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Ubiquitination, and its control by deubiquitinating enzymes (DUBs), mediates protein stability, function, signaling and cell fate. The ovarian tumor (OTU) family DUB OTULIN (FAM105B) exclusively cleaves linear (Met1-linked) poly-ubiquitin chains and plays important roles in auto-immunity, inflammation and infection. OTULIN regulates Met1-linked ubiquitination downstream of tumor necrosis factor receptor 1 (TNFR1), toll-like receptor (TLR) and nucleotide-binding and oligomerization domain-containing protein 2 (NOD2) receptor activation and interacts with the Met1 ubiquitin-specific linear ubiquitin chain assembly complex (LUBAC) E3 ligase. However, despite extensive research efforts, the receptor and cytosolic roles of OTULIN and the distributions of multiple Met1 ubiquitin-associated E3-DUB complexes in the regulation of cell fate still remain controversial and unclear. Apart from that, novel ubiquitin-independent OTULIN functions have emerged highlighting an even more complex role of OTULIN in cellular homeostasis. For example, OTULIN interferes with endosome-to-plasma membrane trafficking and the OTULIN-related pseudo-DUB OTULINL (FAM105A) resides at the endoplasmic reticulum (ER). Here, we discuss how OTULIN contributes to cell fate control and highlight novel ubiquitin-dependent and -independent functions.
TNFR1 is a crucial regulator of NF‐ĸB‐mediated proinflammatory cell survival responses and programmed cell death (PCD). Deregulation of TNFα‐ and TNFR1‐controlled NF‐ĸB signaling underlies major diseases, like cancer, inflammation, and autoimmune diseases. Therefore, although being routinely used, antagonists of TNFα might also affect TNFR2‐mediated processes, so that alternative approaches to directly antagonize TNFR1 are beneficial. Here, we apply quantitative single‐molecule localization microscopy (SMLM) of TNFR1 in physiologic cellular settings to validate and characterize TNFR1 inhibitory substances, exemplified by the recently described TNFR1 antagonist zafirlukast. Treatment of TNFR1‐mEos2 reconstituted TNFR1/2 knockout mouse embryonic fibroblasts (MEFs) with zafirlukast inhibited both ligand‐independent preligand assembly domain (PLAD)‐mediated TNFR1 dimerization as well as TNFα‐induced TNFR1 oligomerization. In addition, zafirlukast‐mediated inhibition of TNFR1 clustering was accompanied by deregulation of acute and prolonged NF‐ĸB signaling in reconstituted TNFR1‐mEos2 MEFs and human cervical carcinoma cells. These findings reveal the necessity of PLAD‐mediated, ligand‐independent TNFR1 dimerization for NF‐ĸB activation, highlight the PLAD as central regulator of TNFα‐induced TNFR1 oligomerization, and demonstrate that TNFR1‐mEos2 MEFs can be used to investigate TNFR1‐antagonizing compounds employing single‐molecule quantification and functional NF‐ĸB assays at physiologic conditions.
The ability to vocalize is ubiquitous in vertebrates, but neural networks underlying vocal control remain poorly understood. Here, we performed simultaneous neuronal recordings in the frontal cortex and dorsal striatum (caudate nucleus, CN) during the production of echolocation pulses and communication calls in bats. This approach allowed us to assess the general aspects underlying vocal production in mammals and the unique evolutionary adaptations of bat echolocation. Our data indicate that before vocalization, a distinctive change in high-gamma and beta oscillations (50–80 Hz and 12–30 Hz, respectively) takes place in the bat frontal cortex and dorsal striatum. Such precise fine-tuning of neural oscillations could allow animals to selectively activate motor programs required for the production of either echolocation or communication vocalizations. Moreover, the functional coupling between frontal and striatal areas, occurring in the theta oscillatory band (4–8 Hz), differs markedly at the millisecond level, depending on whether the animals are in a navigational mode (that is, emitting echolocation pulses) or in a social communication mode (emitting communication calls). Overall, this study indicates that fronto-striatal oscillations could provide a neural correlate for vocal control in bats.
The paper discusses Paul Tillich's changing conception of a "prophetic critique" of contemporary culture and society through the notion of a "kairos", the moment of fullfilled time. It shows how Tillich refers both to a specific notion of prophecy (developed in Max Weber's reflections on charisma) and to a concept of eschatological time (developed in Karl Barth's dialectical theology). In different texts from the 1920ies and the 1950ies, Tillich uses the idea of "kairos" for a critique of the "idols" of bourgeois culture that is both radical and urgent. However, read in their historic sequence, these texts also reveal the difficulty of upholding the urgency of such a critique over time - as a result, Tillich's notion of "kairos" becomes more and more reflexive and self critical as the possibility of prophetic critique is concerned.
EEG microstate periodicity explained by rotating phase patterns of resting-state alpha oscillations
(2020)
Spatio-temporal patterns in electroencephalography (EEG) can be described by microstate analysis, a discrete approximation of the continuous electric field patterns produced by the cerebral cortex. Resting-state EEG microstates are largely determined by alpha frequencies (8-12 Hz) and we recently demonstrated that microstates occur periodically with twice the alpha frequency.
To understand the origin of microstate periodicity, we analyzed the analytic amplitude and the analytic phase of resting-state alpha oscillations independently. In continuous EEG data we found rotating phase patterns organized around a small number of phase singularities which varied in number and location. The spatial rotation of phase patterns occurred with the underlying alpha frequency. Phase rotors coincided with periodic microstate motifs involving the four canonical microstate maps. The analytic amplitude showed no oscillatory behaviour and was almost static across time intervals of 1-2 alpha cycles, resulting in the global pattern of a standing wave.
In n=23 healthy adults, time-lagged mutual information analysis of microstate sequences derived from amplitude and phase signals of awake eyes-closed EEG records showed that only the phase component contributed to the periodicity of microstate sequences. Phase sequences showed mutual information peaks at multiples of 50 ms and the group average had a main peak at 100 ms (10 Hz), whereas amplitude sequences had a slow and monotonous information decay. This result was confirmed by an independent approach combining temporal principal component analysis (tPCA) and autocorrelation analysis.
We reproduced our observations in a generic model of EEG oscillations composed of coupled non-linear oscillators (Stuart-Landau model). Phase-amplitude dynamics similar to experimental EEG occurred when the oscillators underwent a supercritical Hopf bifurcation, a common feature of many computational models of the alpha rhythm.
These findings explain our previous description of periodic microstate recurrence and its relation to the time scale of alpha oscillations. Moreover, our results corroborate the predictions of computational models and connect experimentally observed EEG patterns to properties of critical oscillator networks.
Background and purpose: The aim of the study was to determine the effects of post-traumatically released High Mobility Group Box-1 protein (HMGB1) and extracellular histones on cardiomyocytes (CM). We also evaluated a therapeutic option to capture circulating histones after trauma, using a hemadsorption filter to treat CM dysfunction. Experimental Approach: We evaluated cell viability, calcium handling and mitochondrial respiration of human cardiomyocytes in the presence of HMGB-1 and extracellular histones. In a translational approach, a hemadsorption filter was applied to either directly eliminate extracellular histones or to remove them from blood samples obtained from multiple injured patients. Key results: Incubation of human CM with HMGB-1 or histones is associated with changes in calcium handling, a reduction of cell viability and a substantial reduction of the mitochondrial respiratory capacity. Filtrating plasma from injured patients with a hemadsorption filter reduces histone concentration ex vivo and in vitro, depending on dosage. Conclusion and implications: Danger associated molecular patterns such as HMGB-1 and extracellular histones impair human CM in vitro. A hemadsorption filter could be a therapeutic option to reduce high concentrations of histones.
The interaction of microplastics with freshwater biota and their interaction with other stressors is still not very well understood. Therefore, we investigated the ingestion, excretion and toxicity of microplastics in the freshwater gastropod Lymnaea stagnalis.
MP ingestion was analyzed as tissues levels in L. stagnalis after 6–96 h of exposure to 5–90 μm spherical polystyrene (PS) microplastics. To understand the excretion, tissue levels were determined after 24 h of exposure followed by a 12 h–7 d depuration period. To assess the toxicity, snails were exposed for 28 d to irregular PS microplastics (<63 μm, 6.4–100,000 particles mL−1), both alone and in combination with copper as additional stressor. To compare the toxicity of natural and synthetic particles, we also included diatomite particles. Microplastics ingestion and excretion significantly depended on the particle size and the exposure/depuration duration. An exposure to irregular PS had no effect on survival, reproduction, energy reserves and oxidative stress. However, we observed slight effects on immune cell phagocytosis. Exposure to microplastics did not exacerbate the reproductive toxicity of copper. In addition, there was no pronounced difference between the effects of microplastics and diatomite. The tolerance towards microplastics may originate from an adaptation of L. stagnalis to particle-rich environments or a general stress resilience. In conclusion, despite high uptake rates, PS fragments do not appear to be a relevant stressor for stress tolerant freshwater gastropods considering current environmental levels of microplastics.
Human-induced changes in the environment have increased the number of stressors impacting aquatic organism. In the light of climate change and plastic pollution, thermal stress and microplastics (MP) have become two of the most intensively studied stressors in aquatic ecosystems. Previous studies, however, mostly evaluated the impacts of thermal and MP stress in isolation, thereby neglecting joint effects.
To examine the combined effects of both, we exposed the freshwater mussel Dreissena polymorpha to irregular polystyrene MP (6.4, 160, 4000, 100,000 p mL−1) at either 14, 23 or 27 °C for 14 days and analyzed mortality, mussel activity and clearance rate, energy reserves, oxidative stress and the immunological state. Further, we exposed the mussels to diatomite (natural particle equivalent, 100,000 p mL−1) at each of the three water temperatures to compare MP and natural particle toxicity.
An increase in water temperature has a pronounced effect on D. polymorpha and significantly affects the activity, energy reserves, oxidative stress and immune function. In contrast, the effects by MP are limited to a change in the antioxidative capacity without any interactive effects between MP and thermal exposure. The comparison of the MP with a diatomite exposure revealed only limited influence of the particle type on the response of D. polymorpha to high concentrations of suspended particles.
The results indicate that MPs have minor effects on a freshwater mussel compared to thermal stress, neither alone nor as interactive effect. Limited MP toxicity could be based on adaptation mechanism of dreissenids to suspended solids. Nonetheless, MP may contribute to environmental impacts of multiple anthropogenic stressors, especially if their levels increase in the future. Therefore, we suggest integrating MP into the broader context of multiple stressor studies to understand and assess their joint impacts on freshwater ecosystems.
French suffixations in -age, -ion and -ment are considered roughly equivalent, yet some differences have been pointed out regarding the semantics of the resulting nominalizations. In this study, we confirm the existence of a semantic distinction between them on the basis of a large scale distributional analysis. We show that the distinction is partially determined by the degree of technicality of the denoted action: -age nominals tend to be more technical than -ion ones. We examine this hypothesis through the statistical modeling of technicality. To this end, we propose a linguistic definition of technicality, which we implement using empirical, quantitative criteria estimated in corpora and lexical resources. We show to what extent the differences with respect to these criteria adequately approximate technicality. Our study indicates that this definition of technicality, while amendable, provides new perspectives for the characterization of action nouns.
Background: Data on Candida bloodstream infections in pediatric patients in Europe are limited. We performed a retrospective multicenter European study of the epidemiology and outcome of neonatal and pediatric candidemia.
Material and Methods: All first positive blood cultures from patients ≤ 18 years of age with candidemia were registered. Patients’ demographic and clinical characteristics and causative Candida species were collected and analyzed. Regression analysis was used to identify factors independently associated with mortality.
Results: One thousand three hundred ninety-five episodes of candidemia (57.8% male) were reported from 23 hospitals in 10 European countries. Of the 1395 episodes, 36.4% occurred in neonates (≤ 44 weeks postmenstrual age), 13.8% in infants (> 44 weeks postmenstrual age to 1 year) and 49.8% in children and adolescents. Candida albicans (52.5%) and Candida parapsilosis (28%) were the predominant species. A higher proportion of candidemia caused by C. albicans was observed among neonatal patients (60.2%) with highest rates of C. parapsilosis seen among infants (42%). Children admitted to hematology-oncology wards presented the highest rates of non-albicans Candida species. Candidemia because of C. albicans was more frequent than non-albicans Candida in Northern versus Southern Europe (odds ratio, 2.3; 95% confidence interval, 1.8–2.9; P < 0.001). The all-cause mortality at 30 days was 14.4%. All-cause mortality was higher among patients admitted to the neonatal or pediatric intensive care units than other wards. Over time, no significant changes in species distribution were observed.
Conclusions: This first multicenter European study shows unique characteristics of the epidemiology of pediatric candidemia. The insights obtained from this study will be useful to guide clinical management and antifungal stewardship.
Cyrtinus pygmaeus (Haldeman, 1847) (Coleoptera: Cerambycidae: Lamiinae) is redescribed and newly recorded from Mexico. The female of Decarthria stephensii Hope, 1834 is also redescribed, the number of specimens in the type series is corrected, as is the depository of the types, and the species is newly recorded from Dominica. Two new species of Cyrtinus LeConte, 1852 are described from Mexico: C. fisheri Wappes, Santos-Silva and Nascimento; and C. howdeni Wappes, Santos-Silva and Nascimento. A key to species of Decarthria Hope, 1834 (adapted from an earlier key to Cyrtinini) is provided.
New species of Trachyderini from Mexico and Central America (Coleoptera: Cerambycidae: Cerambycinae)
(2020)
Three new trachyderine species in the subtribe Trachyderina (Coleoptera: Cerambycidae: Cerambycinae: Trachyderini) are described: Entomosterna kovariki Wappes and Santos-Silva, new species, from Belize; Gortonia sumideroensis Wappes and Santos-Silva, new species, from Mexico (Chiapas); and Sphaenothecus vandenberghei Wappes and Santos-Silva, new species, from Nicaragua. A new key to Entomosterna species, and a previous Sphaenothecus key by Chemsak and Noguera (1998) is modified to include the new species, with both provided herein.
Five new species and one new genus in Neotropical Lamiinae (Coleoptera: Cerambycidae) are de-scribed: Cotycicuiara lingafelteri Wappes and Santos-Silva, from Panama (Acanthoderini); Nesozineus morrisi Wappes and Santos-Silva, from Bolivia (Acanthoderini); Trichoanoreina panamensis Wappes and Santos-Silva, from Panama (Acanthoderini); Callisema skillmani Wappes and Santos-Silva, from Bolivia (Calliini); Rileyellus panamensis Wappes and Santos-Silva, new genus and species, from Panama (Desmiphorini). Callia pulchra Melzer, 1930 is placed in synonymy with Callia axillaris (Dalman, 1823).
The following new species of Eupogonius LeConte, 1852 (Coleoptera: Cerambycidae: Lamiinae) are described: E. tlanchinolensis Wappes and Santos-Silva (Mexico, Hidalgo); E. albofasciatus Wappes and Santos- Silva (Mexico, Puebla); E. sonorensis Wappes and Santos-Silva (Mexico, Sonora); E. guerrerensis Wappes and Santos-Silva (Mexico, Guerrero); E. boteroi Wappes and Santos-Silva (Mexico, Guerrero); E. nascimentoi Wappes and Santo-Silva (Mexico, Jalisco and Colima); and E. monzoni Wappes and Santos-Silva (Guatemala, Alta Verapaz). Additionally, a detailed description of the female of Eupogonius fulvovestitus Schaeffer, 1905 is provided for the first time, along with notes on the likely host of the species. New state records in Mexico are provided for Eupogonius comus Bates, 1885, and E. stellatus Chemsak and Noguera, 1995. Other taxonomic or nomenclatural actions included herein are: Eupogonius knabi Fisher, 1925 is transferred to Atelodesmis Chevrolat, 1841, new combination; the gender of the species-group name in Eupogonius azteca Martins, Santos-Silva and Galileo, 2015 is commented on; notes on the geographical distribution of Eupogonius affinis Breuning, 1942, and the problematic morphology of E. infimus (Thomson, 1868) are presented; Eupogonius subaeneus Bates, 1872, and E. marmoratus Fisher, 1925 are revalidated, and E. columbianus Breuning, 1942 is a new synonym of E. subaeneus”.
This article reports an investigation of how inhibition contributes to fluid reasoning when it is decomposed into the reasoning ability, item-position, and speed components to control for possible method effects. Working memory was also taken into consideration. A sample of 223 university students completed a fluid reasoning scale, two tasks tapping prepotent response inhibition, and two working memory tasks. Fixed-links modeling was used to separate the effect of reasoning ability from the effects of item-position and speed. The goodness-of-fit results confirmed the necessity to consider the reasoning ability, item-position, and speed components simultaneously. Prepotent response inhibition was only associated with reasoning ability. This association disappeared when working memory served as a mediator. Taken together, these results reflect the inhomogeneity of what is tapped by the fluid reasoning scale on one hand and, on the other, suggest inhibition as an important component of working memory.
A list of authors and their affiliations appears at the end of the paper New-particle formation is a major contributor to urban smog, but how it occurs in cities is often puzzling. If the growth rates of urban particles are similar to those found in cleaner environments (1–10 nanometres per hour), then existing understanding suggests that new urban particles should be rapidly scavenged by the high concentration of pre-existing particles. Here we show, through experiments performed under atmospheric conditions in the CLOUD chamber at CERN, that below about +5 degrees Celsius, nitric acid and ammonia vapours can condense onto freshly nucleated particles as small as a few nanometres in diameter. Moreover, when it is cold enough (below −15 degrees Celsius), nitric acid and ammonia can nucleate directly through an acid–base stabilization mechanism to form ammonium nitrate particles. Given that these vapours are often one thousand times more abundant than sulfuric acid, the resulting particle growth rates can be extremely high, reaching well above 100 nanometres per hour. However, these high growth rates require the gas-particle ammonium nitrate system to be out of equilibrium in order to sustain gas-phase supersaturations. In view of the strong temperature dependence that we measure for the gas-phase supersaturations, we expect such transient conditions to occur in inhomogeneous urban settings, especially in wintertime, driven by vertical mixing and by strong local sources such as traffic. Even though rapid growth from nitric acid and ammonia condensation may last for only a few minutes, it is nonetheless fast enough to shepherd freshly nucleated particles through the smallest size range where they are most vulnerable to scavenging loss, thus greatly increasing their survival probability. We also expect nitric acid and ammonia nucleation and rapid growth to be important in the relatively clean and cold upper free troposphere, where ammonia can be convected from the continental boundary layer and nitric acid is abundant from electrical storms.
This paper analyses disclosure duties in insurance contract law in Germany on the basis of questions developed in preparation of the World Congress of the International Insurance Law Association (AIDA) 2018. As risk factors are within the policyholder’s sphere of knowledge, the insurer naturally depends on gaining such knowledge from its policyholder in order to calculate and evaluate premium and risk. Legal approaches as to how the insurer may obtain relevant information and the legal consequences differ in national insurance contract laws around the globe. Taking part in this legal comparison, the paper describes the key elements of such a mechanism from a German perspective and comprises both duties of the policyholder and duties of the insurer.
As for the policyholder, these issues are differences between a duty to (spontaneously) disclose and a duty not to misrepresent as a reaction to questions of the insurer, the prerequisites and remedies of such duty, the subjective standard of the disclosure duty and a duty to notify material changes during the contract term. On the other hand, the paper also addresses an insurer’s duty to investigate, a duty to ascertain the policyholder’s understanding of the policy and a duty to inform during the contract term or after the occurrence of an insured event. In doing so, the paper offers a comprehensive and critical overview on the transfer of knowledge in the insurance (pre-)contractual relationship.
“Protection of the environment“ and “sustainability“ are more significant than ever. The legal system contributes an important share to the protection of the environment. However, an overview of the German private environmental liability law shows that conventional tort law is not a suitable basis for civil liability for the environmental consequences of officially approved emissions of greenhouse gases. In general, one of the main problems of private environmental liability law lies in proving the individual causality of the conduct of an emitter, as the lawsuit of a Peruvian homeowner against a German energy company pending before the Higher Regional Court of Hamm illustratively demonstrates. The outcome of this lawsuit, which may have an outstanding significance for the status and development of private environmental liability law in Germany, is awaited with great anticipation. The article also briefly examines recent developments in private environmental liability law outside Germany and the question to what extent insurance can be an instrument to protect the environment.
Rationale: Bronchiolitis obliterans syndrome (BOS) is a severe, chronic inflammation of the airways leading to an obstruction of the bronchioles. So far, there are only a few studies looking at the long‐term development of pulmonary impairment in children with BOS.
Objective: The objective of this study was to investigate the incidence and long‐term outcome of BOS in children who underwent allogeneic hematopoietic stem cell transplantation (HSCT).
Methods: Medical charts of 526 children undergoing HSCT in Frankfurt/Main, Germany between 2000 and 2017 were analyzed retrospectively and as a result, 14 patients with BOS were identified. A total of 271 lung functions (spirometry and body plethysmography), 26 lung clearance indices (LCI), and 46 chest high‐resolution computed tomography (HRCT) of these 14 patients with BOS were evaluated.
Results: Fourteen patients suffered from BOS after HSCT (2.7%), whereby three distinctive patterns of lung function impairment were observed: three out of 14 patients showed a progressive lung function decline; two died and one received a lung transplant. In five out of 14 patients with BOS persisted with a severe obstructive and secondarily restrictive pattern in lung function (forced vital capacity [FVC] < 60%, forced expiratory volume in 1 second [FEV1] < 50%, and FEV1/FVC < 0.7) and increased LCI (11.67‐20.9), six out of 14 patients recovered completely after moderate lung function impairment and signs of BOS on HRCT. Long‐term FVC in absolute numbers was increased indicating that the children still have lung growth.
Conclusion: Our results showed that the incidence of BOS in children is low. BOS was associated with high mortality and may lead to persistent obstructive lung disease; although, lung growth continued to exist.
This article problematizes the assumption that national policies have a direct impact on youth participation at the local level and analyses the relationships between local forms of youth participation and local and national policies. Relying on data from a EU project funded under the HORIZON 2020 programme, the article focuses on formally institutionalized settings of youth participation and elaborates local constellations of youth participation in six European cities. These constellations may be referred to as regimes of youth participation as they reflect wider structures of power and knowledge that influence the way in which young people’s practices in public spaces and their claims of being part of society are recognized. However, the analysis reveals that rather deducing it from the model of welfare regimes, such a typology needs to be developed starting from the local level and should consider the ways in which different relationships between local youth policies and national welfare states affect youth participation.