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Abstract Yersinia pestis has been infecting humans since the Late Neolithic (LN). Whether those early infections were isolated zoonoses or initiators of a pandemic remains unclear. We report Y. pestis infections in two individuals (of 133) from the LN necropolis at Warburg (Germany, 5300–4900 cal BP). Our analyses show that the two genomes belong to distinct strains and reflect independent infection events. All LN genomes known today (n = 4) are basal in the phylogeny and represent separate lineages that probably originated in different animal hosts. In the LN, an opening of the landscape resulted in the introduction of new rodent species, which may have acted as Y. pestis reservoirs. Coincidentally, the number of dogs increased, possibly leading to Y. pestis infections in canines. Indeed, we detect Y. pestis in an LN dog. Collectively, our data suggest that Y. pestis frequently entered human settlements at the time without causing significant outbreaks.

Abstract Terrestrial carnivorans, with their diverse diets and unique adaptations such as the carnassial tooth, offer insights into the connections between functional traits and the climatic and environmental conditions they inhabit. They shed light on functional trait‐environment relationships at the highest trophic levels across a broad range of environmental conditions. In this study, we evaluate the relationship between relative blade length (RBL) of the lower carnassial tooth, a key dietary adaptation among terrestrial carnivorans for slicing and grinding food items, and climate. We propose RBL as an ecometric trait and test the hypothesis that community‐level RBL is correlated with climate and mediated by environmental effects on food availability. Our findings show that communities with higher mean and broader variance of RBL are typically located in warmer and wetter climates, suggesting a relationship between carnivoran dietary diversity and climate. Conversely, communities with a lower mean and narrower variance of RBL predominantly occupy cooler, drier places. This indicates that community‐level carnivoran dietary traits have the potential to serve as indicators of environmental conditions. Given the robust fossil record associated with carnivorans, we also show how RBL can be used as a proxy for reconstructing paleoclimates by examining trait change at seven sites in North America to estimate changes in temperature and precipitation over time in relation to changes in carnivoran community assembly. Understanding the nature of trait‐environment relationships can help us anticipate biological impacts of ongoing environmental change and the geographic regions at the greatest risk of ecological disruption.

Abstract This paper explores the feasibility and potential implications of automated air-taxis as a new mode of urban transport. By applying flight simulation and operations research, we investigate different questions regarding travel time, travel costs, and transport sustainability. As practical application, we consider the transportation service between the city and the airport, as well as on-demand air-taxi services within the city of Vienna. We compare the air-taxis with gasoline taxis and e-taxis, as they serve analogous transportation needs and cater to a similar clientele. In our effort to assess the feasibility of air-taxis, we aim to answer crucial questions that will influence the future of urban transportation. Our study examines how efficient air-taxis are in reducing travel time and explores their cost dynamics, addressing the affordability for passengers and their value of travel time savings. Additionally, we investigate their environmental impact by looking into energy consumption and CO2 emissions. Through a rigorous analysis of empirical data and simulation outcomes, we aim to provide a comprehensive perspective that informs policy decisions and guides the evolution of urban transportation networks in the years to come.

Abstract While our understanding of long-term trends in material wealth inequality in prehistoric societies has expanded in recent decades, we know little about long-term trends in other dimensions of wealth and about social developments within particular societal segments. This paper provides the first evidence of inequality in relational wealth within the upper societal segment of a supra-regional network of communities in prehistoric Central Europe over the first four millennia BCE. To this end, we compiled a novel dataset of 5000 single-funeral burial mounds and employed burial mound volume as a proxy for the buried individual’s relational wealth. Our analysis reveals a consistently high level of inequality among the buried individuals, showing a wave-like pattern with an increasing trend over time. Additionally, our findings show temporal shifts in the size of the upper societal segment. Based on a review of archeological and paleo-environmental evidence, the temporal change in inequality may be explained by technological progress, climate and population dynamics, trade and social networks, and/or sociopolitical transformations.

Abstract The Arnstadt Formation of Saxony-Anhalt, Germany has yielded some of Germany’s most substantial finds of Late Triassic tetrapods, including the sauropodomorph Plateosaurus and the stem-turtle Proganochelys quenstedti. Here, we describe an almost complete skull of a new sphenodontian taxon from this formation (Norian, 227–208 Ma), making it the oldest known articulated sphenodontian skull from Europe and one of the oldest in the world. The material is represented by the dermal skull roof and by the complete maxilla and temporal region, as well as parts of the palate, braincase, and lower jaw. A phylogenetic assessment recovers it as a basal sphenodontian closely related to Planocephalosaurus robinsonae and to Eusphenodontia, making it the earliest-diverging sphenodontian known with an articulated skull. Its cranial anatomy is generally similar to the well-known Diphydontosaurus avonis from the Rhaetian of England, showing that this successful phenotype was already established in the clade around 10 myr earlier than assumed. An analysis of evolutionary change rates recovers high rates of evolution in basal sphenodontians, with decreasing rates throughout the evolution of the group. However, contrary to previous studies, reversals in this trend were identified, indicating additional peaks of evolutionary change. These results improve our understanding of the early sphenodontian diversity in Europe, providing critical information on evolutionary trends throughout the history of the clade and sparking renewed interest in its evolution.

Mechanistic explanations of the impact of climate change on fish growth are currently under debate. However, critical assessments of even the most prominent theories are not always based on accurate interpretations of their underlying mechanistic models. This contribution addresses some of the major misunderstandings still causing the Gill-Oxygen Limitation Theory (GOLT) from being examined based on its actual structuring elements and assumptions, rather than erroneous perceptions. As we argue, recent critiques of the GOLT are based on implausible interpretations of respirometry data that are invoked to distinguish maintenance costs and overhead costs of growth. Discussing the current state of the debate, we emphasize the fact that fasting young and, thus, growing fish for short periods of time is not sufficient to suppress energy (i.e., oxygen) allocation to growth. In the process of dealing with these issues, several cases of apparent ‘counter-evidence’ are discussed. Highlighting the need to base critical discussions and examinations of the GOLT on its actual predictions, we recommend that testing the theory should focus on broad reviews or meta-analyses, e.g., on datasets of gill surface area and the relationship of these data to growth performance under different temperature regimes.

IntroductionSchistosomiasis (SM) is a parasitic disease caused by Schistosoma mansoni. SM causes chronic inflammation induced by parasitic eggs, with collagen/fibrosis deposition in the granuloma process in the liver, spleen, central nervous system, kidneys, and lungs. Pulmonary arterial hypertension (PAH) is a clinical manifestation characterized by high pressure in the pulmonary circulation and right ventricular overload. This study investigated the production of functional autoantibodies (fAABs) against the second loop of the G-protein-coupled receptor (GPCR) in the presence of hepatic and PAH forms of human SM.MethodsUninfected and infected individuals presenting acute and chronic manifestations (e.g., hepatointestinal, hepato-splenic without PAH, and hepato-splenic with PAH) of SM were clinically evaluated and their blood was collected to identify fAABs/GPCRs capable of recognizing endothelin 1, angiotensin II, and a-1 adrenergic receptor. Human serum was analyzed in rat cardiomyocytes cultured in the presence of the receptor antagonists urapidil, losartan, and BQ123.ResultsThe fAABs/GPCRs from chronic hepatic and PAH SM individuals, but not from acute SM individuals, recognized the three receptors. In the presence of the antagonists, there was a reduction in beating rate changes in cultured cardiomyocytes. In addition, binding sites on the extracellular domain functionality of fAABs were identified, and IgG1 and/or IgG3 antibodies were found to be related to fAABs.ConclusionOur data suggest that fAABs against GPCR play an essential role in vascular activity in chronic SM (hepatic and PAH) and might be involved in the development of hypertensive forms of SM.

BackgroundSnakebite is a major poverty-related neglected tropical disease. An integrated scientific approach is needed to understand the dynamics of this important health issue. Our objective was to estimate snakebite occurrence in a tropical area by using a blend of ecological modelling and robust statistical analysis.MethodsThe present study used climatic, environmental, and human population density data to determine the area with snakebite occurrence-probability for the first time in Bangladesh. We also analysed a large, 16-year dataset of hospitalized snakebite cases to reveal the epidemiology of snakebite in the south-eastern zone of the country.FindingsOur results show that cobra bite is the most commonly occurring venomous snakebite in humans (around ~12% of the total yearly snakebite records), and men are more frequently bitten than women (2/3 of human victims are men). Most bites occur during the rainy season for cobra and green pit viper, while krait bites are not restricted to any particular season. As snakebite incidents are closely related to climate conditions, we can model snakebite risk using temperature and precipitation variables. Whereas there is a lack of snakebite reports from several parts of the study area in official records, our models predict that the entire study area is favourable for snakebite incidents. Based on the combined evidence we estimate that about 200,000 snakebite events occur every year in the south-eastern part of Bangladesh alone. Considering future global climate change, our model projections show that snakebite incidence in Bangladesh might not significantly decrease in the future (- 2070-); however, the distribution of probabilities might change, with a predicted increase of snakebite incidence in the hilly areas of the country.ConclusionsUsing climatic data to predict snakebite incidence in Bangladesh allowed us to provide estimations of the total annual number of snakebite cases in the study area. As in most countries, the scarcity of accurate epidemiological data in official records might have masked the real magnitude of this problem. Our analysis suggests that the problem of snakebite envenoming in Bangladesh might be worse than currently perceived. A long-term sustainable snakebite program plan should be designed and institutionalized, considering climatic, geographical and human demographic variables, to obtain better data and facilitate the implementation of accurate snakebite management programs for this country.

Fibroblast growth factor 23 (FGF23) is a member of endocrine FGF family, along with FGF15/19 and FGF21. Recent reports showed that under pathological conditions, liver produces FGF23, although the role of hepatic FGF23 remains nebulous. Here, we investigated the role of hepatic FGF23 in alcoholic liver disease (ALD) and delineated the underlying molecular mechanism. FGF23 expression was compared in livers from alcoholic hepatitis patients and healthy controls. The role of FGF23 was examined in hepatocyte-specific knock-out (LKO) mice of cannabinoid receptor type 1 (CB1R), estrogen related receptor γ (ERRγ), or FGF23. Animals were fed with an alcohol-containing liquid diet alone or in combination with ERRγ inverse agonist. FGF23 is mainly expressed in hepatocytes in the human liver, and it is upregulated in ALD patients. In mice, chronic alcohol feeding leads to liver damage and induced FGF23 in liver, but not in other organs. FGF23 is transcriptionally regulated by ERRγ in response to alcohol-mediated activation of the CB1R. Alcohol induced upregulation of hepatic FGF23 and plasma FGF23 levels is lost in ERRγ-LKO mice, and an inverse agonist mediated inhibition of ERRγ transactivation significantly improved alcoholic liver damage. Moreover, hepatic CYP2E1 induction in response to alcohol is FGF23 dependent. In line, FGF23-LKO mice display decreased hepatic CYP2E1 expression and improved ALD through reduced hepatocyte apoptosis and oxidative stress. We recognized CBIR-ERRγ-FGF23 axis in facilitating ALD pathology through hepatic CYP2E1 induction. Thus, we propose FGF23 as a potential therapeutic target to treat ALD.

Measles remains one of the leading causes of death among young children globally, even though a safe and cost-effective vaccine is available. Vaccine hesitancy and social response to vaccination continue to undermine efforts to eradicate measles. In this study, we consider data about measles vaccination and measles prevalence in Germany for the years 2008–2012 in 345 districts. In the first part of the paper, we show that the probability of a local outbreak does not significantly depend on the vaccination coverage, but—if an outbreak does take place—the scale of the outbreak depends significantly on the vaccination coverage. Additionally, we show that the willingness to be vaccinated is significantly increased by local outbreaks, with a delay of about one year. In the second part of the paper, we consider a deterministic delay model to investigate the consequences of the statistical findings on the dynamics of the infection. Here, we find that the delay might induce oscillations if the vaccination coverage is rather low and the social response to an outbreak is sufficiently strong. The relevance of our findings is discussed at the end of the paper.

Organized sports programmes offer manifold opportunities for learning and personal development. Prisoners in organized sports programmes could profit from these educational opportunities, which could eventually support their process of reintegration into society. However, research on the educational experiences of imprisoned individuals during organized sports activities is scarce. Using quantitative survey data (N = 568 adult male prisoners) collected within the scope of the Hessian Prison Sports Study in Hesse, Germany, the present study examines educational experiences that are instigated through participation in five different prison sports programmes (fitness, racket, and team sports, running groups, and strength training). The results show that participants reported few educational experiences. The most common experiences reported were learning to exert effort and acquiring health-related knowledge. The findings reveal distinct patterns for specific sports programmes. For instance, team sports more frequently address cooperation skills and fairness. This paper advocates for more attention to the educational potential of sports in prison settings, where sports outcomes should be better aligned with the desired educational outcomes.

In the last decades, EU studies have increasingly broadened in terms of their theoretical and methodological approaches. By now, comparative concepts and theories are an integral part of studying the EU, which aids the study of its polity, politics, and policies. Despite the indisputable peculiarity of the EU as a political system, many scholars have stressed the value of using comparative approaches to study it. This thematic issue aims to investigate a specific case—the political system of Canada—as to its merit for comparison with the EU. While both systems have been described as sui generis in the past, forming a class of political system by themselves, recently the similarities between both have been stressed. This thematic issue gathers articles that compare different aspects of these two systems—focusing on polity, politics, and policy—to reap the benefits of the comparative approach and gain new insights into the functioning of both systems. The contributions to the thematic issue show the benefits that both Canadian political science and EU studies can gain from engaging in comparative exercises.

Federal systems face specific challenges in fulfilling their international commitments. In cases of shared jurisdiction, the federal government needs the sub-federal level to contribute to the implementation process. Both Canada and the EU have used side-payments to bring and keep on board reluctant and opposing provinces and member states in the implementation of international agreements. However, both cases have experienced the limits of this strategy. This article aims to make a theoretical contribution by identifying the causal conditions and processes that help explain the success and failure of using side-payments to encourage sub-federal support for the implementation of an international agreement. Based on the study of the implementation of the Paris Agreement in Canada and the EU, I develop a two-fold argument. First, side-payments can be an effective tool to persuade sub-federal governments if they are generally interested in contributing to implementation. They do not work for governments of powerful entities that are unwilling to implement. Second, sub-federal governments react to other actors’ conduct. Side-payments can keep reluctant governments of weak entities on board only as long as no alliance of powerful sub-federal entities is formed that resists the implementation of an international agreement.

Abstract Background Previous studies about health in prisons conclude that incarceration has detrimental consequences for physical and mental health. It is associated with weight gain, decreased fitness, increased cardiovascular risks, and increased risks for mental illnesses, like depression and anxiety. This article examines the relationships between sports activity and health developments among prisoners. We analyze data from the Hessian Prison Sports Study, conducted in 12 prisons of the federal state of Hesse, Germany. Results Based on quantitative survey data of 568 prisoners in regular custody, our empirical findings show that inmates perceive substantial health declines since incarceration. They report substantial decreases in general health (d=-0.52) and life satisfaction (d=-0.84) as well as an increased number of health problems (d = 0.71). However, sport has a potential to buffer this decline of health. Prisoners engaged in sports report a less negative development of their health compared to inactive prisoners. The greater the amount of time spent with sports activities, the better are the health trajectories found. Conclusion Findings add to the public health and prison sport literature by demonstrating health benefits of sporting activities in a vulnerable population group that almost inevitably is exposed to manifold strains and burdens.

Abstract Mammalian megafauna have been critical to the functioning of Earth’s biosphere for millions of years. However, since the Plio-Pleistocene, their biodiversity has declined concurrently with dramatic environmental change and hominin evolution. While these biodiversity declines are well-documented, their implications for the ecological function of megafaunal communities remain uncertain. Here, we adapt ecometric methods to evaluate whether the functional link between communities of herbivorous, eastern African megafauna and their environments (i.e., functional trait-environment relationships) was disrupted as biodiversity losses occurred over the past 7.4 Ma. Herbivore taxonomic and functional diversity began to decline during the Pliocene as open grassland habitats emerged, persisted, and expanded. In the mid-Pleistocene, grassland expansion intensified, and climates became more variable and arid. It was then that phylogenetic diversity declined, and the trait-environment relationships of herbivore communities shifted significantly. Our results divulge the varying implications of different losses in megafaunal biodiversity. Only the losses that occurred since the mid-Pleistocene were coincident with a disturbance to community ecological function. Prior diversity losses, conversely, occurred as the megafaunal species and trait pool narrowed towards those adapted to grassland environments.

High-resolution computed tomography (HRCT) has become a widely used tool for studying the inner ear morphology of vertebrates. Amphisbaenians are one of the most specialized groups of fossorial reptiles but are poorly understood relative to other squamate reptile. In this paper we survey the anatomy of the inner and middle ear of these fossorial reptiles using HRCT models and we describe qualitatively and quantitatively (using 3D morphometrics) the anatomy of the inner ear. Amphisbaenians are diverse in skull anatomy, especially in the configuration of the snout, which correlates with digging modes. We demonstrate that the ear also exhibits a diversity of configurations, which are independent of phylogenetic relationships. Results from morphological analyses also allow us to describe 11 new potentially informative phylogenetic characters including some that help to diagnose amphisbaenians, such as: 1) the globular vestibule, ii) semicircular canals arranged in a circular trajectory, and iii) an extensive area of interaction between the columella footplate and the lagenar recess. Among extant amphisbaenians, Rhineura floridana has the most unusual inner ear configuration, including a horizontal semicircular canal that is in the same orientation as the inclined snout. The new morphological information helps us to better understand the morphology of headfirst-burrowing fossorial reptiles and contributes new data for resolution of phylogenetic relationships among amphisbaenians.

The "princely" barrows of Łęki Małe, Greater Poland are the oldest such monuments within the distribution area of Únětice societies in Central Europe. While in the Circum-Harz group and in Silesia similar rich furnished graves under mounds have appeared as single monuments as early as 1950 BC, Łęki Małe represents a chain of barrows constructed between 2150 BC and 1800 BC. Of the original 14 mounds, only four were preserved well enough that their complex biographies can now be reconstructed. They included ritual activities (before, during, and after the funeral), and also subsequent incursions, including robberies. The long lasting barrow cemetery at Łęki Małe can be linked to a nearby fortified site, Bruszczewo. Together, Łęki Małe and Bruszczewo represent a stable, socially differentiated society that existed for no less than 350-400 years. Therefore, it can be argued that the Early Bronze Age societies of Greater Poland were extremely sustainable in comparison to those of other Únětice regions.

An integrated botanical and chemical approach is used to study surface residues on Funnel Beaker ceramics from the site of Oldenburg LA 77, in northern Germany. Organic residues were discovered adhering to fragments of thick-walled, undecorated ceramic vessels (n = 19) and ceramic discs (n = 2). The surface residues were studied using scanning electron microscopy (SEM), to examine remains of cereals and other plant tissues that survived food preparation and cooking, and using attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and direct time-resolved mass spectrometry (DTMS), to chemically identify specific food components. The SEM results show a reoccurring presence of cereal grain (emmer and barley) and one case of co-occurrence of emmer and fat-hen seeds. The SEM evidence for the use of sprouted emmer grain and milk-ripe barley from the Oldenburg residues greatly enhances our understanding of Neolithic foodways in northwestern Europe. The ATR-FTIR results showed that roughly a third of the surface residues contain traces of the original foods prepared or processed and DTMS results confirm that most of the residues primarily contain polysaccharides and a minimal amount of plant protein and that they lack lipids. Only one residue presents minor indications for a (partly) animal origin. The ceramic vessels were thus used almost exclusively for the processing or cooking of cereal grains. This study offers an intimate view of the cuisine and cooking practices (and in some cases their seasonal timing) in an early agricultural village located in a marginal farming region on the south coast of the Baltic Sea.

Abstract Background Management of mechanically ventilated patients can be improved with monitoring of key pulmonary function parameters that facilitate individualization and optimization. The VQm Pulmonary Health Monitor™ (PHM) (Rostrum Medical Innovations Inc., Vancouver, Canada) is a new monitor that continuously measures pulmonary blood flow (PBF), functional residual capacity (FRC) and a novel parameter: shunt index (Qsi). The goal of this study was to provide an initial assessment of the performance of the VQm PHM™ when compared with reference measures of PBF, FRC and intra-pulmonary shunt. Methods This was a prospective, experimental, large animal (porcine) study. After baseline measurements, three interventions were performed: increased cardiac output (CO) using dobutamine infusion, increased PEEP (from 4 to 12 cmH2O), and experimental shunt induced by an extracorporeal circuit. PBF, FRC and shunt were measured by the VQm Pulmonary Health Monitor™ (PHM) before and after each intervention. The PHM™ uses sequential gas delivery to deliver targeted alveolar concentrations of CO2 or N2O. PBF and FRC were calculated using CO2 bolus delivery and the modified differential Fick equation. Shunt was estimated from the number of breaths required to eliminate N2O after a 25-breath N2O bolus and expressed as Qsi. PHM™-derived PBF and Qsi were compared to thermodilution CO and calculated Berggren shunt, respectively. Results Studies were completed in 19 animals. Measurements of PBF, FRC and Qsi obtained from the PHM™ trended as expected following each intervention. The mean difference between paired values of PBF was − 0.2 ± 0.9 L/min and the 95% limits of agreement were 1.5 and − 1.9 L/min. Concordance was 94.1%. The mean baseline FRC was 1.7 $$\pm$$ 0.4 L and increased to 2.0 $$\pm$$ 0.6 L, following the increase in PEEP (p = 0.0078). For shunt (Qsi), the mean values during low (1 L/min) and high (50% of baseline CO) shunt value were 40 $$\pm$$ 4 and 27 $$\pm$$ 5, respectively, p = 0.002. Conclusions PBF obtained through the modified differential Fick equation and Qsi obtained through N2O uptake and decay dynamics by the VQm PHM™ provide comparable results to reference standards. FRC measurements trended as expected following interventions.

Abstract We present a method that lowers the dose required for an electron ptychographic reconstruction by adaptively scanning the specimen, thereby providing the required spatial information redundancy in the regions of highest importance. The proposed method is built upon a deep learning model that is trained by reinforcement learning, using prior knowledge of the specimen structure from training data sets. We show that using adaptive scanning for electron ptychography outperforms alternative low-dose ptychography experiments in terms of reconstruction resolution and quality.

In this paper we compare multiple types of domestic settlements from different chronological periods in prehistoric continental Europe to inform occupancy patterns and demographic trends. We focus in particular on the evidence of a boom and bust pattern that appears to be constant across all the sites studied. We find evidence of a growth plateau after 200 to 300 years of existence. But because the number of sites used is small, due to the quality restrictions of the data, the results still need to be confirmed by further investigations.

Abstract This article presents the results of a numerical experiment and an analysis of temperature fields (coolers for gas) using cooling elements in the case study gas pipeline. An analysis of the temperature fields demonstrated several principles for the formation of a temperature field, which indicates the need to maintain a relative temperature for gas pumping. The essence of the experiment was to install an unlimited number of cooling elements on the gas pipeline. The purpose of this study was to determine at what distance it is possible to install cooling elements for the optimal gas pumping regime, regarding the synthesis of the control law and the determination of the optimal location and assessment of control error depending on the location of the cooling elements. The developed technique allows for the evaluation of the developed control system's regulation error.

Research on sexual diversity in physical education (PE) focuses primarily on students and rarely on teachers. Against this background, this study takes a look at teachers and explores the question of how lesbian, gay, and bisexual (LGB) teachers experience PE. Our study was conceived as a systematic literature review of qualitative studies published between 1990 and 2022. The processual study selection was carried out according to PRISMA. A total of nine studies were identified that met our inclusion criteria. We analyzed and compared the findings of these studies. On an overarching level, our analysis shows that the identified studies predominantly focus on the challenges and problems associated with the sexuality of LGB teachers. Furthermore, our analysis shows that the PE teachers interviewed in the studies perceive and anticipate school as a homophobic context. From the teachers’ perspective, PE is a special subject that they experience as particularly risky due to their sexuality. Against the backdrop of these experiences, many PE teachers use protective strategies, which mainly consist of hiding their own sexuality and ignoring the perceived homophobia. In the end, research implications are discussed, highlighting the need for ongoing research on LGB PE teachers.

Abstract Increasing urbanisation and intensified agriculture lead to rapid transitions of ecosystems. Species that persist throughout rapid transitions may respond to environmental changes across space and/or time, for instance by altering morphological and/or biochemical traits. We used natural history museum specimens, covering the Anthropocene epoch, to obtain long‐term data combined with recent samples. We tested whether rural and urban populations of two ground beetle species, Harpalus affinis and H. rufipes, exhibit spatio‐temporal intraspecific differences in body size. On a spatial scale, we tested signatures of nitrogen and carbon stable isotopes enrichments in different tissues and body components in recent populations of both species from urban and agricultural habitats. For body size examinations, we used beetles, collected from the early 20th century until 2017 in the Berlin‐Brandenburg region, Germany, where urbanisation and agriculture have intensified throughout the last century. For stable isotope examinations, we used recent beetles from urban and agricultural habitats. Our results revealed no spatio‐temporal changes in body size in both species' females. Body size of H. rufipes males decreased in the city but remained constant in rural areas over time. We discuss our findings with respect to habitat quality, urban heat and interspecific differences in activity pattern. Although nitrogen isotope ratios were mostly higher in specimens from agricultural habitats, some urban beetles reached equal enrichments. Carbon signatures of both species did not differ between habitats, detecting no differences in energy sources. Our results indicate that increasing urbanisation and intensified agriculture are influencing species' morphology and/or biochemistry. However, changes may be species‐ and sex‐specific.

A unifying setup for opinion models originating in statistical physics and stochastic opinion dynamics are developed and used to analyze election data. The results are interpreted in the light of political theory. We investigate the connection between Potts (Curie–Weiss) models and stochastic opinion models in the view of the Boltzmann distribution and stochastic Glauber dynamics. We particularly find that the q-voter model can be considered as a natural extension of the Zealot model, which is adapted by Lagrangian parameters. We also discuss weak and strong effects (also called extensive and nonextensive) continuum limits for the models. The results are used to compare the Curie–Weiss model, two q-voter models (weak and strong effects), and a reinforcement model (weak effects) in explaining electoral outcomes in four western democracies (United States, Great Britain, France, and Germany). We find that particularly the weak effects models are able to fit the data (Kolmogorov–Smirnov test) where the weak effects reinforcement model performs best (AIC). Additionally, we show how the institutional structure shapes the process of opinion formation. By focusing on the dynamics of opinion formation preceding the act of voting, the models discussed in this paper give insights both into the empirical explanation of elections as such, as well as important aspects of the theory of democracy. Therefore, this paper shows the usefulness of an interdisciplinary approach in studying real world political outcomes by using mathematical models.

IntroductionThe COVID-19 pandemic changed not only the working conditions but also the private conditions we live in. Health care professionals especially were confronted with multiple stressors, e.g., the risk of infection, lack of staff, and high workloads.MethodsTo estimate some of the pandemic-related impacts this anonymous personnel survey was conducted in two German military hospitals (Hamburg and Berlin). This study presents a comparative analysis of the hospital staff in general vs. the psychiatric personnel (N = 685) at two measurement time points (MTPs) in April 2021 (n = 399) and December 2021 (n = 286). The survey contains the German version of the Covid Stress Scale (CSS) to assess the perceived level of pandemic-related stress, the Patient Health Questionnaire (German Version: PHQ-D) to screen for three major mental disorders, and the adjustment disorder—New Module (ADNM) to estimate the problems of adaptation to change.ResultsThe results showed a process of adaptation over the two MTPs with significant stress reduction at MTP2 in the general staff. The psychiatric staff did not report significantly higher pandemic-related symptoms. Quite the contrary, not only did the CSS show significantly lower xenophobia, traumatic stress, and compulsive checking, but the PHQ also showed lower stress symptoms and somatic symptoms at both MTPs. Also, the ADNM scores delivered evidence for a more effective adaptation process in psychiatric personnel (e.g., depressive mood, avoidance, anxiety).DiscussionThe presented results must be interpreted while taking the unique situations of German military clinics into account. The supply of protective material was sufficient and there was no dramatic shortage of psychiatric staff during the pandemic. The inpatients were quite often (40%) elective treatments for trauma-related disorders, which could be discontinued in the case of a COVID-19 infection. The results of this study showed good adaptative skills among the psychiatric staff in military hospitals, which could be interpreted as a sign of good resilience. This might have led to lower stress-related symptoms during the COVID-19 pandemic.

In the East European region between Prut and Dnieper, proto-urban mega-sites developed ca. 4100−3600 BCE with population agglomerations of around 10000 inhabitants per site. An outline of complexity categories, based on P. Turchin et al. (2018), illustrates that “computational abilities” are first developed to make the shift from dispersed to agglomerated settlement patterns. The development of an internal decision-making system for a polity that organizes communication via public buildings on different levels, together with a site-specific track system, may be responsible for this shift (or made it possible). However, after generations, this communication pattern was not developed into further collective communication abilities (e.g., into a writing system), while at the same time a tendency toward centralizing decision processes probably destroyed the communication flow. This ultimately led to the collapse of Tripolye mega-sites.

It is widely assumed that LGBT+ people may feel insecure and unwelcome in sports settings, which are often characterized by a binary gender order and a culture of heteronormativity. Previous research also suggests that LGBT+ individuals experience homophobia in the context of sport. Despite these findings, reliable quantitative data on the sports participation levels of sexual minority groups are scarce. The paper addresses this academic void by analyzing sports activity data of sexual minority groups. The 2019 wave of the German Socio-Economic Panel (SOEP) study is analyzed, which includes a novel LGBT+ boost sample of respondents who self-identify as lesbian, gay, bisexual, transgender, or non-binary with regard to gender. The analysis of this sample shows that sports activity levels (with regard to frequency and duration) of homo- and bisexual individuals are comparable to the heterosexual majority. Although findings show that a high share of homo- and bisexual individuals experience sexual discrimination, discrimination is not associated with lower participation rates in sports. We thus conclude that the domain of sport—although by no means free of discrimination—offers sufficient participation opportunities for LGBT+ people.

Abstract A high number of trauma patients are under the influence of alcohol. Since many of them need immediate surgical procedures, it is imperative to be aware of the interaction of alcohol with general anesthesia. To counter challenges that arise from clinical studies, we designed an animal experiment in which 48 adult Wistar rats either received 1 g · kg−1 ethanol, 2 g · kg−1 ethanol or placebo via intraperitoneal application. Subsequently, they were anesthetized with an individual concentration of sevoflurane. The minimum alveolar concentration (MAC) of the different groups was assessed using Dixon’s up-and-down design and isotonic regression methods. The bootstrap estimate of the MAC of sevoflurane in the placebo group was 2.24 vol% (95% CI 1.97–2.94 vol%). In the low dose ethanol group, the bootstrap estimate was 1.65 vol% (95% CI 1.40–1.98 vol%), and in the high dose ethanol group, it was 1.08 vol% (95% CI 0.73–1.42 vol%). We therefore report that intraperitoneal application of 1 g · kg−1 or 2 g · kg−1 ethanol both resulted in a significant reduction of the MAC of sevoflurane in adult Wistar rats: by 26.3% and 51.8% respectively as compared to placebo.

With their rich Late Neolithic to Early Bronze Age archives, the Circumharz region, the Czech Republic/Lower Austria region, and the Northern Alpine Foreland are well-suited for research on potential links between human activities and climate fluctuations of this period with pronounced archaeological changes. In this paper, we reconstruct the rate and density of the available 14C data from 5500 to 3500 calBP (3550-1550 BCE). We ask to what extent population patterns varied over time and space, and whether fluctuations in human populations and their activities varied with local/regional climate changes. To answer these questions, we have compiled an extensive list of published radiocarbon dates and created 14C sum calibrations for each region. We also compare population dynamics with local and regional palaeoclimate records derived from high-resolution speleothems. At the regional scale, the results suggest a causal relationship between regional climate and population trends. Climate and associated environmental changes were thus at least partly responsible for demographic trends. These results also allow us to question the motivation for the construction of so-called "Early Bronze Age princely tombs" in the Circumharz region during a period of population decline. Among other things, it can be argued that the upper echelons of society may have benefited from trade relations. However, this process was accompanied by ecological stress, a cooling of the winter climate, a decline in the total population and an increase in social inequality.

Nord Stream 2 is one of the most discussed energy projects, which affects the economic and political interests of many countries, not only the direct participants. Despite some uncertainty, the project is highly likely to be completed. In this regard, it is important to understand what impact it will have on the European gas market. This article proposes a simulation model for calculating the total cost of construction of the Nord Stream 2 and determines the cost of natural gas. It was concluded that Nord Stream 2 has an economic advantage overliquified natural gas (LNG) delivery schemes, a strategic value for the economies of the EU countries and will ensure the stability of gas supply, which is undoubtedly a priority for European energy policy.

How is acetyl-CoA produced in the context of the endogenous, eukaryotic pyruvate dehydrogenase complex metabolon? Here the authors dissect the embedded transacetylase reaction through biochemical, cryo-EM, HADDOCKing and molecular dynamics methods.

The interaction of the anti-beta1-adrenergic receptor autoantibodies (β1ARAb) and the anti-muscarinic M2 receptor autoantibodies (M2RAb) with cardiac neurotransmitter receptors were identified in human chronic Chagas cardiomyopathy (CCC) related to the ECG and dysautonomia disturbances. Dogs are considered gold model to the study of Trypanosoma cruzi infection due the clinical similarities with CCC. This study aims to evaluate whether anti-β1ARAb, anti-β2ARAb, and anti-muscarinic M2RAb are generated in Beagle dogs infected by T. cruzi using Y and Berenice-78 strains of T. cruzi. Animals were infected with 4.0 x 103 bloodstream trypomastigotes/kg of body weight and, after 25 months of infection, blood sample was collected, and serum stored at -80°C. Dog serum was treated by ammonium sulphate precipitation and the IgG antibodies isolated and added to the beating neonatal rats’ cardiomyocytes. All T. cruzi-infected dogs developed agonistic β1ARAb, β2ARAb, and M2RAb. Animals infected by Berenice strain presented less β2ARAb and M2RAb activities than dogs infected by Y strain of the parasite. In cardiomyocytes culture, the antibodies recognized an epitope on the second extracellular loop of the receptors which were similar to findings in human Chagas disease. There was no detection of antibody against G protein-coupled receptor in serum from uninfected dogs. In conclusion, both Y and Berenice-78 strains of T. cruzi induced dog antibodies, whose targets located in the second extracellular loop of the adrenergic and muscarinic receptors were similar to those observed in individuals with CCC. Therefore, our findings highlight dogs as a promisor model to investigate pathogenic roles of functional Ab against G-protein coupled receptors.

Vaccination hesitancy is a major obstacle to achieving and maintaining herd immunity. Therefore, public health authorities need to understand the dynamics of an anti-vaccine opinion in the population. We introduce a spatially structured mathematical model of opinion dynamics with reinforcement. The model allows as an emergent property for the occurrence of echo chambers, i.e. opinion bubbles in which information that is incompatible with one’s entrenched worldview, is probably disregarded. We scale the model both to a deterministic limit and to a weak-effects limit, and obtain bifurcations, phase transitions and the invariant measure. Fitting the model to measles and meningococci vaccination coverage across Germany, reveals that the emergence of echo chambers dynamics explains the occurrence and persistence of the anti-vaccination opinion in allowing anti-vaxxers to isolate and to ignore pro-vaccination facts. We predict and compare the effectiveness of different policies aimed at influencing opinion dynamics in order to increase vaccination uptake. According to our model, measures aiming at reducing the salience of partisan anti-vaccine information sources would have the largest effect on enhancing vaccination uptake. By contrast, measures aiming at reducing the reinforcement of vaccination deniers are predicted to have the smallest impact.

(1) Background: SARS-CoV-2 infection has been linked to diverse clinical manifestations in humans, including cardiovascular complications. Functional autoantibodies targeting G-protein-coupled receptors have emerged as potential contributors to these effects. This study sought to investigate the production and activity of functional autoantibodies targeting G-protein-coupled receptors after SARS-CoV-2 infection of selected animal species. (2) Methods: The presence of functional autoantibodies such as 2-adrenoceptor, angiotensin II AT1 receptor, muscarinic M2 receptor, and angiotensin 1–7 MAS receptor was assessed in cattle and ferrets experimentally infected with SARS-CoV-2. Bioassays were conducted to evaluate the positive or negative chronotropic responses induced by these autoantibodies. Further experiments identified the extracellular domains to which the functional autoantibodies bind, and receptor antagonists were employed to block the induced responses. (3) Results: Only two out of six cattle that were inoculated with SARS-CoV-2 displayed viral replication and tested positive for functional autoantibodies against G-protein-coupled receptors. These functional autoantibodies specifically recognized β2-adrenoceptor, angiotensin II AT1 receptor, muscarinic M2 receptor, and angiotensin 1–7 MAS receptor and induced distinct positive and negative chronotropic effects in the bioassay. Infected ferrets generated functional autoantibodies against β2-adrenoceptor and muscarinic M2 receptor and presented bioactivity similar to that in cattle. (4) Conclusions: This study uncovers functional autoantibodies targeting G-protein-coupled receptors in cattle and ferrets post-SARS-CoV-2 infection, with implications for cardiovascular function.

Abstract Asian cobras (genus Naja) are venomous snakes distributed from the Middle East to Southeast Asia. Because cobras often live near humans settlements, they are responsible for a large part of snakebite incidents and as such pose a challenge for public health systems. In the light of growing human populations, correctly mapping the present and future ranges of Asian cobras is therefore important for both biological conservation and public health management. Here, we mapped the potential climatic niches of ten Asian cobra species for both the present and the future, with the aim to quantify changes in climate and human population densities relative to their current and future ranges. Our analyses reveal that cobras that are adapted to dry climates and inhabit islands have narrow climatic niches, while those of mainland species with larger geographic ranges are much wider. We also found a higher degree of fragmentation of future cobra distributions; within the next 50 years, Asian cobras will lose an average of around 60% of their current suitable climatic range. In the near future, Naja mandalayensis, N. sputatrix, N. samarensis, and N. philippinensis are likely to have no accessible suitable climate space left. Besides, a further increase of human populations in this region may also exponentially accelerate the effects of anthropogenic impacts. Solutions for conservation may involve awareness and appropriate use of law to overcome the rate of habitat degradation and the increase of animal trade of Asian cobras, while promoting investment on health systems to avoid snakebite fatalities.

A multi-level cell (MLC) operation as a 1–3 bit/cell of the FeFET emerging memory is reported by utilizing optimized Si doped hafnium oxide (HSO) and hafnium zirconium oxide (HZO) based on ferroelectric laminates. An alumina interlayer was used to achieve the thickness independent of the HSO and HZO-based stack with optimal ferroelectric properties. Various split thicknesses of the HSO and HZO were explored with lamination to increase the FeFET maximum memory window (MW) for a practical MLC operation. A higher MW occurred as the ferroelectric stack thickness increased with lamination. The maximum MW (3.5 V) was obtained for the HZO-based laminate; the FeFETs demonstrated a switching speed (300 ns), 10 years MLC retention, and 104 MLC endurance. The transition from instant switching to increased MLC levels was realized by ferroelectric lamination. This indicated an increased film granularity and a reduced variability through the interruption of ferroelectric columnar grains. The 2–3 bit/cell MLC levels and maximum MW were studied in terms of the size-dependent variability to indicate the impact of the ferroelectric area scaling. The impact of an alumina interlayer on the ferroelectric phase is outlined for HSO in comparison to the HZO material. For the same ferroelectric stack thickness with lamination, a lower maximum MW, and a pronounced wakeup effect was observed in HSO laminate compared to the HZO laminate. Both wakeup effect and charge trapping were studied in the context of an MLC operation. The merits of ferroelectric stack lamination are considered for an optimal FeFET-based synaptic device operation. The impact of the pulsing scheme was studied to modulate the FeFET current to mimic the synaptic weight update in long-term synaptic potentiation/depression.

Abstract Contact tracing is one of several strategies employed in many countries to curb the spread of SARS-CoV-2. Digital contact tracing (DCT) uses tools such as cell-phone applications to improve tracing speed and reach. We model the impact of DCT on the spread of the virus for a large epidemiological parameter space consistent with current literature on SARS-CoV-2. We also model DCT in combination with random testing (RT) and social distancing (SD). Modelling is done with two independently developed individual-based (stochastic) models that use the Monte Carlo technique, benchmarked against each other and against two types of deterministic models. For current best estimates of the number of asymptomatic SARS-CoV-2 carriers (approximately 40%), their contagiousness (similar to that of symptomatic carriers), the reproductive number before interventions ( R 0 ${R_{0}}$ at least 3) we find that DCT must be combined with other interventions such as SD and/or RT to push the reproductive number below one. At least 60% of the population would have to use the DCT system for its effect to become significant. On its own, DCT cannot bring the reproductive number below 1 unless nearly the entire population uses the DCT system and follows quarantining and testing protocols strictly. For lower uptake of the DCT system, DCT still reduces the number of people that become infected. When DCT is deployed in a population with an ongoing outbreak where O $\mathcal{O}$ (0.1%) of the population have already been infected, the gains of the DCT intervention come at the cost of requiring up to 15% of the population to be quarantined (in response to being traced) on average each day for the duration of the epidemic, even when there is sufficient testing capability to test every traced person.

Abstract Silicon‐based anodes with lithium ions as charge carriers have the highest predicted theoretical specific capacity of 3579 mA h g−1 (for Li15Si4). Contemporary electrodes do not achieve this theoretical value largely because conventional production paradigms rely on the mixing of weakly coordinated components. In this paper, a semiconductive triazine‐based graphdiyne polymer network is grown around silicon nanoparticles directly on the current collector, a copper sheet. The porous, semiconducting organic framework (1) adheres to the current collector on which it grows via cooperative van der Waals interactions, (2) acts effectively as conductor for electrical charges and binder of silicon nanoparticles via conjugated, covalent bonds, and (3) enables selective transport of electrolyte and Li‐ions through pores of defined size. The resulting anode shows extraordinarily high capacity at the theoretical limit of fully lithiated silicon. Finally, we combine our anodes in proof‐of‐concept battery assemblies using a conventional layered Ni‐rich oxide cathode. Key Points We present a Si‐based anode with superior‐performance close to the limits of theoretical capacities with an advantage of factor ×10 over any hitherto produced, commercial electrode system. Our electrodes sustain physical bending without surface reconstruction or crack formation, and heat shocks without loss of capacity and overall cycling performance. The critical, novelty that enables the extraordinary performance increase and durability of our anodes is a class of semi‐conducting porous organic polymers that replaces all conventional additives in battery ink formulations.

Abstract Climate has a large impact on diversity and evolution of the world’s biota. The Eocene–Oligocene transition from tropical climate to cooler, drier environments was accompanied by global species turnover. A large number of Old World lacertid lizard lineages have diversified after the Eocene–Oligocene boundary. One of the most speciose reptile genera in the arid Palearctic, Acanthodactylus, contains two sub-Saharan species with unresolved phylogenetic relationship and unknown climatic preferences. We here aim to understand how and when adaptation to arid conditions occurred in Acanthodactylus and when tropical habitats where entered. Using whole mitogenomes from fresh and archival DNA and published sequences we recovered a well-supported Acanthodactylus phylogeny and underpinned the timing of diversification with environmental niche analyses of the sub-Saharan species A. guineensis and A. boueti in comparison to all arid Acanthodactylus. We found that A. guineensis represents an old lineage that splits from a basal node in the Western clade, and A. boueti is a derived lineage and probably not its sister. Their long branches characterize them—and especially A. guineensis—as lineages that may have persisted for a long time without further diversification or have undergone multiple extinctions. Environmental niche models verified the occurrence of A. guineensis and A. boueti in hot humid environments different from the other 42 arid Acanthodactylus species. While A. guineensis probably remained in tropical habitat from periods prior to the Eocene–Oligocene boundary, A. boueti entered tropical environments independently at a later period. Our results provide an important baseline for studying adaptation and the transition from humid to arid environments in Lacertidae.

Alexander Immel et al. performed genome-wide analyses of 42 individuals from a collective burial in Niedertiefenbach, Germany from the Wartberg Culture. The authors find that this population had a large hunter-gatherer ancestry component and a distinct HLA pool, which indicates immune defenses against viral pathogens.

Contact tracing is an effective method to control emerging infectious diseases. Since the 1980’s, modellers are developing a consistent theory for contact tracing, with the aim to find effective and efficient implementations, and to assess the effects of contact tracing on the spread of an infectious disease. Despite the progress made in the area, there remain important open questions. In addition, technological developments, especially in the field of molecular biology (genetic sequencing of pathogens) and modern communication (digital contact tracing), have posed new challenges for the modelling community. In the present paper, we discuss modelling approaches for contact tracing and identify some of the current challenges for the field.

BackgroundPregabalin is commonly used perioperatively to reduce post-operative pain and opioid consumption and to prevent the development of chronic pain. It has been shown to reduce anesthetic consumption in balanced anesthesia, but studies investigating its effect on the minimum alveolar concentration (MAC) of volatile anesthetics are lacking. The aim of this study was to investigate the effect of two different doses of pregabalin on the MAC of sevoflurane.MethodsIn a randomized, double-blinded, placebo controlled clinical study, 75 patients were assigned to receive placebo, 300 mg pregabalin, or 150 mg pregabalin, as a capsule 1 h before anesthesia induction with sevoflurane only. After equilibration, the response to skin incision (movement vs. non-movement) was monitored. The MAC was assessed using an up- and down-titration method.ResultsThe MAC of sevoflurane was estimated as 2.16% (95% CI, 2.07–2.32%) in the placebo group, 1.44% (95% CI, 1.26–1.70%) in the 300 mg pregabalin group, and 1.81% (95% CI, 1.49–2.13%) in the 150 mg pregabalin group. We therefore report a 33% reduction in the MAC of sevoflurane in the 300 mg pregabalin group as compared to placebo. The MAC of the 150 mg pregabalin group was reduced by 16% as compared to placebo but was not statistically significant.ConclusionsThe administration of 300 mg pregabalin reduced the MAC of sevoflurane by 33%, while the administration of 150 mg pregabalin did not significantly reduce the MAC of sevoflurane. Pregabalin use led to a small reduction in post-operative pain levels but increased side effects in a dose-dependent manner.

Contrary to pottery or metal artefacts, macro-lithic tools are still not fully integrated into the archaeological research programs concerning the Early Bronze Age of Central Europe. While such kind of archaeological materials usually do not easily allow typological approaches, their constant participation in several productive spheres makes them a crucial element for understanding the economic processes and the organisation of past societies. This paper presents the general results of the investigation carried out on an assemblage of 1073 macro-lithic items recovered in the wet soil area of the site of Bruszczewo (municipality of Śmigiel, Poland). This fortified settlement was inhabited during the Early Bronze Age (2100-1650 BCE) and later on in the Late Bronze Age and Early Iron Age (1100-800 BCE), with minor archaeological evidences from Middle Ages. The methodology applied in this assessment is a holistic one, which combines manufacturing (petrography and morphometry), functional (use-wear and residues) and spatial analyses. This approach has allowed recording a mainly local raw material supplying system, based on the gathering of pebbles in the vicinity of the site and a minimal transformation of raw pieces previous to use. Moreover, Bruszczewo comes out to be a central settlement managing and controlling exogenous ores, such as copper and gold, as shown by residues found on some macro-lithic forging anvils. All in all, the recognition in the macro-lithic tool assemblage of different tasks related to subsistence (food preparation) as well as to manufacture (metallurgy, probably bone working) processes contributes to (a) defining the settlement's organisation and the management of resources in the site and (b) improving our understanding of the role played by central settlements in the socio-economic networks, at a time when the first class societies emerged in Central Europe.

Abstract Background The study of convergently acquired adaptations allows fundamental insight into life’s evolutionary history. Within lepidosaur reptiles—i.e. lizards, tuatara, and snakes—a fully fossorial (‘burrowing’) lifestyle has independently evolved in most major clades. However, despite their consistent use of the skull as a digging tool, cranial modifications common to all these lineages are yet to be found. In particular, bone microanatomy, although highly diagnostic for lifestyle, remains unexplored in the lepidosaur cranium. This constitutes a key gap in our understanding of their complexly interwoven ecology, morphology, and evolution. In order to bridge this gap, we reconstructed the acquisition of a fossorial lifestyle in 2813 lepidosaurs and assessed the skull roof compactness from microCT cross-sections in a representative subset (n = 99). We tested this and five macroscopic morphological traits for their convergent evolution. Results We found that fossoriality evolved independently in 54 lepidosaur lineages. Furthermore, a highly compact skull roof, small skull diameter, elongate cranium, and low length ratio of frontal and parietal were repeatedly acquired in concert with a fossorial lifestyle. Conclusions We report a novel case of convergence that concerns lepidosaur diversity as a whole. Our findings further indicate an early evolution of fossorial modifications in the amphisbaenian ‘worm-lizards’ and support a fossorial origin for snakes. Nonetheless, our results suggest distinct evolutionary pathways between fossorial lizards and snakes through different contingencies. We thus provide novel insights into the evolutionary mechanisms and constraints underlying amniote diversity and a powerful tool for the reconstruction of extinct reptile ecology.

Abstract Aims Aptamer BC 007, a 15‐mer single‐strand DNA oligonucleotide (5'‐GGTTGGTGTGGTTGG‐3'), was developed to neutralize functional autoantibodies that bind to the extracellular domains of G protein‐coupled receptors (GPCR‐AAB), leading to the modulation of receptor‐mediated signalling cascades that induce pathophysiological states. Among the GPCR‐AAB, there are those directed against the β1‐adrenergic receptor (β1‐AAB) that are highly present in patients with dilated cardiomyopathy (DCM) and are increasingly accepted as disease drivers. Using Doberman Pinschers (DP) with DCM, which possess similarities with human DCM among these β1‐AAB positivity for that the disease‐driving role in DP DCM was demonstrated, the safety of BC 007, efficacy for neutralizing β1‐AAB, and the DP's outcome were investigated. Methods and results Fourteen client‐owned β1‐AAB‐positive DP with electrocardiographically and echocardiographically indicated DCM were treated with BC 007. For controlling, two groups were created: 14 β1‐AAB‐positive DP with DCM not treated with BC 007 (Control 1) and 14 DP with DCM closely matched to the BC 007‐treated DP (Control 2), retrospectively selected from the institutional database of DP. After treatment, DP were monitored both echocardiographically, and for β1‐AAB, and survival curves were calculated. Based on clinical and laboratory examination, no adverse effects associated with BC 007 treatment were observed during the study. Forty‐eight hours after treatment, the DP's blood was free of β1‐AAB, which led to a reduction or stabilization of left ventricular end‐systolic volume (ESVI) during β1‐AAB free time in 10 of the treated DP. In one DP, where β1‐AAB returned after 3 months and ESVI worsened again, a second BC 007 treatment after 9 months again cleared the blood from β1‐AAB and improved the ESVI. Compared with the controls, DP treated with BC 007 showed a significantly longer survival time [572 days, interquartile range (IQR) 442–840 days] vs. Control group 1 (266 days, IQR 97–438 days; logrank: P = 0.009) and Control group 2 (229 days, IQR 174–319 days; logrank: P = 0.012). Conclusions Treatment with BC 007 for β1‐AAB neutralization was safe, resulted in a long‐lasting reduction of β1‐AAB combined with improved cardiac function and prolonged the survival of DP with DCM. Using a natural large animal model of DCM considered superior to small animal models of immunization‐induced cardiomyopathy, combined with a study design comparable with clinical trials, we believe that our results provide the basis for optimism that treatment with BC 007 might also be effective in human patients with DCM.

Glaucoma disease is characterized by an increased intraocular pressure (IOP), glaucomatous alterations of the optic disc and corresponding visual field defects. Even lowering the main risk factor IOP until an individual target level does not prevent this neurodegenerative disorder from proceeding. Several autoimmune mechanisms were discovered, partly showing a functionality. One of these autoimmune phenomena targets the ß2-adrenergic receptor (ß2-AR; i.e. agonistic autoantibodies; ß2-agAAb) and is linked to an elevated IOP and an impaired retinal microcirculation. As neurodegenerative disorder, Alzheimer’s Disease (AD) is postulated to share a common molecular mechanism with glaucoma. In the present study we investigated autoimmune phenomena targeting the ß2-AR in patients with AD. Sera of the patients were analyzed in a rat cardiomyocyte bioassay for the presence of functional autoantibodies against ß2-AR. In addition, different species of amyloid beta (Aß) monomers were tested (Aß1-14, Aß10-25, Aβ10–37 Aß1-40, Aß1-42, Aβ28–40, and Aß-[Pyr]3–43). Our results demonstrate that none of the short-chain Aß (Aß1-14, Aß10-25, or Aβ28–40) showed any agonistic or inhibitory effect on ß2-AR. Contrary, long-chain Aß-[Pyr]3–43, representing a major neurogenic plaque component, exerted an activation that after blocking by the ß2-AR antagonist ICI118.551, could be identified as that the effect was realized via the ß2-AR. Moreover, the long chain Aß1-40, Aβ1–42, and Aβ10–37, yet not the short-chain Aß peptides prevented the clenbuterol induced desensitization of the ß2-AR. In addition, we identified functional autoantibodies in the sera of AD patients, activating the ß2-AR, like the ß2-agAAb found in patients with glaucoma. As autoimmune mechanisms were reportedly involved in the pathogenesis of glaucoma and Alzheimer’s Disease, we postulate that overstimulation of the ß2-AR pathway can induce an adrenergic overdrive, that may play an important role in the multifactorial interplay of neurodegenerative disorders.

We describe the restorative treatment of an 86-year-old female patient who was referred to our specialist prosthodontics clinic. Due to secondary osteoporosis, she underwent oral antiresorptive therapy with ibandronic acid for 10 years. Although she was classified as a patient at increased risk of drug-induced osteonecrosis of the jaw, she eventually signed a consent form for fixed implant-supported prosthetic rehabilitation in her 4th sextant. However, after tooth extraction, the bone ridge was too small at the intended implant positions. Therefore, guided bone regeneration was performed with a computer-aided design/computer-aided manufacturing three-dimensional printed titanium mesh. Finally, a continuous augmented hard tissue ridge above 7 mm was found, and three implants were inserted. Eventually, after four months of submerged healing, the implants were loaded with single crowns. Now, the patient is seen regularly for supportive peri-implant therapy.