of the preparation with the printed teeth and standard training teeth was also rated in an evaluation form done by an expert group consisting of five experienced dentists.
Results
The workflow was feasible and cost‐effective for the production of the teeth. The overall rating of the printed tooth was Ø 2.0 ± 0.34 in the questionnaire completed by the students. The students rated the printed tooth model (Ø 2.1 ± 0.85) as significantly better than the standard model tooth (Ø 3.3 ± 0.77; P = .000). The students reported great benefits in the use of this model tooth, for example valuable replacement of a standard model and real teeth, direct control of material loss. The quality of the preparation was evaluated by the expert group as significantly better with an overall mean grade of Ø 2.6 ± 0.37 for the printed teeth compared to Ø 2.9 ± 0.42 for the standard model teeth (P = .000).
Conclusions
The feasibility of this teaching concept was confirmed. The students favoured to work on the innovative 3D‐teeth with internal preparation, emphasising the usefulness of this technique in dental education. The expert group confirmed also the significant training effect of this tooth model in contrast to a standard model tooth.
Background
Fabry disease (FD) is an X‐linked lysosomal storage and multi‐system disorder due to mutations in the α‐galactosidase A (α‐GalA) gene. We investigated the impact of individual amino acid exchanges in the α‐GalA 3D‐structure on the clinical phenotype of FD patients.
Patients and methods
We enrolled 80 adult FD patients with α‐GalA missense mutations and stratified them into three groups based on the amino acid exchange location in the α‐GalA 3D‐structure: patients with active site mutations, buried mutations and other mutations. Patient subgroups were deep phenotyped for clinical and laboratory parameters and FD‐specific treatment.
Results
Patients with active site or buried mutations showed a severe phenotype with multi‐organ involvement and early disease manifestation. Patients with other mutations had a milder phenotype with less organ impairment and later disease onset. α‐GalA activity was lower in patients with active site or buried mutations than in those with other mutations (P < 0.01 in men; P < 0.05 in women) whilst lyso‐Gb3 levels were higher (P < 0.01 in men; <0.05 in women).
Conclusions
The type of amino acid exchange location in the α‐GalA 3D‐structure determines disease severity and temporal course of symptom onset. Patient stratification using this parameter may become a useful tool in the management of FD patients.
Besides their widespread use in coordination chemistry, 2,2’‐bipyridines are known for their ability to undergo cis–trans conformational changes in response to metal ions and acids, which has been primarily investigated at the molecular level. However, the exploitation of such conformational switching in self‐assembly has remained unexplored. In this work, the use of 2,2’‐bipyridines as acid‐responsive conformational switches to tune supramolecular polymerization processes has been demonstrated. To achieve this goal, we have designed a bipyridine‐based linear bolaamphiphile, 1, that forms ordered supramolecular polymers in aqueous media through cooperative aromatic and hydrophobic interactions. Interestingly, addition of acid (TFA) induces the monoprotonation of the 2,2’‐bipyridine moiety, leading to a switch in the molecular conformation from a linear (trans) to a V‐shaped (cis) state. This increase in molecular distortion along with electrostatic repulsions of the positively charged bipyridine‐H\(^{+}\) units attenuate the aggregation tendency and induce a transformation from long fibers to shorter thinner fibers. Our findings may contribute to opening up new directions in molecular switches and stimuli‐responsive supramolecular materials.
Depending on the connectivity of solubilizing oligoethylene glycol (OEG) side chains to the π‐cores of amphiphilic naphthalene and perylene bisimide dyes, self‐assembly in water occurs either upon heating or cooling. Herein, we show that this effect originates from differences in the enwrapping capability of the π‐cores by the OEG chains. Rylene bisimides bearing phenyl substituents with three OEG chains attached directly to the hydrophobic π‐cores are strongly sequestered by the OEG chains. These molecules self‐assemble at elevated temperatures in an entropy‐driven process according to temperature‐ and concentration‐dependent UV/Vis spectroscopy and calorimetric dilution studies. In contrast, for rylene bisimides in which phenyl substituents with three OEG chains are attached via a methylene spacer, leading to much weaker sequestration, self‐assembly originates upon cooling in an enthalpy‐driven process. Our explanation for this controversial behavior is that the aggregation in the latter case is dictated by the release of “high energy water” from the hydrophobic π‐surfaces as well as dispersion interactions between the π‐scaffolds which drive the self‐assembly in an enthalpically driven process. In contrast, for the former case we suggest that in addition to the conventional explanation of a dehydration of hydrogen‐bonded water molecules from OEG units it is in particular the increase in conformational entropy of back‐folded OEG side chains upon aggregation that provides the pronounced gain in entropy that drives the aggregation process. Thus, our studies revealed that a subtle change in the attachment of solubilizing substituents can switch the thermodynamic signature for the self‐assembly of amphiphilic dyes in water from enthalpy‐ to entropy‐driven.
Aim
To assess the suitability of several 3D‐printed resins for the manufacturing of tooth replicas for endodontic training in comparison with commercially available replicas by analysing the properties of the materials and comparing them with real teeth during endodontic training.
Methodology
Tooth replicas were 3D‐printed using four resins (NextDent Model, NextDent C&B, V‐Print ee and Vero White Plus) and compared with two commercially available products (VDW and Smile Factory) as well as extracted human teeth. Martens hardness, indentation modulus and radiopacity were investigated on these tooth replicas. Experienced dentists evaluated the suitability of the replicas for endodontic training by comparing them with real teeth in terms of appearance, anatomy, radiopacity, similarity to dentine during access opening, canal gauging and canal instrumentation. Data were analysed using the Kolmogorov–Smirnov and Mann–Whitney U‐test.
Results
The greatest hardness values were recorded for human dentine (P < 0.001), followed by V‐Print ee and the commercial tooth replica of Smile Factory. The greatest radiopacity was associated with VOC and dentine (P < 0.001) in comparison with the other materials tested. The appearance of the in‐house printed tooth replicas was subjectively evaluated by the dentists as being more realistic than the commercially available products. No differences between the replicas was detected during mechanical instrumentation of root canals.
Conclusion
None of the tooth replicas were able to simulate human dentine from the perspectives evaluated. V‐Print ee had radiopacity comparable with dentine, but its hardness was not comparable with dentine.
Purpose
The aim of this study was to compare the wave‐CAIPI (controlled aliasing in parallel imaging) trajectory to the Cartesian sampling for accelerated free‐breathing 4D lung MRI.
Methods
The wave‐CAIPI k‐space trajectory was implemented in a respiratory self‐gated 3D spoiled gradient echo pulse sequence. Trajectory correction applying the gradient system transfer function was used, and images were reconstructed using an iterative conjugate gradient SENSE (CG SENSE) algorithm. Five healthy volunteers and one patient with squamous cell carcinoma in the lung were examined on a clinical 3T scanner, using both sampling schemes. For quantitative comparison of wave‐CAIPI and standard Cartesian imaging, the normalized mutual information and the RMS error between retrospectively accelerated acquisitions and their respective references were calculated. The SNR ratios were investigated in a phantom study.
Results
The obtained normalized mutual information values indicate a lower information loss due to acceleration for the wave‐CAIPI approach. Average normalized mutual information values of the wave‐CAIPI acquisitions were 10% higher, compared with Cartesian sampling. Furthermore, the RMS error of the wave‐CAIPI technique was lower by 19% and the SNR was higher by 14%. Especially for short acquisition times (down to 1 minute), the undersampled Cartesian images showed an increased artifact level, compared with wave‐CAIPI.
Conclusion
The application of the wave‐CAIPI technique to 4D lung MRI reduces undersampling artifacts, in comparison to a Cartesian acquisition of the same scan time. The benefit of wave‐CAIPI sampling can therefore be traded for shorter examinations, or enhancing image quality of undersampled 4D lung acquisitions, keeping the scan time constant.
Aims
Heart failure (HF) leads to repeat hospitalisations and reduces the duration and quality of life. Pulmonary artery pressure (PAP)‐guided HF management using the CardioMEMS™ HF system was shown to be safe and reduce HF hospitalisation (HFH) rates in New York Heart Association (NYHA) class III patients. However, these findings have not been replicated in health systems outside the United States. Therefore, the CardioMEMS European Monitoring Study for Heart Failure (MEMS‐HF) evaluated the safety, feasibility, and performance of this device in Germany, The Netherlands, and Ireland.
Methods and results
A total of 234 NYHA class III patients (68 ± 11 years, 22% female, ≥1 HFH in the preceding year) from 31 centres were implanted with a CardioMEMS sensor and underwent PAP‐guided HF management. One‐year rates of freedom from device‐ or system‐related complications and from sensor failure (co‐primary outcomes) were 98.3% [95% confidence interval (CI) 95.8–100.0] and 99.6% (95% CI 97.6–100.0), respectively. Survival rate was 86.2%. For the 12 months post‐ vs. pre‐implant, HFHs decreased by 62% (0.60 vs. 1.55 events/patient‐year; hazard ratio 0.38, 95% CI 0.31–0.48; P < 0.0001). After 12 months, mean PAP decreased by 5.1 ± 7.4 mmHg, Kansas City Cardiomyopathy Questionnaire (KCCQ) overall/clinical summary scores increased from 47.0 ± 24.0/51.2 ± 24.8 to 60.5 ± 24.3/62.4 ± 24.1 (P < 0.0001), and the 9‐item Patient Health Questionnaire sum score improved from 8.7 ± 5.9 to 6.3 ± 5.1 (P < 0.0001).
Conclusion
Haemodynamic‐guided HF management proved feasible and safe in the health systems of Germany, The Netherlands, and Ireland. Physician‐directed treatment modifications based on remotely obtained PAP values were associated with fewer HFH, sustainable PAP decreases, marked KCCQ improvements, and remission of depressive symptoms.
Carrion plays an essential role in shaping the structure and functioning of ecosystems and has far‐reaching implications for biodiversity conservation. The change in availability and type of carcasses throughout ecosystems can involve negative effects for scavenging communities. To address this issue, there have been recent conservation management measures of carrion provision in natural systems. However, the optimal conditions under which exposing carcasses to optimize conservation outcomes are still limited. Here, we used camera traps throughout elevational and vegetational gradients to monitor the consumption of 48 deer carcasses over a study period of six years by evaluating 270,279 photographs resulting out of 15,373 trap nights. We detected 17 species visiting carcass deployments, including five endangered species. Our results show that large carcasses, the winter season, and a heterogeneous surrounding habitat enhanced the frequency of carcass visits and the species richness of scavenger assemblages. Contrary to our expectations, carcass species, condition (fresh/frozen), and provision schedule (continuous vs single exposure) did not influence scavenging frequency or diversity. The carcass visitation frequency increased with carcass mass and lower temperatures. The effect of large carcasses was especially pronounced for mesopredators and the Eurasian lynx (Lynx lynx). Lynx were not too influenced in its carrion acquisition by the season, but exclusively preferred remote habitats containing higher forest cover. Birds of prey, mesopredators, and top predators were also positively influenced by the visiting rate of ravens (Corvus corax), whereas no biotic or abiotic preferences were found for wild boars (Sus scrofa). This study provides evidence that any ungulate species of carrion, either in a fresh or in previously frozen condition, attracts a high diversity of scavengers especially during winter, thereby supporting earlier work that carcass provisions may support scavenger communities and endangered species.
A method is reported for making hollow channels within hydrogels decorated with cell‐adhesion peptides exclusively at the channel surface. Sacrificial fibers of different diameters are used to introduce channels within poly(ethylene glycol) hydrogels crosslinked with maleimide‐thiol chemistry, which are backfilled with a cysteine‐containing peptide solution which is conjugated to the lumen with good spatial efficiency. This allows for peptide patterning in only the areas of the hydrogel where they are needed when used as cell‐guides, reducing the amount of required peptide 20‐fold when compared to bulk functionalization. The power of this approach is highlighted by successfully using these patterned hydrogels without active perfusion to guide fibroblasts and olfactory ensheathing cells—the latter having unique potential in neural repair therapies.
Columnar Liquid Crystals from Star‐Shaped Conjugated Mesogens as Nano‐Reservoirs for Small Acceptors
(2020)
Shape‐persistent conjugated mesogens with oligothiophene arms of different lengths have been synthesized. Such mesogens possess free intrinsic space between their conjugated arms. They form columnar liquid‐crystalline phases, in which the void is filled by dense helical packing in the neat phase similar to an oligo(phenylene vinylene) derivative of equal size. The void can also be compensated by the inclusion of the small acceptor molecule 2,4,7‐trinitrofluorenone. In solution, the acceptor interacts with the core as the largest π‐surface, while in the solid material, it is incorporated between the arms and sandwiched by the star‐shaped neighbours along the columnar assemblies. The TNF acceptors are not nanosegregated from the star‐shaped donors, thus the liquid crystal structure converts to a nano‐reservoir for TNF (endo‐receptor). These host–guest arrangements are confirmed by comprehensive X‐ray scattering experiments and solid‐state NMR spectroscopy. This results in ordered columnar hexagonal phases at high temperatures, which change to helical columnar mesophases or to columnar soft crystals at room temperature.
SLC2A3 encodes the predominantly neuronal glucose transporter 3 (GLUT3), which facilitates diffusion of glucose across plasma membranes. The human brain depends on a steady glucose supply for ATP generation, which consequently fuels critical biochemical processes, such as axonal transport and neurotransmitter release. Besides its role in the central nervous system, GLUT3 is also expressed in nonneural organs, such as the heart and white blood cells, where it is equally involved in energy metabolism. In cancer cells, GLUT3 overexpression contributes to the Warburg effect by answering the cell's increased glycolytic demands. The SLC2A3 gene locus at chromosome 12p13.31 is unstable and prone to non‐allelic homologous recombination events, generating multiple copy number variants (CNVs) of SLC2A3 which account for alterations in SLC2A3 expression. Recent associations of SLC2A3 CNVs with different clinical phenotypes warrant investigation of the potential influence of these structural variants on pathomechanisms of neuropsychiatric, cardiovascular, and immune diseases. In this review, we accumulate and discuss the evidence how SLC2A3 gene dosage may exert diverse protective or detrimental effects depending on the pathological condition. Cellular states which lead to increased energetic demand, such as organ development, proliferation, and cellular degeneration, appear particularly susceptible to alterations in SLC2A3 copy number. We conclude that better understanding of the impact of SLC2A3 variation on disease etiology may potentially provide novel therapeutic approaches specifically targeting this GLUT.
The increasingly frequent use of immunomodulatory agents in dermatology requires the observance of specific recommendations for immunization. These recommendations are developed and regularly updated by the German Standing Committee on Vaccination (STIKO), an independent advisory group at the Robert Koch Institute. Dermatological patients on immunosuppressive treatment should ideally receive all vaccinations included in the standard immunization schedule. Additionally, it is recommended that they also undergo vaccination against the seasonal flu, pneumococci, and herpes zoster (inactivated herpes zoster subunit vaccine for patients ≥ 50 years). Additional immunizations against Haemophilus influenzae type B, hepatitis B and meningococci may be indicated depending on individual comorbidities and exposure risk. Limitations of use, specific contraindications and intervals to be observed between vaccination and immunosuppression depend on the immunosuppressive agent used and its dosing. Only under certain conditions may live‐attenuated vaccines be administered in patients on immunosuppressive therapy. Given its strong suppressive effect on the humoral immune response, no vaccines – except for flu shots – should be given within six months after rituximab therapy.
This CME article presents current recommendations on immunization in immunocompromised individuals, with a special focus on dermatological patients. Its goal is to enable readers to provide competent counseling and to initiate necessary immunizations in this vulnerable patient group.
Melt electrowriting, a high‐resolution additive manufacturing technology, has so far been developed with vertical stacking of fiber layers, with a printing trajectory that is constant for each layer. In this work, microscale layer shifting is introduced through deliberately offsetting the printing trajectory for each printed layer. Inaccuracies during the printing of sinusoidal walls are corrected via layer shifting, resulting in accurate control of their geometry and mechanical properties. Furthermore, more substantial layer shifting allows stacking of fiber layers in a horizontal manner, overcoming the electrostatic autofocusing effect that favors vertical layer stacking. Novel nonlinear geometries, such as overhangs, wall texturing and branching, and smooth and abrupt changes in printing trajectory are presented, demonstrating the flexibility of the layer shifting approach beyond the state‐of‐the‐art. The practice of microscale layer shifting for melt electrowriting enables more complex geometries that promise to have a profound impact on the development of products in a broad range of applications.
Pyridoxal 5′‐phosphate (PLP) is an essential cofactor for neurotransmitter metabolism. Pyridoxal phosphatase (PDXP) deficiency in mice increases PLP and γ‐aminobutyric acid levels in the brain, yet how PDXP is regulated is unclear. Here, we identify the Ca\(^{2+}\)‐ and integrin‐binding protein 1 (CIB1) as a PDXP interactor by yeast two‐hybrid screening and find a calmodulin (CaM)‐binding motif that overlaps with the PDXP‐CIB1 interaction site. Pulldown and crosslinking assays with purified proteins demonstrate that PDXP directly binds to CIB1 or CaM. CIB1 or CaM does not alter PDXP phosphatase activity. However, elevated Ca\(^{2+}\) concentrations promote CaM binding and, thereby, diminish CIB1 binding to PDXP, as both interactors bind in a mutually exclusive way. Hence, the PDXP‐CIB1 complex may functionally differ from the PDXP‐Ca\(^{2+}\)‐CaM complex.
Bis‐NHC Aluminium and Gallium Dihydride Cations [(NHC)\(_{2}\)EH\(_{2}\)]\(^{+}\) (E = Al, Ga)
(2020)
The NHC alane and gallane adducts (NHC)·AlH\(_{2}\)I (NHC = Me\(_{2}\)Im\(^{Me}\) 7, iPr\(_{2}\)Im 8, iPr\(_{2}\)Im\(^{Me}\) 9) and (NHC)·GaH\(_{2}\)I (NHC = Me\(_{2}\)Im\(^{Me}\) 10, iPr\(_{2}\)Im\(^{Me}\) 11, Dipp\(_{2}\)Im 12; R\(_{2}\)Im = 1,3‐di‐organyl‐imidazolin‐2‐ylidene; Dipp = 2,6‐diisopropylphenyl; iPr = isopropyl; Me\(_{2}\)Im\(^{Me}\) = 1,3,4,5‐tetra‐methyl‐imidazolin‐2‐ylidene) were prepared either by the simple yet efficient reaction of the NHC adduct (NHC)·AlH\(_{3}\) with elemental iodine or by the treatment of (NHC)·GaH\(_{3}\) with an excess of methyl iodide at room temperature. The reaction of one equivalent of the group 13 NHC complexes with an additional equivalent of the corresponding NHC afforded cationic aluminium and gallium hydrides [(NHC)\(_{2}\)·AlH\(_{2}\)]\(^{+}\)I− (NHC = Me\(_{2}\)Im\(^{Me}\) 13, iPr\(_{2}\)Im 14, iPr\(_{2}\)Im\(^{Me}\) 15) and [(NHC)\(_{2}\)·GaH\(_{2}\)]\(^{+}\)I− (NHC = Me\(_{2}\)Im\(^{Me}\) 16, iPr\(_{2}\)Im\(^{Me}\) 17) and the normal and abnormal NHC coordinated compound [(Dipp\(_{2}\)Im)·GaH\(_{2}\)(aDipp\(_{2}\)Im)]+I− 18. Compounds 7–18 were isolated and characterized by means of elemental analysis, IR and multinuclear NMR spectroscopy and by X‐ray diffraction of the compounds 7, 9, 10, 15, 16 and 18.
Land‐use intensification leads to loss and degradation of habitats and is thus a major driver of biodiversity loss. Restoration strategies typically focus on promoting biodiversity but often neglect that land‐use intensification could have changed the underlying mechanisms of community assembly. Since assembly mechanisms determine the diversity and composition of communities, we propose that evaluation of restoration strategies should consider effects of restoration on biodiversity and community assembly. Using a multi‐taxon approach, we tested whether a strategy that promotes forest biodiversity by restoring deadwood habitats also affects assembly patterns.
We assessed saproxylic (i.e. deadwood‐dependent) beetles and fungi, as well as non‐saproxylic plants and birds in 68 beech forest plots in southern Germany, 8 years after the commencement of a restoration project. To assess changes in community assembly, we analysed the patterns of functional–phylogenetic diversity, community‐weighted mean (CWM) traits and their diversity. We hypothesized that restoration increases habitat amount and heterogeneity of deadwood and reduces canopy cover and thereby decreases the strength of environmental filters imposed by past silvicultural intensification, such as a low amount in deadwood.
With the restoration of deadwood habitats, saproxylic beetle communities became less functionally–phylogenetically similar, whereas the assembly patterns of saproxylic fungi and non‐saproxylic taxa remained unaffected by deadwood restoration. Among the traits analysed, deadwood diameter niche position of species was most strongly affected indicating that the enrichment of large deadwood objects led to lower functional–phylogenetical similarity of saproxylic beetles. Community assembly and traits of plants were mainly influenced by microclimate associated with changes in canopy cover.
Synthesis and applications. Our results indicate that the positive effects of deadwood restoration on saproxylic beetle richness are associated with an increase in deadwood amount. This might be linked to an increase in deadwood heterogeneity, and therefore decreasing management‐induced environmental filters. Deadwood enrichment can thus be considered an effective restoration strategy which reduces the negative effects of intense forest management on saproxylic taxa by not only promoting biodiversity but also by decreasing the environmental filters shaping saproxylic beetle communities, thus allowing the possibly for more interactions between species and a higher functional diversity.
Monitoring variations in the functioning of the autonomic nervous system may help personalize training of runners and provide more pronounced physiological adaptations and performance improvements. We systematically reviewed the scientific literature comparing physiological adaptations and/or improvements in performance following training based on responses of the autonomic nervous system (ie, changes in heart rate variability) and predefined training. PubMed, SPORTDiscus, and Web of Science were searched systematically in July 2019. Keywords related to endurance, running, autonomic nervous system, and training. Studies were included if they (a) involved interventions consisting predominantly of running training; (b) lasted at least 3 weeks; (c) reported pre‐ and post‐intervention assessment of running performance and/or physiological parameters; (d) included an experimental group performing training adjusted continuously on the basis of alterations in HRV and a control group; and (e) involved healthy runners. Five studies involving six interventions and 166 participants fulfilled our inclusion criteria. Four HRV‐based interventions reduced the amount of moderate‐ and/or high‐intensity training significantly. In five interventions, improvements in performance parameters (3000 m, 5000 m, Loadmax, Tlim) were more pronounced following HRV‐based training. Peak oxygen uptake (VO\(_{2peak}\)) and submaximal running parameters (eg, LT1, LT2) improved following both HRV‐based and predefined training, with no clear difference in the extent of improvement in VO\(_{2peak}\). Submaximal running parameters tended to improve more following HRV‐based training. Research findings to date have been limited and inconsistent. Both HRV‐based and predefined training improve running performance and certain submaximal physiological adaptations, with effects of the former training tending to be greater.
Background
Though risk for recurrent vascular events is high following ischemic stroke, little knowledge about risk factors for secondary events post‐stroke exists.
Objectives
Coagulation factors XII, XI, and VIII (FXII, FXI, and FVIII) have been implicated in first thrombotic events, and our aim was to estimate their effects on vascular outcomes within 3 years after first stroke.
Patients/Methods
In the Prospective Cohort with Incident Stroke Berlin (PROSCIS‐B) study, we followed participants aged 18 and older for 3 years after first mild to moderate ischemic stroke event or until occurrence of recurrent stroke, myocardial infarction, or all‐cause mortality. We compared high coagulation factor activity levels to normal and low levels and also analyzed activities as continuous variables. We used Cox proportional hazards models adjusted for age, sex, and cardiovascular risk factors to estimate hazard ratios (HRs) for the combined endpoint.
Results
In total, 94 events occurred in 576 included participants, resulting in an absolute rate of 6.6 events per 100 person‐years. After confounding adjustment, high FVIII activity showed the strongest relationship with the combined endpoint (HR = 2.05, 95% confidence interval [CI] 1.28–3.29). High FXI activity was also associated with a higher hazard (HR = 1.80, 95% CI 1.09–2.98), though high FXII activity was not (HR = 0.86, 95% CI 0.49–1.51). Continuous analyses yielded similar results.
Conclusions
In our study of mild to moderate ischemic stroke patients, high activity levels of FXI and FVIII but not FXII were associated with worse vascular outcomes in the 3‐year period after first ischemic stroke.
COVID‐19, caused by the coronavirus SARS‐CoV‐2, has become pandemic. A further level of complexity opens up as soon as we look at diseases whose pathogenesis and therapy involve different immunological signaling pathways, which are potentially affected by COVID‐19. Medical treatments must often be reassessed and questioned in connection with this infection.
This article summarizes the current knowledge of COVID‐19 in the light of major dermatological and allergological diseases. It identifies medical areas lacking sufficient data and draws conclusions for the management of our patients during the pandemic. We focus on common chronic inflammatory skin diseases with complex immunological pathogenesis: psoriasis, eczema including atopic dermatitis, type I allergies, autoimmune blistering and inflammatory connective tissue diseases, vasculitis, and skin cancers. Since several other inflammatory skin diseases display related or comparable immunological reactions, clustering of the various inflammatory dermatoses into different disease patterns may help with therapeutic decisions. Thus, following these patterns of skin inflammation, our review may supply treatment recommendations and thoughtful considerations for disease management even beyond the most frequent diseases discussed here.
Unlike the conventional p‐doping of organic semiconductors (OSCs) using acceptors, here, an efficient doping concept for diketopyrrolopyrrole‐based polymer PDPP[T]\(_{2}\)‐EDOT (OSC‐1) is presented using an oxidized p‐type semiconductor, Spiro‐OMeTAD(TFSI)\(_{2}\) (OSC‐2), exploiting electron transfer from HOMO\(_{OSC-1}\) to HOMO\(_{OSC-2}\). A shift of work function toward the HOMO\(_{OSC-1}\) upon doping is confirmed by ultraviolet photoelectron spectroscopy (UPS). Detailed X‐ray photoelectron spectroscopy (XPS) and UV–vis–NIR absorption studies confirm HOMO\(_{OSC-1}\) to HOMO\(_{OSC-2}\) electron transfer. The reduction products of Spiro‐OMeTAD(TFSI)\(_{2}\) to Spiro‐OMeTAD(TFSI) and Spiro‐OMeTAD is also confirmed and their relative amounts in doped samples is determined. Mott–Schottky analysis shows two orders of magnitude increase in free charge carrier density and one order of magnitude increase in the charge carrier mobility. The conductivity increases considerably by four orders of magnitude to a maximum of 10 S m\(^{-1}\) for a very low doping ratio of 8 mol%. The doped polymer films exhibit high thermal and ambient stability resulting in a maximum power factor of 0.07 µW m\(^{-1}\) K\(^{-2}\) at a Seebeck coefficient of 140 µV K\(^{-1}\) for a very low doping ratio of 4 mol%. Also, the concept of HOMO\(_{OSC-1}\) to HOMO\(_{OSC-2}\) electron transfer is a highly efficient, stable and generic way to p‐dope other conjugated polymers.
Background
Patients with acute leukaemia have a high incidence of fungal infections. This has primarily been shown in acute myeloid leukaemia and is different for acute lymphoblastic leukaemia. Until now no benefit of mould active prophylaxis has been demonstrated in the latter population.
Methods
In this retrospective single‐centre study, we analysed the incidence, clinical relevance, and outcome of invasive fungal diseases (IFD) as well as the impact of antifungal prophylaxis for the first 100 days following the primary diagnosis of acute lymphoblastic leukaemia.
Results
In 58 patients a high rate of proven, probable, and possible fungal infections could be demonstrated with a 3.4%, 8.6%, and 17.2% likelihood, respectively. The incidence might be even higher, as nearly 40% of all patients had no prolonged neutropenia for more than 10 days, excluding those from the European Organization of Research and Treatment of cancer and the Mycoses Study Group criteria for probable invasive fungal disease. The diagnosed fungal diseases had an impact on the duration of hospitalisation, which was 13 days longer for patients with proven/probable IFD compared to patients with no signs of fungal infection. Use of antifungal prophylaxis did not significantly affect the risk of fungal infection.
Conclusion
Patients with acute lymphoblastic leukaemia are at high risk of acquiring an invasive fungal disease. Appropriate criteria to define fungal infections, especially in this population, and strategies to reduce the risk of infection, including antifungal prophylaxis, need to be further evaluated.
We synthesized a series of new mono‐, di‐, tri‐ and tetra‐substituted perylene derivatives with strong bis(para‐methoxyphenyl)amine (DPA) donors at the uncommon 2,5,8,11‐positions. The properties of our new donor‐substituted perylenes were studied in detail to establish a structure‐property relationship. Interesting trends and unusual properties are observed for this series of new perylene derivatives, such as a decreasing charge transfer (CT) character with increasing number of DPA moieties and individual reversible oxidations for each DPA moiety. Thus, (DPA)‐Per possesses one reversible oxidation while (DPA)\(_{4}\)‐Per has four. The mono‐ and di‐substituted derivatives display unusually large Stokes shifts not previously reported for perylenes. Furthermore, transient absorption measurements of the new derivatives reveal an excited state with lifetimes of several hundred microseconds, which sensitizes singlet oxygen with quantum yields of up to 0.83.
Aim
To assess the prevalence and severity of periodontitis in patients with moderate chronic kidney disease (CKD) and comparing the results with the self‐reported periodontitis awareness of the study subjects.
Material and methods
The periodontal status of 270 patients with moderate CKD randomly selected from a cohort of 5,217 subjects participating in the prospective observational German Chronic Kidney Disease (GCKD) project was analysed by recording bleeding on probing (BOP), probing pocket depth (PPD) and clinical attachment level (CAL). Furthermore, the awareness of the study subjects of their periodontal conditions was evaluated by a self‐reported questionnaire.
Results
24.4% of the CKD study patients showed no or only mild signs of periodontal disease, 47.6% displayed moderate and 27% severe periodontitis. Questionnaire data revealed that 62.3% of the study subjects with severe periodontitis were not aware of the presence of the disease, 44.4% denied having received any systematic periodontal therapy so far, although 50% of them indicated to visit their dentist regularly for professional tooth cleanings.
Conclusion
While the clinical study data confirm an increased prevalence of periodontitis in CKD patients, their self‐reported awareness of periodontitis was low.
DNA metabarcoding was utilized for a large‐scale, multiyear assessment of biodiversity in Malaise trap collections from the Bavarian Forest National Park (Germany, Bavaria). Principal component analysis of read count‐based biodiversities revealed clustering in concordance with whether collection sites were located inside or outside of the National Park. Jaccard distance matrices of the presences of barcode index numbers (BINs) at collection sites in the two survey years (2016 and 2018) were significantly correlated. Overall similar patterns in the presence of total arthropod BINs, as well as BINs belonging to four major arthropod orders across the study area, were observed in both survey years, and are also comparable with results of a previous study based on DNA barcoding of Sanger‐sequenced specimens. A custom reference sequence library was assembled from publicly available data to screen for pest or invasive arthropods among the specimens or from the preservative ethanol. A single 98.6% match to the invasive bark beetle Ips duplicatus was detected in an ethanol sample. This species has not previously been detected in the National Park.
S2k guidelines for the treatment of pemphigus vulgaris/foliaceus and bullous pemphigoid: 2019 update
(2020)
cAAC‐Stabilized 9,10‐diboraanthracenes—Acenes with Open‐Shell Singlet Biradical Ground States
(2020)
Narrow HOMO–LUMO gaps and high charge‐carrier mobilities make larger acenes potentially high‐efficient materials for organic electronic applications. The performance of such molecules was shown to significantly increase with increasing number of fused benzene rings. Bulk quantities, however, can only be obtained reliably for acenes up to heptacene. Theoretically, (oligo)acenes and (poly)acenes are predicted to have open‐shell singlet biradical and polyradical ground states, respectively, for which experimental evidence is still scarce. We have now been able to dramatically lower the HOMO–LUMO gap of acenes without the necessity of unfavorable elongation of their conjugated π system, by incorporating two boron atoms into the anthracene skeleton. Stabilizing the boron centers with cyclic (alkyl)(amino)carbenes gives neutral 9,10‐diboraanthracenes, which are shown to feature disjointed, open‐shell singlet biradical ground states.
Both, jawless and jawed vertebrates possess three lymphocyte lineages defined by highly diverse antigen receptors: Two T‐cell‐ and one B‐cell‐like lineage. In both phylogenetic groups, the theoretically possible number of individual antigen receptor specificities can even outnumber that of lymphocytes of a whole organism. Despite fundamental differences in structure and genetics of these antigen receptors, convergent evolution led to functional similarities between the lineages. Jawed vertebrates possess αβ and γδ T‐cells defined by eponymous αβ and γδ T‐cell antigen receptors (TCRs). “Conventional” αβ T‐cells recognize complexes of Major Histocompatibility Complex (MHC) class I and II molecules and peptides. Non‐conventional T‐cells, which can be αβ or γδ T‐cells, recognize a large variety of ligands and differ strongly in phenotype and function between species and within an organism. This review describes similarities and differences of non‐conventional T‐cells of various species and discusses ligands and functions of their TCRs. A special focus is laid on Vγ9Vδ2 T‐cells whose TCRs act as sensors for phosphorylated isoprenoid metabolites, so‐called phosphoantigens (PAg), associated with microbial infections or altered host metabolism in cancer or after drug treatment. We discuss the role of butyrophilin (BTN)3A and BTN2A1 in PAg‐sensing and how species comparison can help in a better understanding of this human Vγ9Vδ2 T‐cell subset.
Hypophosphatasia (HPP) is a rare, inherited, metabolic disease caused by deficient tissue non‐specific alkaline phosphatase activity. This study aims to assess patient‐reported pain, disability and health‐related quality of life (HRQoL) in a real‐world cohort of adults with HPP who were not receiving asfotase alfa during the analysis. Adults (≥18 years old) with HPP (confirmed by ALPL gene mutation and/or low serum alkaline phosphatase activity for age/sex) were identified from the Global HPP Registry (NCT02306720). Demographics, clinical characteristics, and data on patient‐reported pain, disability, and HRQoL (assessed by Brief Pain Inventory Short Form [BPI‐SF], Health Assessment Questionnaire Disability Index [HAQ‐DI], and 36‐Item Short‐Form Health Survey version 2 [SF‐36v2], respectively) were stratified by pediatric‐ and adult‐onset HPP and summarized descriptively. Of the 304 adults included (median [min, max] age 48.6 [18.8, 79.8] years; 74% women), 45% had adult‐onset HPP and 33% had pediatric‐onset HPP (unknown age of onset, 22%). Of those with data, 38% had experienced ≥5 HPP manifestations and 62% had a history of ≥1 fracture/pseudofracture. Median (Q1, Q3) BPI‐SF scores were 3.5 (1.5, 5.3) for pain severity and 3.3 (0.9, 6.2) for pain interference. Median (Q1, Q3) disability on the HAQ‐DI was 0.3 (0.0, 0.7). Median (Q1, Q3) physical and mental component summary scores on the SF‐36v2 were 42.4 (32.7, 49.9) and 45.3 (36.3, 54.8), respectively. Greater numbers of HPP manifestations experienced/body systems affected correlated significantly with poorer scores on the BPI‐SF, HAQ‐DI, and SF‐36v2 (all p < 0.05). No significant differences between adults with pediatric‐ and adult‐onset HPP were observed for patient‐reported outcomes, except for disability and the BPI‐SF question “pain at its worst,” which were significantly higher among adults with pediatric‐ versus adult‐onset HPP (p = 0.03 and 0.04, respectively). These data from the Global HPP Registry show that adults with HPP have a substantial burden of illness that is associated with reduced patient‐reported HRQoL, regardless of age of disease onset.
Planar Cyclopenten‐4‐yl Cations: Highly Delocalized π Aromatics Stabilized by Hyperconjugation
(2020)
Theoretical studies predicted the planar cyclopenten‐4‐yl cation to be a classical carbocation, and the highest‐energy isomer of C\(_{5}\)H\(_{7}\)\(^{+}\). Hence, its existence has not been verified experimentally so far. We were now able to isolate two stable derivatives of the cyclopenten‐4‐yl cation by reaction of bulky alanes Cp\(^{R}\)AlBr\(_{2}\) with AlBr3. Elucidation of their (electronic) structures by X‐ray diffraction and quantum chemistry studies revealed planar geometries and strong hyperconjugation interactions primarily from the C−Al σ bonds to the empty p orbital of the cationic sp\(^{2}\) carbon center. A close inspection of the molecular orbitals (MOs) and of the anisotropy of current (induced) density (ACID), as well as the evaluation of various aromaticity descriptors indicated distinct aromaticity for these cyclopenten‐4‐yl derivatives, which strongly contrasts the classical description of this system. Here, strong delocalization of π electrons spanning the whole carbocycle has been verified, thus providing rare examples of π aromaticity involving saturated sp\(^{3}\) carbon atoms.
Three different perfluoroalkylated borafluorenes (\(^{F}\)Bf) were prepared and their electronic and photophysical properties were investigated. The systems have four trifluoromethyl moieties on the borafluorene moiety as well as two trifluoromethyl groups at the ortho positions of their exo‐aryl moieties. They differ with regard to the para substituents on their exo‐aryl moieties, being a proton \(^{F}\)Xyl\(^{F}\)Bf, \(^{F}\)Xyl: 2,6‐bis(trifluoromethyl)phenyl), a trifluoromethyl group (\(^{F}\)Mes\(^{F}\)Bf, \(^{F}\)Mes: 2,4,6‐tris(trifluoromethyl)phenyl) or a dimethylamino group (p‐NMe\(_{2}\)‐\(^{F}\)Xyl\(^{F}\)Bf, p‐NMe\(_{2}\)‐\(^{F}\)Xyl: 4‐(dimethylamino)‐2,6‐bis(trifluoromethyl)phenyl), respectively. All derivatives exhibit extraordinarily low reduction potentials, comparable to those of perylenediimides. The most electron‐deficient derivative \(^{F}\)Mes\(^{F}\)Bf was also chemically reduced and its radical anion isolated and characterized. Furthermore, all compounds exhibit very long fluorescent lifetimes of about 250 ns up to 1.6 μs; however, the underlying mechanisms responsible for this differ. The donor‐substituted derivative p‐NMe\(_{2}\)‐\(^{F}\)Xyl\(^{F}\)Bf exhibits thermally activated delayed fluorescence (TADF) from a charge‐transfer (CT) state, whereas the \(^{F}\)Mes\(^{F}\)Bf and FXylFBf borafluorenes exhibit only weakly allowed locally excited (LE) transitions due to their symmetry and low transition‐dipole moments.
Using a new divergent approach, conjugated triarylborane dendrimers were synthesized up to the 2nd generation. The synthetic strategy consists of three steps: 1) functionalization, via iridium catalyzed C−H borylation; 2) activation, via fluorination of the generated boronate ester with K[HF\(_{2}\)] or [N(nBu\(_{4}\))][HF\(_{2}\)]; and 3) expansion, via reaction of the trifluoroborate salts with aryl Grignard reagents. The concept was also shown to be viable for a convergent approach. All but one of the conjugated borane dendrimers exhibit multiple, distinct and reversible reduction potentials, making them potentially interesting materials for applications in molecular accumulators. Based on their photophysical properties, the 1st generation dendrimers exhibit good conjugation over the whole system. However, the conjugation does not increase further upon expansion to the 2nd generation, but the molar extinction coefficients increase linearly with the number of triarylborane subunits, suggesting a potential application as photonic antennas.
Aims
Inhibition of neprilysin and angiotensin II receptor by sacubitril/valsartan (Val) (LCZ696) reduces mortality in heart failure (HF) patients compared with sole inhibition of renin–angiotensin system. Beneficial effects of increased natriuretic peptide levels upon neprilysin inhibition have been proposed, whereas direct effects of sacubitrilat (Sac) (LBQ657) on myocardial Ca\(^{2+}\) cycling remain elusive.
Methods and results
Confocal microscopy (Fluo‐4 AM) was used to investigate pro‐arrhythmogenic sarcoplasmic reticulum (SR) Ca\(^{2+}\) leak in freshly isolated murine and human ventricular cardiomyocytes (CMs) upon Sac (40 μmol/L)/Val (13 μmol/L) treatment. The concentrations of Sac and Val equalled plasma concentrations of LCZ696 treatment used in PARADIGM‐HF trial. Epifluorescence microscopy measurements (Fura‐2 AM) were performed to investigate effects on systolic Ca\(^{2+}\) release, SR Ca\(^{2+}\) load, and Ca\(^{2+}\)‐transient kinetics in freshly isolated murine ventricular CMs. The impact of Sac on myocardial contractility was evaluated using in toto‐isolated, isometrically twitching ventricular trabeculae from human hearts with end‐stage HF. Under basal conditions, the combination of Sac/Val did not influence diastolic Ca\(^{2+}\)‐spark frequency (CaSpF) nor pro‐arrhythmogenic SR Ca\(^{2}\) leak in isolated murine ventricular CMs (n CMs/hearts = 80/7 vs. 100/7, P = 0.91/0.99). In contrast, Sac/Val treatment reduced CaSpF by 35 ± 9% and SR Ca\(^{2+}\) leak by 45 ± 9% in CMs put under catecholaminergic stress (isoproterenol 30 nmol/L, n = 81/7 vs. 62/7, P < 0.001 each). This could be attributed to Sac, as sole Sac treatment also reduced both parameters by similar degrees (reduction of CaSpF by 57 ± 7% and SR Ca2+ leak by 76 ± 5%; n = 101/4 vs. 108/4, P < 0.01 each), whereas sole Val treatment did not. Systolic Ca2+ release, SR Ca\(^{2+}\) load, and Ca\(^{2+}\)‐transient kinetics including SERCA activity (k\(_{SERCA}\)) were not compromised by Sac in isolated murine CMs (n = 41/6 vs. 39/6). Importantly, the combination of Sac/Val and Sac alone also reduced diastolic CaSpF and SR Ca\(^{2+}\) leak (reduction by 74 ± 7%) in human left ventricular CMs from patients with end‐stage HF (n = 71/8 vs. 78/8, P < 0.05 each). Myocardial contractility of human ventricular trabeculae was not acutely affected by Sac treatment as the developed force remained unchanged over a time course of 30 min (n trabeculae/hearts = 3/3 vs. 4/3).
Conclusion
This study demonstrates that neprilysin inhibitor Sac directly improves Ca\(^{2+}\) homeostasis in human end‐stage HF by reducing pro‐arrhythmogenic SR Ca\(^{2+}\) leak without acutely affecting systolic Ca\(^{2+}\) release and inotropy. These effects might contribute to the mortality benefits observed in the PARADIGM‐HF trial.
Stabilisierung planarer Cyclopenten‐4‐yl‐Kationen durch Hyperkonjugation und π‐Delokalisierung
(2020)
Theoretischen Untersuchungen zufolge stellt das planare Cyclopenten-4-yl-Kation das energetisch ungünstigste C\(_{5}\)H\(_{7}\)\(^{+}\)-Isomer dar und ist am ehesten als klassisches Carbokation zu beschreiben, wobei dessen Existenz experimentell bislang noch nicht nachgewiesen werden konnte. Durch Umsetzung sterisch überfrachteter Alane vom Typ Cp\(^{R}\)AlBr\(_{2}\) mit AlBr3 ist uns nun die Isolierung zweier stabiler Derivate des Cyclopenten-4-yl-Kations gelungen. Untersuchungen zu deren (elektronischer) Struktur (XRD, QM) offenbarten planare Geometrien und starke Hyperkonjugationswechselwirkungen zwischen den C-Al-σ-Bindungen und dem unbesetzten p-Orbital der kationischen sp\(^{2}\)-Kohlenstoffzentren. Die Analyse der Molekülorbitale (MOs), der Anisotropie der induzierten Stromdichte (ACID) sowie verschiedener Aromatizitätsdeskriptoren deuten hierbei auf ein hohes Maß an Delokalisierung und π-Aromatizität in diesen Systemen hin, was einer klassischen Beschreibung grundlegend widerspricht. Unsere Cyclopenten-4-yl-Kationen gehören somit zu den wenigen Beispielen aromatischer Carbocyclen, in denen eine Delokalisierung der π-Elektronen über gesättigte sp\(^{3}\)-Kohlenstoffatome hinweg beobachtet wird.
Background and Objective
This updated systematic review evaluated the efficacy, tolerability and safety of opioids compared to placebo in chronic non‐cancer neuropathic pain.
Databases and Data Treatment
Clinicaltrials.gov, CENTRAL, PubMed and PsycINFO were searched from October 2013 to June 2019. Randomized controlled trials comparing opioids with placebo and at least 4 weeks double‐blinded duration were analysed. Primary outcomes were pain relief of 50% or greater, disability, tolerability and safety. Effects were summarized by a random effects model using risk differences (RD) or standardized mean differences (SMD). We added four new studies with 662 participants for a total of 16 included studies with 2,199 participants. Study duration ranged between 4 and 12 weeks. Studies with a parallel and cross‐over design: Based on low to moderate quality evidence, opioids (buprenorphine, hydromorphone, morphine, oxycodone, tramadol) provided a clinically relevant pain relief of 50% or greater and reduction of disability compared to placebo. There was no clinically relevant harm with regards to the drop out rate due to adverse and serious adverse events by opioids compared to placebo. Enriched enrolment randomized withdrawal design: Based on low to moderate quality evidence, tapentadol provided a clinically relevant pain relief of 50% or greater and reduction of disability compared to placebo in diabetic polyneuropathy. There was no clinically relevant harm with regards to the drop out rate due to adverse and serious adverse events by tapentadol compared to placebo.
Conclusions
Some opioids provided a short‐term substantial pain relief in highly selected patients in some neuropathic pain syndromes.
Significance
Some opioids (buprenorphine, morphine, oxycodone, tramadol, tapentadol) provide substantial pain relief compared to placebo in postherpetic neuralgia and peripheral neuropathies of different aetiologies for 4–12 weeks. There is insufficient evidence to support or refute the suggestion that these drugs are effective in other neuropathic pain conditions. The safety of opioids with regards to abuse and deaths in the studies analysed cannot be extrapolated to routine clinical care.
Pictures in a rapid serial visual presentation (RSVP) stream are better remembered when they are simultaneously presented with targets of an unrelated detection task than when they are presented with distractors. However, it is unclear whether this so-called “attentional boost effect” depends on the intentionality of encoding. While there are studies suggesting that the attentional boost effect even occurs when encoding is incidental, there are several methodological issues with these studies, which may have undermined the incidental encoding instructions. The present study (N = 141) investigated the role of the intentionality of encoding with an improved experimental design. Specifically, to prevent a spill-over of intentional resources to the pictures in the RSVP stream, the speed of the stream was increased (to four pictures per second) and each picture was presented only once during the course of the experiment. An attentional boost effect was only found when encoding was intentional but not when encoding was incidental. Interestingly, memory performance for incidentally encoded pictures was nevertheless substantially above chance, independently of whether images were presented with search-relevant targets or distractors. These results suggest that the attentional boost effect is a memory advantage that occurs only under intentional encoding conditions, and that perceptual long-term memory representations are formed as a natural product of perception, independently of the presence of behaviorally relevant events.
Alzheimer′s disease (AD) is a neurological disorder with still no preventive or curative treatment. Flavonoids are phytochemicals with potential therapeutic value. Previous studies described the flavanone sterubin isolated from the Californian plant Eriodictyon californicum as a potent neuroprotectant in several in vitro assays. Herein, the resolution of synthetic racemic sterubin (1) into its two enantiomers, (R)‐1 and (S)‐1, is described, which has been performed on a chiral chromatographic phase, and their stereochemical assignment online by HPLC‐ECD coupling. (R)‐1 and (S)‐1 showed comparable neuroprotection in vitro with no significant differences. While the pure stereoisomers were configurationally stable in methanol, fast racemization was observed in the presence of culture medium. We also established the occurrence of extracted sterubin as its pure (S)‐enantiomer. Moreover, the activity of sterubin (1) was investigated for the first time in vivo, in an AD mouse model. Sterubin (1) showed a significant positive impact on short‐ and long‐term memory at low dosages.
Objective
Impairment of glycinergic neurotransmission leads to complex movement and behavioral disorders. Patients harboring glycine receptor autoantibodies suffer from stiff‐person syndrome or its severe variant progressive encephalomyelitis with rigidity and myoclonus. Enhanced receptor internalization was proposed as the common molecular mechanism upon autoantibody binding. Although functional impairment of glycine receptors following autoantibody binding has recently been investigated, it is still incompletely understood.
Methods
A cell‐based assay was used for positive sample evaluation. Glycine receptor function was assessed by electrophysiological recordings and radioligand binding assays. The in vivo passive transfer of patient autoantibodies was done using the zebrafish animal model.
Results
Glycine receptor function as assessed by glycine dose–response curves showed significantly decreased glycine potency in the presence of patient sera. Upon binding of autoantibodies from 2 patients, a decreased fraction of desensitized receptors was observed, whereas closing of the ion channel remained fast. The glycine receptor N‐terminal residues \(^{29}\)A to \(^{62}\)G were mapped as a common epitope of glycine receptor autoantibodies. An in vivo transfer into the zebrafish animal model generated a phenotype with disturbed escape behavior accompanied by a reduced number of glycine receptor clusters in the spinal cord of affected animals.
Interpretation
Autoantibodies against the extracellular domain mediate alterations of glycine receptor physiology. Moreover, our in vivo data demonstrate that the autoantibodies are a direct cause of the disease, because the transfer of human glycine receptor autoantibodies to zebrafish larvae generated impaired escape behavior in the animal model compatible with abnormal startle response in stiff‐person syndrome or progressive encephalitis with rigidity and myoclonus patients.
Different types of high‐yield, easily scalable syntheses for cyano(fluoro)borates Kt[BF\(_{n}\)(CN)\(_{4-n}\)] (n=0–2) (Kt=cation), which are versatile building blocks for materials applications and chemical synthesis, have been developed. Tetrafluoroborates react with trimethylsilyl cyanide in the presence of metal‐free Brønsted or Lewis acid catalysts under unprecedentedly mild conditions to give tricyanofluoroborates or tetracyanoborates. Analogously, pentafluoroethyltrifluoroborates are converted into pentafluoroethyltricyanoborates. Boron trifluoride etherate, alkali metal salts, and trimethylsilyl cyanide selectively yield dicyanodifluoroborates or tricyanofluoroborates. Fluorination of cyanohydridoborates is the third reaction type that includes direct fluorination with, for example, elemental fluorine, stepwise halogenation/fluorination reactions, and electrochemical fluorination (ECF) according to the Simons process. In addition, fluorination of [BH(CN)\(_{2}\){OC(O)Et}]\(^{-}\) to result in [BF(CN)\(_{2}\){OC(O)Et}]\(^{-}\) is described.
Altered autophagy accompanied by abnormal autophagic (rimmed) vacuoles detectable by light and electron microscopy is a common denominator of many familial and sporadic non‐inflammatory muscle diseases. Even in the era of next generation sequencing (NGS), late‐onset vacuolar myopathies remain a diagnostic challenge. We identified 32 adult vacuolar myopathy patients from 30 unrelated families, studied their clinical, histopathological and ultrastructural characteristics and performed genetic testing in index patients and relatives using Sanger sequencing and NGS including whole exome sequencing (WES). We established a molecular genetic diagnosis in 17 patients. Pathogenic mutations were found in genes typically linked to vacuolar myopathy (GNE, LDB3/ZASP, MYOT, DES and GAA), but also in genes not regularly associated with severely altered autophagy (FKRP, DYSF, CAV3, COL6A2, GYG1 and TRIM32) and in the digenic facioscapulohumeral muscular dystrophy 2. Characteristic histopathological features including distinct patterns of myofibrillar disarray and evidence of exocytosis proved to be helpful to distinguish causes of vacuolar myopathies. Biopsy validated the pathogenicity of the novel mutations p.(Phe55*) and p.(Arg216*) in GYG1 and of the p.(Leu156Pro) TRIM32 mutation combined with compound heterozygous deletion of exon 2 of TRIM32 and expanded the phenotype of Ala93Thr‐caveolinopathy and of limb‐girdle muscular dystrophy 2i caused by FKRP mutation. In 15 patients no causal variants were detected by Sanger sequencing and NGS panel analysis. In 12 of these cases, WES was performed, but did not yield any definite mutation or likely candidate gene. In one of these patients with a family history of muscle weakness, the vacuolar myopathy was eventually linked to chloroquine therapy. Our study illustrates the wide phenotypic and genotypic heterogeneity of vacuolar myopathies and validates the role of histopathology in assessing the pathogenicity of novel mutations detected by NGS. In a sizable portion of vacuolar myopathy cases, it remains to be shown whether the cause is hereditary or degenerative.
Opioid receptors (ORs) are classified among the oldest and best investigated drug targets due to their fundamental role in the treatment of pain and related disorders. ORs are divided in three conventional subtypes (μ, κ, δ) and the non‐classical nocicepetin receptor. All ORs are family A G protein‐coupled receptors (GPCRs), and are located on the cell surface. Modern biophysical methods use light to investigate physiological processes at organismal, cellular and subcellular level. Many of these methods rely on fluorescent ligands, thus highlighting their importance. This review addresses the advancements in the development of opioid fluorescent ligands and their use in biological, pharmacological and imaging applications.
Salvage logging, or logging after natural disturbances such as wildfires, insect outbreaks, and windstorms, is carried out to recover some of a forest's natural and/or economic capital. However, trade‐offs between management objectives and a lack of consensus on the ecological consequences of salvage logging impair science‐based decision making on the management of forests after natural disturbances. We conducted a global meta‐analysis of the impacts of salvage logging on regulating ecosystem services and on fuel loads, as a frequent post‐disturbance objective is preventing subsequent wildfires that could be fueled by the accumulation of dead trunks and branches. Salvage logging affected ecosystem services in a moderately negative way, regardless of disturbance type and severity, time elapsed since salvage logging, intensity of salvage logging, and the group of regulating ecosystem services being considered. However, prolonging the time between natural disturbance and salvage logging mitigated negative effects on regulating ecosystem services. Salvage logging had no overall effect on surface fuels; rather, different fuel types responded differently depending on the time elapsed since salvage logging. Delaying salvage logging by ~2–4 years may reduce negative ecological impacts without affecting surface fuel loads.
Investigations concerning the reactivity of Ni(0) complexes [Ni(NHC)\(_{2}\)] of NHCs (N‐heterocyclic carbene) of different steric demand, Mes\(_{2}\)Im (= 1,3‐dimesitylimidazoline‐2‐ylidene) and iPr\(_{2}\)Im (= 1,3‐diisopropyl‐imidazoline‐2‐ylidene), with olefins, ketones and aldehydes are reported. The reaction of [Ni(Mes\(_{2}\)Im)\(_{2}\)] 1 with ethylene or methyl acrylate afforded the complexes [Ni(Mes\(_{2}\)Im)\(_{2}\)(η\(^{2}\)‐C\(_{2}\)H\(_{4}\))] 3 and [Ni(Mes\(_{2}\)Im)\(_{2}\)(η\(^{2}\)‐(C,C)‐H\(_{2}\)C=CHCOOMe)] 4, as it was previously reported for [Ni\(_{2}\)(iPr\(_{2}\)Im)\(_{4}\)(µ‐(η\(^{2}\):η\(^{2}\))‐COD)] 2 as a source for [Ni(iPr\(_{2}\)Im)\(_{2}\)]. In contrast to 2, complex 1 does not react with sterically more demanding olefins such as tetramethylethylene, 1,1‐diphenylethylene and cyclohexene. The reaction of [Ni(NHC)\(_{2}\)] with more π‐acidic ketones or aldehydes led to formation of complexes with side‐on η\(^{2}\)‐(C,O)‐coordinating ligands: [Ni(iPr\(_{2}\)Im)\(_{2}\)(η\(^{2}\)‐O=CH\(^{t}\)Bu)] 5, [Ni(iPr\(_{2}\)Im)\(_{2}\)(η\(^{2}\)‐O=CHPh)] 6, [Ni(iPr\(_{2}\)Im)\(_{2}\)(η\(^{2}\)‐O=CMePh)] 7, [Ni(iPr\(_{2}\)Im)\(_{2}\)(η\(^{2}\)‐O=CPh\(_{2}\))] 8, [Ni(iPr\(_{2}\)Im)\(_{2}\)(η\(^{2}\)‐O=C(4‐F‐C\(_{6}\)H\(_{4}\))\(_{2}\))] 9, [Ni(iPr\(_{2}\)Im)\(_{2}\)(η\(^{2}\)‐O=C(OMe)(CF\(_{3}\)))] 10 and [Ni(Mes\(_{2}\)Im)\(_{2}\)(η\(^{2}\)‐O=CHPh)] 11, [Ni(Mes\(_{2}\)Im)\(_{2}\)(η\(^{2}\)‐O=CH(CH(CH\(_{3}\))\(_{2}\)))] 12, [Ni(Mes\(_{2}\)Im)\(_{2}\)(η\(^{2}\)‐O=CH(4‐NMe\(_{2}\)‐C\(_{6}\)H\(_{4}\)))] 13, [Ni(Mes\(_{2}\)Im)\(_{2}\)(η\(^{2}\)‐O=CH(4‐OMe‐C\(_{6}\)H\(_{4}\)))] 14, [Ni(Mes\(_{2}\)Im)\(_{2}\)(η\(^{2}\)‐O=CPh\(_{2}\))] 15 and [Ni(Mes\(_{2}\)Im)\(_{2}\)(η\(^{2}\)‐O=C(4‐F‐C\(_{6}\)H\(_{4}\))\(_{2}\))] 16. The reaction of 1 and 2 with these simple aldehydes and ketones does not lead to a significantly different outcome, but NHC ligand rotation is hindered for the Mes\(_{2}\)Im complexes 3, 4 and 11–16 according to NMR spectroscopy. The solid‐state structures of 3, 4, 11 and 12 reveal significantly larger C\(_{NHC}\)‐Ni‐C\(_{NHC}\) angles in the Mes\(_{2}\)Im complexes compared to the iPr\(_{2}\)Im complexes. As electron transfer in d\(^{8}\)‐ (or d\(^{10}\)‐) ML\(_{2}\) complexes to π‐acidic ligands depends on the L–M–L bite angle, the different NHCs lead thus to a different degree of electron transfer and activation of the olefin, aldehyde or ketone ligand, i.e., [Ni(iPr\(_{2}\)Im)\(_{2}\)] is the better donor to these π‐acidic ligands. Furthermore, we identified two different side products from the reaction of 1 with benzaldehyde, trans‐[Ni(Mes\(_{2}\)Im)\(_{2}\)H(OOCPh)] 17 and [Ni\(_{2}\)(Mes\(_{2}\)Im)\(_{2}\)(µ\(_{2}\)‐CO)(µ\(_{2}\)‐η\(^{2}\)‐C,O‐PhCOCOPh)] 18, which indicate that radical intermediates and electron transfer processes might be of importance in the reaction of 1 with aldehydes and ketones.
Pulmonary mucosal immune response is critical for preventing opportunistic Aspergillus fumigatus infections. Although fungus‐specific CD4\(^{+}\) T cells in blood are described to reflect the actual host–pathogen interaction status, little is known about Aspergillus‐specific pulmonary T‐cell responses. Here, we exploit the domestic pig as human‐relevant large animal model and introduce antigen‐specific T‐cell enrichment in pigs to address Aspergillus‐specific T cells in the lung compared to peripheral blood. In healthy, environmentally Aspergillus‐exposed pigs, the fungus‐specific T cells are detectable in blood in similar frequencies as observed in healthy humans and exhibit a Th1 phenotype. Exposing pigs to 10\(^{6}\) cfu/m\(^{3}\) conidia induces a long‐lasting accumulation of Aspergillus‐specific Th1 cells locally in the lung and also systemically. Temporary immunosuppression during Aspergillus‐exposure showed a drastic reduction in the lung‐infiltrating antifungal T‐cell responses more than 2 weeks after abrogation of the suppressive treatment. This was reflected in blood, but to a much lesser extent. In conclusion, by using the human‐relevant large animal model the pig, this study highlights that the blood clearly reflects the mucosal fungal‐specific T‐cell reactivity in environmentally exposed as well as experimentally exposed healthy pigs. But, immunosuppression significantly impacts the mucosal site in contrast to the initial systemic immune response.
DYT-TOR1A is the most common inherited dystonia caused by a three nucleotide (GAG) deletion (dE) in the TOR1A gene. Death early after birth and cortical anomalies of the full knockout in rodents underscore its developmental importance. We therefore explored the timed effects of TOR1A-wt and TOR1A-dE during differentiation in a human neural in vitro model. We used lentiviral tet-ON expression of TOR1A-wt and -dE in induced neural stem cells derived from healthy donors. Overexpression was induced during proliferation of neural precursors, during differentiation and after differentiation into mature neurons. Overexpression of both wildtype and mutated protein had no effect on the viability and cell number of neural precursors as well as mature neurons when initiated before or after differentiation. However, if induced during differentiation, overexpression of TOR1A-wt and -dE led to a pronounced reduction of mature neurons in a dose dependent manner. Our data underscores the importance of physiological expression levels of TOR1A as crucial for proper neuronal differentiation. We did not find evidence for a specific impact of the mutated TOR1A on neuronal maturation.
Purpose of Review
This article provides an overview of current findings on Theory of Mind (ToM) in human children and adults and highlights the relationship between task specifications and their outcome in socio-cognitive research.
Recent Findings
ToM, the capacity to reason about and infer others’ mental states, develops progressively throughout childhood—the exact time course is still a matter of debate. Neuroimaging studies indicate the involvement of a widespread neuronal network during mentalizing, suggesting that ToM is a multifaceted process. Accordingly, the tasks and trainings that currently exist to investigate and enhance ToM are heterogeneous, and the outcomes largely depend on the paradigm that was used.
Summary
We argue for the implementation of multiple-task batteries in the assessment of socio-cognitive abilities. Decisions for a particular paradigm need to be carefully considered and justified. We want to emphasize the importance of targeted research on the relationship between task specifications and outcomes.
The norepinephrine transporter (NET) is a major target for the evaluation of the cardiac sympathetic nerve system in patients with heart failure and Parkinson's disease. It is also used in the therapeutic applications against certain types of neuroendocrine tumors, as exemplified by the clinically used \(^{123/131}\)I-MIBG as theranostic single-photon emission computed tomography (SPECT) agent. With the development of more advanced positron emission tomography (PET) technology, more radiotracers targeting NET have been reported, with superior temporal and spatial resolutions, along with the possibility of functional and kinetic analysis. More recently, fluorine-18-labelled NET tracers have drawn increasing attentions from researchers, due to their longer radiological half-life relative to carbon-11 (110 min vs. 20 min), reduced dependence on on-site cyclotrons, and flexibility in the design of novel tracer structures. In the heart, certain NET tracers provide integral diagnostic information on sympathetic innervation and the nerve status. In the central nervous system, such radiotracers can reveal NET distribution and density in pathological conditions. Most radiotracers targeting cardiac NET-function for the cardiac application consistent of derivatives of either norepinephrine or MIBG with its benzylguanidine core structure, e.g. \(^{11}\)C-HED and \(^{18}\)F-LMI1195. In contrast, all NET tracers used in central nervous system applications are derived from clinically used antidepressants. Lastly, possible applications of NET as selective tracers over organic cation transporters (OCTs) in the kidneys and other organs controlled by sympathetic nervous system will also be discussed.
We review the physical aggregation of value added and capital in terms of work performance and information processing and its relation to the deflated monetary time series of output and capital. In growth accounting it complements the time series of labor and energy, measured in hours worked per year and kilowatt-hours consumed per year, respectively. This aggregation is the conceptual basis on which those energy-dependent production functions have been constructed that reproduce economic growth of major industrial countries in the 20th century with small residuals and output elasticities that are for energy much larger and for labor much smaller than the cost shares of these factors. Accounting for growth in such a way, which deviates from that of mainstream economics, may serve as a first step towards integrating the First and the Second Law of Thermodynamics into economics.
Ketamine is commonly used as an anaesthetic agent and has more recently gained attention as an antidepressant. It has been linked to increased stimulus‐locked excitability, inhibition of interneurons and modulation of intrinsic neuronal oscillations. However, the functional network mechanisms are still elusive. A better understanding of these anaesthetic network effects may improve upon previous interpretations of seminal studies conducted under anaesthesia and have widespread relevance for neuroscience with awake and anaesthetized subjects as well as in medicine. Here, we investigated the effects of anaesthetic doses of ketamine (15 mg kg\(^{-1}\) h\(^{-1}\)i.p.) on the network activity after pure‐tone stimulation within the auditory cortex of male Mongolian gerbils (Meriones unguiculatus). We used laminar current source density (CSD) analysis and subsequent layer‐specific continuous wavelet analysis to investigate spatiotemporal response dynamics on cortical columnar processing in awake and ketamine‐anaesthetized animals. We found thalamocortical input processing within granular layers III/IV to be significantly increased under ketamine. This layer‐dependent gain enhancement under ketamine was not due to changes in cross‐trial phase coherence but was rather attributed to a broadband increase in magnitude reflecting an increase in recurrent excitation. A time–frequency analysis was indicative of a prolonged period of stimulus‐induced excitation possibly due to a reduced coupling of excitation and inhibition in granular input circuits – in line with the common hypothesis of cortical disinhibition via suppression of GABAergic interneurons.
First‐line treatment of pediatric low‐grade glioma using surgery, radio‐ or chemotherapy fails in a relevant proportion of patients. We analyzed efficacy of subsequent surgical and nonsurgical therapies of the German cohort of the SIOP‐LGG 2004 study (2004‐2012, 1558 registered patients; median age at diagnosis 7.6 years, median observation time 9.2 years, overall survival 98%/96% at 5/10 years, 15% neurofibromatosis type 1 [NF1]). During follow‐up, 1078/1558 patients remained observed without (n = 217), with 1 (n = 707), 2 (n = 124) or 3 to 6 (n = 30) tumor volume reductions; 480/1558 had 1 (n = 332), 2 (n = 80), 3 or more (n = 68) nonsurgical treatment‐lines, accompanied by up to 4 tumor‐reductive surgeries in 215/480; 265/480 patients never underwent any neurosurgical tumor volume reduction (163/265 optic pathway glioma). Patients with progressing tumors after first‐line adjuvant treatment were at increased risk of suffering further progressions. Risk factors were young age (<1 year) at start of treatment, tumor dissemination or progression within 18 months after start of chemotherapy. Progression‐free survival rates declined with subsequent treatment‐lines, yet remaining higher for patients with NF1. In non‐NF1‐associated tumors, vinblastine monotherapy vs platinum‐based chemotherapy was noticeably less effective when used as second‐line treatment. Yet, for the entire cohort, results did not favor a certain sequence of specific treatment options. Rather, all can be aligned as a portfolio of choices which need careful balancing of risks and benefits. Future molecular data may predict long‐term tumor biology.
Fraser syndrome (FS) is a rare autosomal recessive multiple congenital malformation syndrome characterized by cryptophthalmos, cutaneous syndactyly, renal agenesis, ambiguous genitalia, and laryngotracheal anomalies. It is caused by biallelic mutations of FRAS1, FREM2, and GRIP1 genes, encoding components of a protein complex that mediates embryonic epithelial–mesenchymal interactions. Anecdotal reports have described abnormal orodental findings in FS, but no study has as yet addressed the orodental findings of FS systematically. We reviewed dental radiographs of 10 unrelated patients with FS of different genetic etiologies. Dental anomalies were present in all patients with FS and included hypodontia, dental crowding, medial diastema, and retained teeth. A very consistent pattern of shortened dental roots of most permanent teeth as well as altered length/width ratio with shortened dental crowns of upper incisors was also identified. These findings suggest that the FRAS1–FREM complex mediates critical mesenchymal–epithelial interactions during dental crown and root development. The orodental findings of FS reported herein represent a previously underestimated manifestation of the disorder with significant impact on orodental health for affected individuals. Integration of dentists and orthodontists into the multidisciplinary team for management of FS is therefore recommended.
Immuno‐oncology therapies engage the immune system to treat cancer. BiTE (bispecific T‐cell engager) technology is a targeted immuno‐oncology platform that connects patients' own T cells to malignant cells. The modular nature of BiTE technology facilitates the generation of molecules against tumor‐specific antigens, allowing off‐the‐shelf immuno‐oncotherapy. Blinatumomab was the first approved canonical BiTE molecule and targets CD19 surface antigens on B cells, making blinatumomab largely independent of genetic alterations or intracellular escape mechanisms. Additional BiTE molecules in development target other hematologic malignancies (eg, multiple myeloma, acute myeloid leukemia, and B‐cell non‐Hodgkin lymphoma) and solid tumors (eg, prostate cancer, glioblastoma, gastric cancer, and small‐cell lung cancer). BiTE molecules with an extended half‐life relative to the canonical BiTE molecules are also being developed. Advances in immuno‐oncology made with BiTE technology could substantially improve the treatment of hematologic and solid tumors and offer enhanced activity in combination with other treatments.
GNAQ and GNA11 mutant nonuveal melanoma: a subtype distinct from both cutaneous and uveal melanoma
(2020)
Background
GNAQ and GNA11 mutant nonuveal melanoma represent a poorly characterized rare subgroup of melanoma with a gene mutation profile similar to uveal melanoma.
Objectives
To characterize these tumours in terms of clinical behaviour and genetic characteristics.
Methods
Patients with nonuveal GNAQ/11 mutated melanoma were identified from the prospective multicentre tumour tissue registry ADOREG, Tissue Registry in Melanoma (TRIM) and additional cooperating skin cancer centres. Extensive data on patient, tumour and treatment characteristics were collected retrospectively. Targeted sequencing was used to determine tumour mutational burden. Immunohistochemistry staining was performed for programmed death‐ligand 1 and BRCA1‐associated protein (BAP)1. Existing whole‐exome cutaneous and uveal melanoma data were analysed for mutation type and burden.
Results
We identified 18 patients with metastatic GNAQ/11 mutant nonuveal melanoma. Tumours had a lower tumour mutational burden and fewer ultraviolet signature mutations than cutaneous melanomas. In addition to GNAQ and GNA11 mutations (nine each), six splicing factor 3b subunit 1 (SF3B1), three eukaryotic translation initiation factor 1A X‐linked (EIF1AX) and four BAP1 mutations were detected. In contrast to uveal melanoma, GNAQ/11 mutant nonuveal melanomas frequently metastasized lymphatically and concurrent EIF1AX, SF3B1 and BAP1 mutations showed no apparent association with patient prognosis. Objective response to immunotherapy was poor with only one partial response observed in 10 treated patients (10%).
Conclusions
Our findings suggest that GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is both clinically and genetically distinct from cutaneous and uveal melanoma. As they respond poorly to available treatment regimens, novel effective therapeutic approaches for affected patients are urgently needed.
What is already known about this topic?
The rare occurrence of GNAQ/11 mutations in nonuveal melanoma has been documented.
GNAQ/11 mutant nonuveal melanomas also harbour genetic alterations in EIF1AX, SF3B1 and BAP1 that are of prognostic relevance in uveal melanoma.
What does this study add?
GNAQ/11 mutant nonuveal melanomas show metastatic spread reminiscent of cutaneous melanoma, but not uveal melanoma.
GNAQ/11 mutant nonuveal melanomas have a low tumour mutational burden that is higher than uveal melanoma, but lower than cutaneous melanoma.
What is the translational message?
Primary GNAQ/11 mutant nonuveal melanomas are a subtype of melanoma that is clinically and genetically distinct from both cutaneous and uveal melanoma.
As metastatic GNAQ/11 mutant nonuveal melanomas respond poorly to available systemic therapies, including immune checkpoint inhibition, novel therapeutic approaches for these tumours are urgently needed.
When aiming at cell‐based therapies in osteoarthritis (OA), proinflammatory conditions mediated by cytokines such as IL‐1β need to be considered. In recent studies, the phytoalexin resveratrol (RSV) has exhibited potent anti‐inflammatory properties. However, long‐term effects on 3D cartilaginous constructs under inflammatory conditions with regard to tissue quality, especially extracellular matrix (ECM) composition, have remained unexplored. Therefore, we employed long‐term model cultures for cell‐based therapies in an in vitro OA environment and evaluated effects of RSV. Pellet constructs made from expanded porcine articular chondrocytes were cultured with either IL‐1β (1–10 ng/ml) or RSV (50 μM) alone, or a cotreatment with both agents. Treatments were applied for 14 days, either directly after pellet formation or after a preculture period of 7 days. Culture with IL‐1β (10 ng/ml) decreased pellet size and DNA amount and severely compromised glycosaminoglycan (GAG) and collagen content. Cotreatment with RSV distinctly counteracted the proinflammatory catabolism and led to partial rescue of the ECM composition in both culture systems, with especially strong effects on GAG. Marked MMP13 expression was detected in IL‐1β‐treated pellets, but none upon RSV cotreatment. Expression of collagen type I was increased upon IL‐1β treatment and still observed when adding RSV, whereas collagen type X, indicating hypertrophy, was detected exclusively in pellets treated with RSV alone. In conclusion, RSV can counteract IL‐1β‐mediated degradation and distinctly improve cartilaginous ECM deposition in 3D long‐term inflammatory cultures. Nevertheless, potential hypertrophic effects should be taken into account when considering RSV as cotreatment for articular cartilage repair techniques.
Objective
Most patients with bipolar disorders (BD) exhibit prodromal symptoms before a first (hypo)manic episode. Patients with clinically significant symptoms fulfilling at‐risk criteria for serious mental illness (SMI) require effective and safe treatment. Cognitive‐behavioral psychotherapy (CBT) has shown promising results in early stages of BD and in patients at high risk for psychosis. We aimed to investigate whether group CBT can improve symptoms and functional deficits in young patients at risk for SMI presenting with subthreshold bipolar symptoms.
Method
In a multicenter, randomized, controlled trial, patients at clinical risk for SMI presenting with subthreshold bipolar symptoms aged 15‐30 years were randomized to 14 weeks of at‐risk for BD‐specific group CBT or unstructured group meetings. Primary efficacy endpoints were differences in affective symptomatology and psychosocial functioning at 14 weeks. At‐risk status was defined as a combination of subthreshold bipolar symptomatology, reduction of psychosocial functioning and a family history for (schizo)affective disorders. A prespecified interim analysis was conducted at 75% of the targeted sample.
Results
Of 128 screened participants, 75 were randomized to group CBT (n = 38, completers = 65.8%) vs unstructured group meetings (n = 37, completers = 78.4%). Affective symptomatology and psychosocial functioning improved significantly at week 14 (P < .001) and during 6 months (P < .001) in both groups, without significant between‐group differences. Findings are limited by the interim character of the analysis, the use of not fully validated early detection interviews, a newly adapted intervention manual, and the substantial drop‐outs.
Conclusions
Results suggest that young patients at‐risk for SMI presenting with subthreshold bipolar symptoms benefit from early group sessions. The degree of specificity and psychotherapeutic interaction needed requires clarification.