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New lichens from Africa
(2021)
The following species are described as new to science, mostly based on specimens collected by the first author: Candelariella flavosorediata from Réunion, Chiodecton leprarioides from Réunion, Lecanactis leprarica from Cameroon, Multisporidea nitida, which is a new species and a new, monotypic genus in the Malmideaceae from Réunion, Neoprotoparmelia fuscosorediata from Kenya, Pyrrhospora endaurantia from Kenya, and Tapellaria isidiata from Cameroon.
In a continuation of my investigation of tropical lichenized fungi, a treatment of new or otherwise interesting lichens mainly from Brazil and Venezuela is presented. A total of 34 species are reported here, most of them new discoveries for at least one the two countries or a new discovery for a state, including 11 species new to science. These are Malmidea albomarginata Kalb & Hernández from Venezuela, differing from M. granifera by the thin, white apothecial margins and a white to yellowish medulla, M. allobakeri Kalb & M. Cáceres from Brazil, differing from M. bakeri in lacking atranorin and in having smaller ascospores, M. allopapillosa Kalb from Venezuela, differing from M. papillosa in having atranorin as a major metabolite, M. atlanticoides Kalb & M. Cáceres from Brazil, differing from M. atlantica in containing atranorin and an unknown anthraquinone as major metabolites, M. hechicerae from Venezuela, differing from M. coralliformis by the K+ lemon-yellow medulla of the thallus, M. hernandeziana Kalb from Venezuela, differing from M. fellhaneroides in having a chocolate-brown hypothecium, larger apothecia and larger ascospores, M. isidiifera Kalb from Brazil and Venezuela, differing from M. piperis in having granular to coralloid isidia and atranorin as a major metabolite, M. leucopiperis Kalb from Brazil and Venezuela, differing from M. piperis in the pale-colored hypothecium, M. rhodopisoides Kalb from Brazil, differing from M. rhodopis in having granular isidia, M. subcinerea Kalb from Venezuela, differing from M. cinerea in producing no lichen substances, and M. volcaniana Kalb & Hernández from Venezuela and Brazil, differing from M. sulphureosorediata in having an alternative anthraquinone-chemistry. In addition, the new combination Stigmatochroma glaucothecum (Fée) Kalb is proposed. New reports for Venezuela include Bacidiopsora microphylla Kalb, B. silvicola (Malme) Kalb (new also for Guatemala), Buellia albula (Nyl.) Müll. Arg., Coenogonium pyrophthalmum (Mont.) Lücking, Aptroot & Sipman, Dirinaria rhodocladonica Kalb, Schumm & Elix, Malmidea badimioides (M. Cáceres & Lücking) M. Cáceres & Kalb (new also for Mexico), M. leptoloma (Müll. Arg.) Kalb & Lücking, M. nigromarginata (Malme) Lücking & Breuss, M. perplexa Kalb, M. polycampia (Tuck.) Kalb & Lücking, M. rhodopis (Tuck.) Kalb, Rivas Plata & Lumbsch, M. sulphureosorediata M. Cáceres, D. A. Mota & Aptroot, M. vinosa (Eschw.) Kalb, Rivas Plata & Lumbsch, Psilolechia lucida (Ach.) Choisy, Rhizocarpon sipmanianum Kalb & Aptroot, Sipmaniella sulfureofusca (Fée) Kalb, Stigmatochroma glaucothecum (Fée) Kalb and Vainionora aemulans (Vain.) Kalb. A collection of Pyxine caesiopruinosa (Nyl.) Imsh. from Venezuela is mentioned and its differentiation from P. albovirens (G. Mey.) Aptroot is discussed. New reports for Brazil include Malmidea atlantica (M. Cáceres & Lücking) M. Cáceres & Kalb (for Bahia state) and M. sulphureosorediata (for São Paulo state). A morphological, anatomical and chemical comparison of type material of Malmidea polycampia (Tuck.) Kalb & Lücking and M. flavopustulosa (M. Cáceres & Lücking) M. Cáceres & Kalb revealed that both names are synonym, the first one having priority. For many species revised descriptions and revised chemistry are presented based on South American material. To facilitate the identification of anthraquinones occurring in Malmidea species a table of relative Rfvalues in solvents A, B' and C is presented.
The species, Bactrospora lamprospora (Nyl.) Lendemer is treated as a synonym of B. metabola (Nyl.) Egea & Torrente. The comparission of characters of all accessible materials and type specimens confirmed that B. lamprospora is conspecific with B. metabola. The distinguishing characters of B. metabola from other species in this group are initially a Homalotropa-type ascospores becomes muriform at maturity, with up to 24–30 transverse septa and ascospore size of 48–105 × 7–14 μm.
Purpose: To compare Cancer-specific mortality (CSM) in patients with Squamous cell carcinoma (SCC) vs. non-SCC penile cancer, since survival outcomes may differ between histological subtypes. Methods: Within the Surveillance, Epidemiology and End Results database (2004–2016), penile cancer patients of all stages were identified. Temporal trend analyses, cumulative incidence and Kaplan–Meier plots, multivariable Cox regression and Fine and Gray competing-risks regression analyses tested for CSM differences between non-SCC vs. SCC penile cancer patients. Results: Of 4,120 eligible penile cancer patients, 123 (3%) harbored non-SCC vs. 4,027 (97%) SCC. Of all non-SCC patients, 51 (41%) harbored melanomas, 42 (34%) basal cell carcinomas, 10 (8%) adenocarcinomas, eight (6.5%) skin appendage malignancies, six (5%) epithelial cell neoplasms, two (1.5%) neuroendocrine tumors, two (1.5%) lymphomas, two (1.5%) sarcomas. Stage at presentation differed between non-SCC vs. SCC. In temporal trend analyses, non-SCC diagnoses neither decreased nor increased over time (p > 0.05). After stratification according to localized, locally advanced, and metastatic stage, no CSM differences were observed between non-SCC vs. SCC, with 5-year survival rates of 11 vs 11% (p = 0.9) for localized, 33 vs. 37% (p = 0.4) for locally advanced, and 1-year survival rates of 37 vs. 53% (p = 0.9) for metastatic penile cancer, respectively. After propensity score matching for patient and tumor characteristics and additional multivariable adjustment, no CSM differences between non-SCC vs. SCC were observed. Conclusion: Non-SCC penile cancer is rare. Although exceptions exist, on average, non-SCC penile cancer has comparable CSM as SCC penile cancer patients, after stratification for localized, locally invasive, and metastatic disease.
New drugs are urgently needed to combat the global TB epidemic. Targeting simultaneously multiple respiratory enzyme complexes of Mycobacterium tuberculosis is regarded as one of the most effective treatment options to shorten drug administration regimes, and reduce the opportunity for the emergence of drug resistance. During infection and proliferation, the cytochrome bd oxidase plays a crucial role for mycobacterial pathophysiology by maintaining aerobic respiration at limited oxygen concentrations. Here, we present the cryo-EM structure of the cytochrome bd oxidase from M. tuberculosis at 2.5 Å. In conjunction with atomistic molecular dynamics (MD) simulation studies we discovered a previously unknown MK-9-binding site, as well as a unique disulfide bond within the Q-loop domain that defines an inactive conformation of the canonical quinol oxidation site in Actinobacteria. Our detailed insights into the long-sought atomic framework of the cytochrome bd oxidase from M. tuberculosis will form the basis for the design of highly specific drugs to act on this enzyme.
Purpose: In patients with pyogenic spondylodiscitis, surgery is considered the treatment of choice to conduct proper debridement, stabilise the spine and avoid extended bed rest, which in turn is a risk factor for complications such as deep vein thrombosis and pulmonary embolism. Methods: We conducted a retrospective clinical study with analysis of a group of 99 patients who had undergone treatment for pyogenic discitis at our institution between June 2012 and August 2017. Included parameters were age, sex, disease pattern, the presence of deep vein thrombosis, resuscitation, in-hospital mortality, present anticoagulation, preexisting comorbidities, tobacco abuse, body mass index, microbiological germ detection and laboratory results. Results: Among the analysed cohort, 12% of the treated patients for pyogenic spondylodiscitis suffered from a radiologically confirmed pulmonary embolism. Coronary heart disease (p < 0.01), female sex (p < 0.01), anticoagulation at admission (p < 0.01) and non-O blood type (p < 0.001) were associated with development of pulmonary embolism. Pulmonary embolism was significantly associated with resuscitation (p < 0.005) and deep vein thrombosis (p < 0.001). Neurosurgery was not associated with increased risk for pulmonary embolism compared to conservative-treated patients (p > 0.05). Conclusion: Surgery for pyogenic spondylodiscitis was not associated with an elevated risk of pulmonary embolism in our analysis. However, we describe several risk factors for pulmonary embolism in this vulnerable cohort. Prospective studies are necessary to improve prevention and postoperative management in patients with pyogenic spondylodiscitis.
Plastic products leach chemicals that induce in vitro toxicity under realistic use conditions
(2021)
Plastic products contain complex mixtures of extractable chemicals that can be toxic. However, humans and wildlife will only be exposed to plastic chemicals that are released under realistic conditions. Thus, we investigated the toxicological and chemical profiles leaching into water from 24 everyday plastic products covering eight polymer types. We performed migration experiments over 10 days at 40 °C and analyzed the migrates using four in vitro bioassays and nontarget high-resolution mass spectrometry (UPLC-QTOF-MSE). All migrates induced baseline toxicity, 22 an oxidative stress response, 13 antiandrogenicity, and one estrogenicity. Overall, between 17 and 8681 relevant chemical features were present in the migrates. In other words, between 1 and 88% of the plastic chemicals associated with one product were migrating. Further, we tentatively identified ∼8% of all detected features implying that most plastic chemicals remain unknown. While low-density polyethylene, polyvinyl chloride, and polyurethane induced most toxicological endpoints, a generalization for other materials is not possible. Our results demonstrate that plastic products readily leach many more chemicals than previously known, some of which are toxic in vitro. This highlights that humans are exposed to many more plastic chemicals than currently considered in public health science and policies.
As a first step towards a realistic phenomenological description of vector and axial-vector mesons in nuclear matter, we calculate the spectral functions of the ρ and the a1 meson in a chiral baryon-meson model as a low-energy effective realization of QCD, taking into account the effects of fluctuations from scalar mesons, nucleons, and vector mesons within the functional renormalization group (FRG) approach. The phase diagram of the effective hadronic theory exhibits a nuclear liquid-gas phase transition as well as a chiral phase transition at a higher baryon-chemical potential. The in-medium ρ and a1 spectral functions are calculated by using the previously introduced analytically-continued FRG (aFRG) method. Our results show strong modifications of the spectral functions—in particular near the critical endpoints of both phase transitions—which may well be of relevance for electromagnetic rates in heavy-ion collisions or neutrino emissivities in neutron-star merger events.
Contemporary information systems make widespread use of artificial intelligence (AI). While AI offers various benefits, it can also be subject to systematic errors, whereby people from certain groups (defined by gender, age, or other sensitive attributes) experience disparate outcomes. In many AI applications, disparate outcomes confront businesses and organizations with legal and reputational risks. To address these, technologies for so-called “AI fairness” have been developed, by which AI is adapted such that mathematical constraints for fairness are fulfilled. However, the financial costs of AI fairness are unclear. Therefore, the authors develop AI fairness for a real-world use case from e-commerce, where coupons are allocated according to clickstream sessions. In their setting, the authors find that AI fairness successfully manages to adhere to fairness requirements, while reducing the overall prediction performance only slightly. However, they find that AI fairness also results in an increase in financial cost. Thus, in this way the paper’s findings contribute to designing information systems on the basis of AI fairness.
HLA-DRB1 and HLA-DQB1 genetic diversity modulates response to lithium in bipolar affective disorders
(2021)
Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p < 1 × 10−3; FDR < 0.09 in the recessive model). Alanine or Leucine at position 74 of the HLA-DRB1 heavy chain was associated with a good response while Arginine or Glutamic acid with a poor response. As these variants have been implicated in common inflammatory/autoimmune processes, our findings strongly suggest that HLA-mediated low inflammatory background may contribute to the efficient response to Li in BD patients, while an inflammatory status overriding Li anti-inflammatory properties would favor a weak response.
J.R.R. Tolkien's "enigmatic and unfinished" book "The Silmarillion" - posthumously published by Christopher Tolkien in 1977 - is often referred to as being a mythic work, or a collection of mythopoeic tales, but what exactly does that description entail? Logically, Tolkien's writings, by virtue of being labeled 'mythic' alongside of mythologies such as "The Iliad", "Metamorphoses", and "The Odyssey", must possess qualities which warrant the description. While Tolkien's mythology is in a different category since his mythology is specifically designed for Middle-earth, there are still important overlaps through which inspiration and influences may be traced.
Species of the genus Aphelopus Dalman (Hymenoptera, Dryinidae) are important natural enemies of leafhoppers. The genus is relatively diverse in China, with 35 recorded species. In order to further make use of these important parasitoids in biological control programs, species of Aphelopus collected across China are studied using an integrative approach (combined DNA barcoding and morphology). Of the 17 studied species, two are newly recorded from China: A. nivealis Mita & Olmi, 2014 and A. prolatus Mita & Olmi, 2014, and four are described as new to science: A. incognitus Chen, Olmi & Guglielmino sp. nov., A. maculiala Olmi, Chen & Ødegaard sp. nov., A. taianensis Olmi, Ødegaard & Chen sp. nov., and A. zaifui Olmi, Chen & Liu sp. nov. The total number of Aphelopus species known from China is raised from 35 to 39. Keys to the Oriental and Eastern Palaearctic species of Aphelopus are modified to include the new species. Application of DNA barcoding in the species delimitation of Dryinidae is discussed.
In this study, we report the results of a taxonomic survey of terrestrial isopods from Isla Grande, a ca 2 km2 island located in the north of Cartagena de Indias, Colombia. We found a total of 17 species belonging to nine families and 10 genera. Eight of these species have been reported only from the Caribbean region, nine are recorded for the first time in Colombia, and three are new to science and described here: Tylos negroi López-Orozco, Carpio-Díaz & Campos-Filho sp. nov., Stenoniscus nestori López-Orozco, Taiti & Campos-Filho sp. nov. and Armadilloniscus luisi Carpio-Díaz, Taiti & Campos-Filho sp. nov. Our revision also determined that the genus Microphiloscia is a junior synonym of Halophiloscia; and moreover, Halophiloscia trichoniscoides comb. nov. is redescribed. We also provide illustrations for Armadilloniscus caraibicus and Armadilloniscus ninae. Most (16) of the species were found in coastal habitats (i.e., beaches, coastal lagoons and mangroves), whereas the tropical dry forest harbored only two species. Molecular phylogenetic inferences supported the presence of three species of Tylos in Isla Grande (i.e., one new species and a new lineage within each of two known species). Our work on Tylos highlights the importance of combining taxonomic and molecular analyses to support taxonomic decisions and uncover cryptic diversity. Due to the multiple threats to Caribbean coastal habitats, taxonomic and molecular genetic research are urgently needed to understand biodiversity patterns of oniscideans in the Caribbean, which will inform strategies for their protection. Such studies will also contribute to our knowledge of their evolution, ecology, and potential uses, as well as the factors that have shaped the remarkable Caribbean biodiversity.
Review of the Panorpa wormaldi group (Mecoptera: Panorpidae), with descriptions of two new species
(2022)
Panorpa Linnaeus, 1758 is the largest genus in the scorpionfly family Panorpidae. In this paper, a taxonomic review of the Panorpa wormaldi group is provided, with two new species described from China: Panorpa fengyanga Wang & Suzuki, sp. nov. from Zhejiang, and Panorpa zhuohengi Wang & Suzuki, sp. nov. from Guangdong. The male of Panorpa implicata Cheng, 1957 is discovered and described for the first time. A distributional map and keys to species are also provided for this group. Species number in this group is updated from 17 to 19. In addition, their biogeographical and evolutionary implications are briefly discussed.
Trieces Townes, 1946 is one of the largest metopiine genera for which species have been described from all zoogeographical regions except the Indomalayan. The present study reports a major range extension of Trieces with the description of three new species from India. The described species are members of the onitis species group. An identification key to the Palearctic and Indomalayan species of the onitis group is included with the revised generic diagnosis and a key to separate Trieces from its closest genus Chorinaeus. Distribution pattern and character plasticity of Trieces are also discussed.
History films personalize, dramatize and emotionalize historical events and characters. They revive the past by exemplifying it in the present, engage ongoing discourses of history and as a result have proven to be the most influential medium in conveying history to large audiences. History films are regarded as an attractive, motivating and efficient (supplementary) teaching and learning medium in history as well as in foreign language classes. As part of the course "Historical Survey of Germany" (BA German-programme at University Putra Malaysia) history film projects on important periods and events in German history were conducted. The article introduces a film project on World War II and describes the pedagogical approach which aims to develop three core competencies of historical understanding – Content Knowledge, Historical Empathy/Perspective Recognition and Narrative Analysis. It discusses selected general findings provided as qualitative data in group and individual assignments. While the responses to questions related to Content Knowledge and Narrative Analysis show that students achieved higher competency levels, the participants showed shortcomings in the rational examination of historical characters, their perspectives and motivations for their actions. Time, practice and guidance can be identified as key factors in developing historical literacy competencies further.
Using representative linked employer-employee data for Germany, this paper analyzes short- and long-run differences in labor market performance of workers joining start-ups instead of incumbent firms. Applying entropy balancing and following individuals over ten years, we find huge and long-lasting drawbacks from entering a start-up in terms of wages, yearly income, and (un)employment. These disadvantages hold for all groups of workers and types of start-ups analyzed. Although our analysis of different subsequent career paths highlights important heterogeneities, it does not reveal any strategy through which workers joining start-ups can catch up with the income of similar workers entering incumbent firms.
Support for innovative on-street parking policies: empirical evidence from an urban neighborhood
(2020)
Municipalities and planners often hesitate to implement restrictive parking policies because residents regularly oppose any changes to on-street parking space. Residential parking is one key factor of parking management because its location and availability influence a household's car ownership and use. Moreover, as more residents regularly use other means of transportation that need space and infrastructure in the urban realm, and as parking takes up a vast amount of land, municipalities are considering the reuse of on-street parking space for other purposes. As public acceptability is a precondition for the successful implementation of a proposed policy, our empirical analysis investigates to what extent residents support restrictive and demand-oriented on-street parking policies in the dense, highly urbanized neighborhood of Frankfurt-Bornheim, Germany (N = 1027). Surprisingly, despite some variations, the majority of the residents in our survey are in favor of the policy options suggested. Support for the demand-oriented policies (extension of bicycle infrastructure, improved sharing supply and mobility hubs, neighborhood garages, and improved public transit supply) is higher than the acceptance of the restrictive policies, and of policies that are a combination of restrictive and demand-oriented policies. However, surprisingly, a majority is still in favor of many of these (extension of parking fees and parking restrictions, and reuse of parking space for better livability). Furthermore, we classify residents who live in a household with private cars into the stage model of self-regulated behavior change to analyze their intention towards a reduction in private car use. Results from linear regression analyses indicate that residents who have intentions to change their behavior towards car use reduction assess the policy options more similarly to car-free households and regular bike users, and not like the other car-owning households. The findings suggest that while the residents support financial-related policies the least, they are more receptive towards parking policies than policy makers and planners assume if the reuse of parking lots creates space for other users or if it increases the quality of life, for instance, by adding bike lanes, wider sidewalks or greenery. Hence, a combination of restrictive and demand-oriented on-street parking policies results in high acceptance among residents, and the communication from municipalities regarding the implementation of the different policies needs to vary depending on the kind of household.
In two-dimensional (2D) NbSe2 crystal, which lacks inversion symmetry, strong spin-orbit coupling aligns the spins of Cooper pairs to the orbital valleys, forming Ising Cooper pairs (ICPs). The unusual spin texture of ICPs can be further modulated by introducing magnetic exchange. Here, we report unconventional supercurrent phase in van der Waals heterostructure Josephson junctions (JJs) that couples NbSe2 ICPs across an atomically thin magnetic insulator (MI) Cr2Ge2Te6. By constructing a superconducting quantum interference device (SQUID), we measure the phase of the transferred Cooper pairs in the MI JJ. We demonstrate a doubly degenerate nontrivial JJ phase (ϕ), formed by momentum-conserving tunneling of ICPs across magnetic domains in the barrier. The doubly degenerate ground states in MI JJs provide a two-level quantum system that can be utilized as a new dissipationless component for superconducting quantum devices. Our work boosts the study of various superconducting states with spin-orbit coupling, opening up an avenue to designing new superconducting phase-controlled quantum electronic devices.
Strict environmental regulation may deter foreign direct investment (FDI). The paper develops the hypothesis that regulation predominantly discourages FDI that is conducted as Greenfield investment rather than mergers and acquisitions (M&A). The hypothesis is tested with German firm-level FDI data. Empirically, stricter regulation reduces new Greenfield projects in polluting industries, but indeed has a much smaller impact on the number of M&As. This significant difference is compatible with the fact that existing operations often benefit from grandfathering rules, which provide softer regulation for pre-exisiting plants, and with the expectation that for M&As part of the regulation is capitalized in the purchase price. The heterogeneous effects help explaining mixed results in previous studies that have neglected the mode of entry.
TRIANNI mice carry an entire set of human immunoglobulin V region gene segments and are a powerful tool to rapidly isolate human monoclonal antibodies. After immunizing these mice with DNA encoding the spike protein of SARS-CoV-2 and boosting with spike protein, we identified 29 hybridoma antibodies that reacted with the SARS-CoV-2 spike protein. Nine antibodies neutralize SARS-CoV-2 infection at IC50 values in the subnanomolar range. ELISA-binding studies and DNA sequence analyses revealed one cluster of three clonally related neutralizing antibodies that target the receptor-binding domain and compete with the cellular receptor hACE2. A second cluster of six clonally related neutralizing antibodies bind to the N-terminal domain of the spike protein without competing with the binding of hACE2 or cluster 1 antibodies. SARS-CoV-2 mutants selected for resistance to an antibody from one cluster are still neutralized by an antibody from the other cluster. Antibodies from both clusters markedly reduced viral spread in mice transgenic for human ACE2 and protected the animals from SARS-CoV-2-induced weight loss. The two clusters of potent noncompeting SARS-CoV-2 neutralizing antibodies provide potential candidates for therapy and prophylaxis of COVID-19. The study further supports transgenic animals with a human immunoglobulin gene repertoire as a powerful platform in pandemic preparedness initiatives.
In local scalar quantum field theories at finite temperature correlation functions are known to satisfy certain nonperturbative constraints, which for two-point functions in particular implies the existence of a generalization of the standard Källén-Lehmann representation. In this work, we use these constraints in order to derive a spectral representation for the shear viscosity arising from the thermal asymptotic states, η0. As an example, we calculate η0 in ϕ4 theory, establishing its leading behavior in the small and large coupling regimes.
The organisation of parking is a key challenge to more sustainable mobility in urban areas, as its pricing and availability affect the rates of private car ownership and use. However, changing parking policies is a challenging issue for local politicians and planners because residents frequently oppose changes or restrictions to conditions they have taken for granted such as on-street parking in a public space. The aim of this paper is firstly to assess how the parking policy of an urban neighbourhood can be structured to contribute to more sustainable mobility and to increase liveability in the neighbourhood. The second aim is to apply the policies reviewed to an example neighbourhood. For this purpose, we systematically reviewed academic literature and identified five types of relevant parking policies: (i) maximum parking requirements, (ii) physical detachment of residence and parking space, (iii) residential parking permits and the limitation of available parking space, (iv) performance-based pricing and (v) parking as a demand management strategy. We discovered that most research focuses on econometric models about parking and that studies rarely address the effects of parking on the quality of life in neighbourhoods. Therefore, we need further research regarding the relationship of parking and liveability. We conclude that for the implementation of such parking policies in an example neighbourhood, the municipality needs to develop a mobility vision for its city. It has to understand parking as a tool for transportation demand management to increase the acceptance of parking policy concepts and to avoid spillover problems. Finally, in the German case, as in most other countries, states and municipalities need to redesign their legal frameworks to be able to manage parking supply better and to react to changes related to digital developments and parking. The findings have implications for other European neighbourhoods regarding the transfer from research to local circumstances and applications for the whole city.
Specialized transporter proteins facilitate controlled uptake and extrusion of molecules across biological membranes that would otherwise be impermeable to them. The superfamily of solute carriers (SLC) comprises the second largest group of membrane proteins in humans, acting on a variety of small polar and non-polar molecules and ions. Because of their central role in metabolism, malfunctioning of these proteins often is pathogenic. The interest in SLC transporters as drug targets – as well as for drug delivery – has therefore increased in the past years. For many SLC subfamilies, however, structural and functional information remains scarce to date.
The here presented data provides important insights into different aspects of the transport mechanism of the SLC23 and SLC26 protein families. Importantly, we show that SLC23 nucleobase transporters, in contrast to what was been previously reported, work as uniporters rather than as proton-coupled symporters. In order to do so, we developed the first and only in vitro transport assay for the SLC23 family, which enables investigation of protein function in a defined environment. Moreover, we provide a hypothesis on the role of the extremely conserved negative charged substrate binding site residue found not only in the SLC23, but also SLC4 and SLC26 families. Based on a detailed analysis of binding and transport we conclude that this conserved negative charged has a relevance for protein stability rather than for substrate binding, which explains its conservation for all three protein families that otherwise differ in their substrate specificities and modes of transport. Lastly, we investigated the relevance of oligomerization for the SLC23 and SLC26 families, highlighting the importance of the STAS domain for forming active dimers in the SLC26 anion transporter family.
In this thesis, molecular dynamics (MD) simulations are used to study the interaction of different proteins with lipid bilayers. MD simulations can be used as a “computational microscope” to gain atomistic insights into the interactions between proteins and lipids that can barely be accessed in such detail by experimental methods. The different chapters of this thesis address the lipid sensing functionality of amphipathic helices (AHs) when bound to membranes, the folding of AHs at lipid-water interfaces as well as the conformational dynamics of the HIV-1 Env glycoproteins in viral-like and experimental bilayers. In the last chapter the possibilities to enhance the performance of MD simulations are explored, leading to a more efficient usage of computational resources.
Purpose: Scientific and clinical achievements in radiation, medical, and surgical oncology are changing the landscape of interdisciplinary oncology. The German Society for Radiation Oncology (DEGRO) working group of young clinicians and scientists (yDEGRO) and the DEGRO representation of associate and full professors (AKRO) are aware of the essential role of radiation oncology in multidisciplinary treatment approaches. Together, yDEGRO and AKRO endorsed developing a German radiotherapy & radiation oncology vision 2030 to address future challenges in patient care, research, and education. The vision 2030 aims to identify priorities and goals for the next decade in the field of radiation oncology. Methods: The vision development comprised three phases. During the first phase, areas of interest, objectives, and the process of vision development were defined jointly by the yDEGRO, AKRO, and the DEGRO board. In the second phase, a one-day strategy retreat was held to develop AKRO and yDEGRO representatives’ final vision from medicine, biology, and physics. The third phase was dedicated to vision interpretation and program development by yDEGRO representatives. Results: The strategy retreat’s development process resulted in conception of the final vision “Innovative radiation oncology Together – Precise, Personalized, Human.” The first term “Innovative radiation oncology” comprises the promotion of preclinical research and clinical trials and highlights the development of a national committee for strategic development in radiation oncology research. The term “together” underpins collaborations within radiation oncology departments as well as with other partners in the clinical and scientific setting. “Precise” mainly covers technological precision in radiotherapy as well as targeted oncologic therapeutics. “Personalized” emphasizes biology-directed individualization of radiation treatment. Finally, “Human” underlines the patient-centered approach and points towards the need for individual longer-term career curricula for clinicians and researchers in the field. Conclusion: The vision 2030 balances the ambition of physical, technological, and biological innovation as well as a comprehensive, patient-centered, and collaborative approach towards radiotherapy & radiation oncology in Germany.
The Weissert Event ~133 million years ago marked a profound global cooling that punctuated the Early Cretaceous greenhouse. We present modelling, high-resolution bulk organic carbon isotopes and chronostratigraphically calibrated sea surface temperature (SSTs) based on an organic paleothermometer (the TEX86 proxy), which capture the Weissert Event in the semi-enclosed Weddell Sea basin, offshore Antarctica (paleolatitude ~54 °S; paleowater depth ~500 meters). We document a ~3–4 °C drop in SST coinciding with the Weissert cold end, and converge the Weddell Sea data, climate simulations and available worldwide multi-proxy based temperature data towards one unifying solution providing a best-fit between all lines of evidence. The outcome confirms a 3.0 °C ( ±1.7 °C) global mean surface cooling across the Weissert Event, which translates into a ~40% drop in atmospheric pCO2 over a period of ~700 thousand years. Consistent with geologic evidence, this pCO2 drop favoured the potential build-up of local polar ice.
Nature's non-material contributions to people are difficult to quantify and one aspect in particular, nature's contributions to communication (NCC), has so far been neglected. Recent advances in automated language processing tools enable us to quantify diversity patterns underlying the distribution of plant and animal taxon labels in creative literature, which we term BiL (biodiversity in literature). We assume BiL to provide a proxy for people's openness to nature's non-material contributions enhancing our understanding of NCC. We assembled a comprehensive list of 240,000 English biological taxon labels. We pre-processed and searched a subcorpus of digitised literature on Project Gutenberg for these labels. We quantified changes in biodiversity indices commonly used in ecological studies for 16,000 books, encompassing 4,000 authors, as proxies for BiL between 1705 and 1969. We observed hump-shape patterns for taxon label richness, abundance and Shannon diversity indicating a peak of BiL in the middle of the 19th century. This is also true for the ratio of biological to general lexical richness. The variation in label use between different sections within books, quantified as β-diversity, declined until the 1830s and recovered little, indicating a less specialised use of taxon labels over time. This pattern corroborates our hypothesis that before the onset of industrialisation BiL may have increased, reflecting several concomitant influences such as the general broadening of literary content, improved education and possibly an intensified awareness of the starting loss of biodiversity during the period of romanticism. Given that these positive trends continued and that we do not find support for alternative processes reducing BiL, such as language streamlining, we suggest that this pronounced trend reversal and subsequent decline of BiL over more than 100 years may be the consequence of humans’ increasing alienation from nature owing to major societal changes in the wake of industrialisation. We conclude that our computational approach of analysing literary communication using biodiversity indices has a high potential for understanding aspects of non-material contributions of biodiversity to people. Our approach can be applied to other corpora and would benefit from additional metadata on taxa, works and authors.
Background: Cases of immune complex vasculitis have been reported following COVID-19 infections; so far none in association with novel mRNA-based COVID-19 vaccination. This case report describes a cutaneous immune complex vasculitis after vaccination with BNT162b2. Case presentation: A 76-year old male with liver cirrhosis developed an immune complex vasculitis 12 days after the second injection of BNT162b2. On physical examination, the patient presented with pruritic purpuric macules on hands and feet, flexor and extensor parts of both legs and thighs and lower abdomen, and bloody diarrhoea. Laboratory testing showed elevated inflammatory markers. After short treatment with oral steroids all clinical manifestations and laboratory findings resolved. Conclusions: An increasing number of clinical manifestations have been attributed to COVID-19 infection and vaccination. This is the first written report of immune complex vasculitis after vaccination with BNT162b2. We present our case report and a discussion in the light of type three hypersensitivity reaction.
Rationale: Both attention deficit-/hyperactivity disorder (ADHD) and alcohol use disorder (AUD) are accompanied by deficits in response inhibition. Furthermore, the prevalence of comorbidity of ADHD and AUD is high. However, there is a lack of research on whether the same neuronal subprocesses of inhibition (i.e., interference inhibition, action withholding and action cancellation) exhibit deficits in both psychiatric disorders. Methods: We examined these three neural subprocesses of response inhibition in patient groups and healthy controls: non-medicated individuals with ADHD (ADHD; N = 16), recently detoxified and abstinent individuals with alcohol use disorder (AUD; N = 15), and healthy controls (HC; N = 15). A hybrid response inhibition task covering interference inhibition, action withholding, and action cancellation was applied using a 3T functional magnetic resonance imaging (fMRI). Results: Individuals with ADHD showed an overall stronger hypoactivation in attention related brain areas compared to AUD or HC during action withholding. Further, this hypoactivation was more accentuated during action cancellation. Individuals with AUD recruited a broader network, including the striatum, compared to HC during action withholding. During action cancellation, however, they showed hypoactivation in motor regions. Additionally, specific neural activation profiles regarding group and subprocess became apparent. Conclusions: Even though deficits in response inhibition are related to both ADHD and AUD, neural activation and recruited networks during response inhibition differ regarding both neuronal subprocesses and examined groups. While a replication of this study is needed in a larger sample, the results suggest that tasks have to be carefully selected when examining neural activation patterns of response inhibition either in research on various psychiatric disorders or transdiagnostic questions.
Background: This study investigates the willingness of men-who-have-sex-with-men (MSM) to use HIV pre-exposure prophylaxis (PrEP). Research in the HIV/AIDS field typically relies on clinical and epidemiological studies, thereby often excluding social dimensions of the illness as well as factors explaining its prevention. The current study analyzes HIV-prevention through an interdisciplinary theoretical approach. It aims to comprehensively understand the mechanisms associated with the willingness to take PrEP among MSM in terms of psychological, social, behavioral, cultural, and demographic factors. Methods: We analyze data from the survey “Gay Men and AIDS” conducted in Germany in 2013 prior to market approval for PrEP. Analyses were performed using the statistical software SPSS 25.0, while results were visualized using the R programming language. Results: We find that perceived risk of infection, social norms (anticipated HIV-stigma), practices (e.g. regular condomless sex), and socio-demographic factors (young age, being single) all have a positive effect on the willingness to take PrEP, while education reveals a negative, and income no effect. Conclusions: Results indicate that beyond well-established socio-psychological mechanisms of health behavior, social factors play a crucial role in understanding the willingness of PrEP uptake. This study enriches existing health behavior theories with sociological concepts such as social norms and social practices.
Patients with neuroendocrine tumors (NET) often go through a long phase between onset of symptoms and initial diagnosis. Assessment of time to diagnosis and pre-clinical pathway in patients with gastroenteropancreatic NET (GEP-NET) with regard to metastases and symptoms. Retrospective analysis of patients with GEP-NET at a tertiary referral center from 1984 to 2019; inclusion criteria: Patients ≥18 years, diagnosis of GEP-NET; statistical analysis using non-parametrical methods. Four hundred eighty-six patients with 488 tumors were identified; median age at first diagnosis (478/486, 8 unknown) was 59 years; 52.9% male patients. Pancreatic NET: 143/488 tumors; 29.3%; small intestinal NET: 145/488 tumors, 29.7%. 128/303 patients (42.2%) showed NET specific and 122/486 (25%) patients other tumor-specific symptoms. 222/279 patients had distant metastases at initial diagnosis (187/222 liver metastases). 154/488 (31.6%) of GEP-NET were incidental findings. Median time from tumor manifestation (e.g., symptoms related to NET) to initial diagnosis across all entities was 19.5 (95% CI: 12–28) days. No significant difference in patients with or without distant metastases (median 73 vs 105 days, P = .42). A large proportion of GEP-NET are incidental findings and only about half of all patients are symptomatic at the time of diagnosis. We did not find a significant influence of the presence of metastases on time to diagnosis, which shows a large variability with a median of <30 days.
In partially molten regions inside the Earth, melt buoyancy may trigger upwelling of both solid and fluid phases, i.e., diapirism. If the melt is allowed to move separately with respect to the matrix, melt perturbations may evolve into solitary porosity waves. While diapirs may form on a wide range of scales, porosity waves are restricted to sizes of a few times the compaction length. Thus, the size of a partially molten perturbation in terms of compaction length controls whether material is dominantly transported by porosity waves or by diapirism. We study the transition from diapiric rise to solitary porosity waves by solving the two-phase flow equations of conservation of mass and momentum in 2D with porosity-dependent matrix viscosity. We systematically vary the initial size of a porosity perturbation from 1.8 to 120 times the compaction length. If the perturbation is of the order of a few compaction lengths, a single solitary wave will emerge, either with a positive or negative vertical matrix flux. If melt is not allowed to move separately to the matrix a diapir will emerge. In between these end members we observe a regime where the partially molten perturbation will split up into numerous solitary waves, whose phase velocity is so low compared to the Stokes velocity that the whole swarm of waves will ascend jointly as a diapir, just slowly elongating due to a higher amplitude main solitary wave. Only if the melt is not allowed to move separately to the matrix will no solitary waves build up, but as soon as two-phase flow is enabled solitary waves will eventually emerge. The required time to build them up increases nonlinearly with the perturbation radius in terms of compaction length and might be too long to allow for them in nature in many cases.
Investigation of the sympathetic regulation in delayed onset muscle soreness: results of an RCT
(2021)
Sports-related pain and injury is directly linked to tissue inflammation, thus involving the autonomic nervous system (ANS). In the present experimental study, we disable the sympathetic part of the ANS by applying a stellate ganglion block (SGB) in an experimental model of delayed onset muscle soreness (DOMS) of the biceps muscle. We included 45 healthy participants (female 11, male 34, age 24.16 ± 6.67 years [range 18–53], BMI 23.22 ± 2.09 kg/m2) who were equally randomized to receive either (i) an SGB prior to exercise-induced DOMS (preventive), (ii) sham intervention in addition to DOMS (control/sham), or (iii) SGB after the induction of DOMS (rehabilitative). The aim of the study was to determine whether and to what extent sympathetically maintained pain (SMP) is involved in DOMS processing. Focusing on the muscular area with the greatest eccentric load (biceps distal fifth), a significant time × group interaction on the pressure pain threshold was observed between preventive SGB and sham (p = 0.034). There was a significant effect on pain at motion (p = 0.048), with post hoc statistical difference at 48 h (preventive SGB Δ1.09 ± 0.82 cm VAS vs. sham Δ2.05 ± 1.51 cm VAS; p = 0.04). DOMS mediated an increase in venous cfDNA -as a potential molecular/inflammatory marker of DOMS- within the first 24 h after eccentric exercise (time effect p = 0.018), with a peak at 20 and 60 min. After 60 min, cfDNA levels were significantly decreased comparing preventive SGB to sham (unpaired t-test p = 0.008). At both times, 20 and 60 min, cfDNA significantly correlated with observed changes in PPT. The 20-min increase was more sensitive, as it tended toward significance at 48 h (r = 0.44; p = 0.1) and predicted the early decrease of PPT following preventive stellate blocks at 24 h (r = 0.53; p = 0.04). Our study reveals the broad impact of the ANS on DOMS and exercise-induced pain. For the first time, we have obtained insights into the sympathetic regulation of pain and inflammation following exercise overload. As this study is of a translational pilot character, further research is encouraged to confirm and specify our observations.
The analysis of charcoal fragments in peat and lake sediments is the most widely used approach to reconstruct past biomass burning. With a few exceptions, this method typically relies on the quantification of the total charcoal content of the sediment. To enhance charcoal analyses for the reconstruction of past fire regimes and make the method more relevant to studies of both plant evolution and fire management, the extraction of more information from charcoal particles is critical. Here, I used a muffle oven to burn seven fuel types comprising 17 species from boreal Siberia (near Teguldet village), which are also commonly found in the Northern Hemisphere, and built on published schemes to develop morphometric and finer diagnostic classifications of the experimentally charred particles. I then combined these results with those from fossil charcoal from a peat core taken from the same location (Ulukh-Chayakh mire) in order to demonstrate the relevance of these experiments to the fossil charcoal records. Results show that graminoids, Sphagnum, and wood (trunk) lose the most mass at low burn temperatures (<300 ∘C), whereas heathland shrub leaves, brown moss, and ferns lose the most mass at high burn temperatures. This suggests that species with low mass retention in high-temperature fires are likely to be under-represented in the fossil charcoal record. The charcoal particle aspect ratio appeared to be the strongest indicator of the fuel type burnt. Graminoid charcoal particles are the most elongate (6.7–11.5), with a threshold above 6 that may be indicative of wetland graminoids; leaves are the shortest and bulkiest (2.1–3.5); and twigs and wood are intermediate (2.0–5.2). Further, the use of fine diagnostic features was more successful in separating wood, graminoids, and leaves, but it was difficult to further differentiate these fuel types due to overlapping features. High-aspect-ratio particles, dominated by graminoid and Sphagnum morphologies, may be robust indicators of low-temperature surface fires, whereas abundant wood and leaf morphologies as well as low-aspect-ratio particles are indicative of higher-temperature fires. However, the overlapping morphologies of leaves and wood from trees and shrubs make it hard to distinguish between high-intensity surface fires, combusting living shrubs and dead wood and leaves, and high-intensity crown fires that have burnt living trees. Distinct particle shape may also influence charcoal transportation, with elongated particles (graminoids) potentially having a more heterogeneous distribution and being deposited farther away from the origin of fire than the rounder, polygonal leaf particles. Despite these limitations, the combined use of charred-particle aspect ratios and fuel morphotypes can aid in the more robust interpretation of fuel source and fire-type changes. Lastly, I highlight the further investigations needed to refine the histories of past wildfires.
We investigate whether the bank crisis management framework of the European banking union can effectively bar the detrimental influence of national interests in cross-border bank failures. We find that both the internal governance structure and decision making procedure of the Single Resolution Board (SRB) and the interplay between the SRB and national resolution authorities in the implementation of supranationally devised resolution schemes provide inroads that allow opposing national interests to obstruct supranational resolution. We also show that the Single Resolution Fund (SRG), even after the ratification of the reform of the European Stability Mechanism (ESM) and the introduction of the SRF backstop facility, is inapt to overcome these frictions. We propose a full supranationalization of resolution decision making. This would allow European authorities in charge of bank crisis management to operate autonomously and achieve socially optimal outcomes beyond national borders.
Sublinear circuits are generalizations of the affine circuits in matroid theory, and they arise as the convex-combinatorial core underlying constrained non-negativity certificates of exponential sums and of polynomials based on the arithmetic-geometric inequality. Here, we study the polyhedral combinatorics of sublinear circuits for polyhedral constraint sets. We give results on the relation between the sublinear circuits and their supports and provide necessary as well as sufficient criteria for sublinear circuits. Based on these characterizations, we provide some explicit results and enumerations for two prominent polyhedral cases, namely the non-negative orthant and the cube [− 1,1]n.
We derive a shape derivative formula for the family of principal Dirichlet eigenvalues λs(Ω) of the fractional Laplacian (−Δ)s associated with bounded open sets Ω⊂RN of class C1,1. This extends, with a help of a new approach, a result in Dalibard and Gérard-Varet (Calc. Var. 19(4):976–1013, 2013) which was restricted to the case s=12. As an application, we consider the maximization problem for λs(Ω) among annular-shaped domains of fixed volume of the type B∖B¯¯¯¯′, where B is a fixed ball and B′ is ball whose position is varied within B. We prove that λs(B∖B¯¯¯¯′) is maximal when the two balls are concentric. Our approach also allows to derive similar results for the fractional torsional rigidity. More generally, we will characterize one-sided shape derivatives for best constants of a family of subcritical fractional Sobolev embeddings.
Solving an inverse elliptic coefficient problem by convex non-linear semidefinite programming
(2021)
Several applications in medical imaging and non-destructive material testing lead to inverse elliptic coefficient problems, where an unknown coefficient function in an elliptic PDE is to be determined from partial knowledge of its solutions. This is usually a highly non-linear ill-posed inverse problem, for which unique reconstructability results, stability estimates and global convergence of numerical methods are very hard to achieve. The aim of this note is to point out a new connection between inverse coefficient problems and semidefinite programming that may help addressing these challenges. We show that an inverse elliptic Robin transmission problem with finitely many measurements can be equivalently rewritten as a uniquely solvable convex non-linear semidefinite optimization problem. This allows to explicitly estimate the number of measurements that is required to achieve a desired resolution, to derive an error estimate for noisy data, and to overcome the problem of local minima that usually appears in optimization-based approaches for inverse coefficient problems.
Purpose: Early detection of adenocarcinomas in the esophagus is crucial for achieving curative endoscopic therapy. Targeted biopsies of suspicious lesions, as well as four-quadrant biopsies, represent the current diagnostic standard. However, this procedure is time-consuming, cost-intensive, and examiner-dependent. The aim of this study was to test whether impedance spectroscopy is capable of distinguishing between healthy, premalignant, and malignant lesions. An ex vivo measurement method was developed to examine esophageal lesions using impedance spectroscopy immediately after endoscopic resection. Methods: After endoscopic resection of suspicious lesions in the esophagus, impedance measurements were performed on resected cork-covered tissue using a measuring head that was developed, with eight gold electrodes, over 10 different measurement settings and with frequencies from 100 Hz to 1 MHz. Results: A total of 105 measurements were performed in 60 patients. A dataset of 400 per investigation and a total of more than 42,000 impedance measurements were therefore collected. Electrical impedance spectroscopy (EIS) was able to detect dysplastic esophageal mucosa with a sensitivity of 81% in Barrett’s esophagus. Conclusion: In summary, EIS was able to distinguish different tissue characteristics in the different esophageal tissues. EIS thus holds potential for further development of targeted biopsies during surveillance endoscopy.
Introduction: In an emergency department, the majority of pediatric trauma patients present because of minor injuries. The aim of this study was to evaluate temporal changes in age-related injury pattern, trauma mechanism, and surgeries in pediatric patients. Methods: This retrospective study included patients < 18 years of age following trauma from 01/2009 to 12/2018 at a level I trauma center. They were divided into two groups: group A (A: 01/2009 to 12/2013) and group B (B: 01/2014 to 12/2018). Injury mechanism, injury pattern, and surgeries were analyzed. As major injuries fractures, dislocations, and organ injuries and as minor injuries contusions and superficial wounds were defined. Results: 23,582 patients were included (58% male, median age 8.2 years). There was a slight increase in patients comparing A (n = 11,557) and B (n = 12,025) with no difference concerning demographic characteristics. Significant more patients (A: 1.9%; B: 2.4%) were admitted to resuscitation room, though the number of multiple injured patients was not significantly different. In A (25.5%), major injuries occurred significantly less frequently than in B (27.0%), minor injuries occurred equally. Extremity fractures were significantly more frequent in B (21.5%) than in A (20.2%), peaking at 8–12 years. Most trauma mechanisms of both groups were constant, with a rising of sport injuries at 8–12 years. Conclusion: Although number of patients increases only slightly over a decade, there was a clear increase in major injuries, particularly extremity fractures, peaking at 8–12 years. At this age also sport accidents significantly increased. At least, admittance to resuscitation room rose but without an increase of multiple injured patients.
Introduction: Improvements in both musculoskeletal and non-musculoskeletal manifestations are important treatment goals in psoriatic arthritis (PsA). Objective: These post hoc analyses determined whether additional benefits related to various PsA domains are observed in patients simultaneously achieving 50% improvement in American College of Rheumatology criteria (ACR50) and 100% improvement in Psoriasis Area Severity Index (PASI100), the primary endpoint of the SPIRIT-H2H study. Methods: Patients with active PsA and psoriasis in SPIRIT-H2H (N = 566) were categorised into two sets of four response groups irrespective of treatment allocation (approved dosages of ixekizumab or adalimumab): patients who simultaneously achieved ACR50 and PASI100 response, achieved ACR50 response only, achieved PASI100 response only, or did not achieve ACR50 or PASI100 response after 24 and 52 weeks of treatment. Patients achieving simultaneous ACR50 and PASI100 response were compared with the other patient response groups at the corresponding time point for efficacy and health-related quality of life (HRQoL) outcomes. Results: Patients simultaneously achieving ACR50 and PASI100 responses at week 24 or 52 showed higher rates of ACR70 response, minimal disease activity, Disease Activity in Psoriatic Arthritis ≤ 4, resolution of enthesitis and dactylitis, and HRQoL improvement at weeks 24 and 52, respectively, than the other corresponding response groups at both time points. Conclusion: High levels of disease control, such as those obtained with simultaneous achievement of ACR50 and PASI100 response, were linked to better outcomes across a wide range of endpoints that are important for patients with PsA. Patients meeting this combined endpoint showed more comprehensive and thus greater control of disease activity.
Purpose: To investigate short-term (3 months follow-up) changes in visual quality following Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial dystrophy (FED). Methods: In this prospective institutional case series, 51 patients that underwent DMEK for FED were included. Assessment included the Quality of Vision (QoV) questionnaire preoperatively, at 1 month, and 3 months after surgery. Secondary outcome measures were anterior segment parameters acquired by Scheimpflug imaging, corrected distance visual acuity (CDVA), and endothelial cell density (ECD). Results: Glare, hazy vision, blurred vision, and daily fluctuation in vision were the symptoms mostly reported preoperatively. All symptoms demonstrated a significant reduction of item scores for severity, frequency, and bothersome in the course after DMEK (P < 0.01). Glare and fluctuation in vision remained to some extent during the follow-up period (median score = 1). Preoperatively, corneal densitometry correlated moderately to weakly with severity of hazy vision (rs = 0.39; P = 0.03) and frequency (rs = 0.26; P = 0.02) as well as severity (rs = 0.27; P = 0.03) of blurry vision. CDVA and central corneal thickness (CCT) did not correlate with visual complains. Conclusions: Following DMEK for FED, patient-reported visual symptoms assessed by the QoV questionnaire represent a useful tool providing valuable information on the impact of DMEK on visual quality that cannot be directly estimated by morphological parameters and visual acuity only.
Leukemia patients bearing the t(4;11)(q21;q23) translocations can be divided into two subgroups: those expressing both reciprocal fusion genes, and those that have only the MLL-AF4 fusion gene. Moreover, a recent study has demonstrated that patients expressing both fusion genes have a better outcome than patients that are expressing the MLL-AF4 fusion protein alone. All this may point to a clonal process where the reciprocal fusion gene AF4-MLL could be lost during disease progression, as this loss may select for a more aggressive type of leukemia. Therefore, we were interested in unraveling the decisive role of the AF4-MLL fusion protein at an early timepoint of disease development. We designed an experimental model system where the MLL-AF4 fusion protein was constitutively expressed, while an inducible AF4-MLL fusion gene was induced for only 48 h. Subsequently, we investigated genome-wide changes by RNA- and ATAC-Seq experiments at distinct timepoints. These analyses revealed that the expression of AF4-MLL for only 48 h was sufficient to significantly change the genomic landscape (transcription and chromatin) even on a longer time scale. Thus, we have to conclude that the AF4-MLL fusion protein works through a hit-and-run mechanism, probably necessary to set up pre-leukemic conditions, but being dispensable for later disease progression.
Background: Due to the coronavirus disease 2019 (COVID-19) pandemic, interventions in the upper airways are considered high-risk procedures for otolaryngologists and their colleagues. The purpose of this study was to evaluate limitations in hearing and communication when using a powered air-purifying respirator (PAPR) system to protect against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) transmission and to assess the benefit of a headset. Methods: Acoustic properties of the PAPR system were measured using a head and torso simulator. Audiological tests (tone audiometry, Freiburg speech test, Oldenburg sentence test (OLSA)) were performed in normal-hearing subjects (n = 10) to assess hearing with PAPR. The audiological test setup also included simulation of conditions in which the target speaker used either a PAPR, a filtering face piece (FFP) 3 respirator, or a surgical face mask. Results: Audiological measurements revealed that sound insulation by the PAPR headtop and noise, generated by the blower-assisted respiratory protection system, resulted in significantly deteriorated hearing thresholds (4.0 ± 7.2 dB hearing level (HL) vs. 49.2 ± 11.0
Introns of human transfer RNA precursors (pre-tRNAs) are excised by the tRNA splicing endonuclease TSEN in complex with the RNA kinase CLP1. Mutations in TSEN/CLP1 occur in patients with pontocerebellar hypoplasia (PCH), however, their role in the disease is unclear. Here, we show that intron excision is catalyzed by tetrameric TSEN assembled from inactive heterodimers independently of CLP1. Splice site recognition involves the mature domain and the anticodon-intron base pair of pre-tRNAs. The 2.1-Å resolution X-ray crystal structure of a TSEN15–34 heterodimer and differential scanning fluorimetry analyses show that PCH mutations cause thermal destabilization. While endonuclease activity in recombinant mutant TSEN is unaltered, we observe assembly defects and reduced pre-tRNA cleavage activity resulting in an imbalanced pre-tRNA pool in PCH patient-derived fibroblasts. Our work defines the molecular principles of intron excision in humans and provides evidence that modulation of TSEN stability may contribute to PCH phenotypes.
Objectives: To evaluate the predictive value of volumetric bone mineral density (BMD) assessment of the lumbar spine derived from phantomless dual-energy CT (DECT)-based volumetric material decomposition as an indicator for the 2-year occurrence risk of osteoporosis-associated fractures. Methods: L1 of 92 patients (46 men, 46 women; mean age, 64 years, range, 19–103 years) who had undergone third-generation dual-source DECT between 01/2016 and 12/2018 was retrospectively analyzed. For phantomless BMD assessment, dedicated DECT postprocessing software using material decomposition was applied. Digital files of all patients were sighted for 2 years following DECT to obtain the incidence of osteoporotic fractures. Receiver operating characteristic (ROC) analysis was used to calculate cut-off values and logistic regression models were used to determine associations of BMD, sex, and age with the occurrence of osteoporotic fractures. Results: A DECT-derived BMD cut-off of 93.70 mg/cm3 yielded 85.45% sensitivity and 89.19% specificity for the prediction to sustain one or more osteoporosis-associated fractures within 2 years after BMD measurement. DECT-derived BMD was significantly associated with the occurrence of new fractures (odds ratio of 0.8710, 95% CI, 0.091–0.9375, p < .001), indicating a protective effect of increased DECT-derived BMD values. Overall AUC was 0.9373 (CI, 0.867–0.977, p < .001) for the differentiation of patients who sustained osteoporosis-associated fractures within 2 years of BMD assessment. Conclusions: Retrospective DECT-based volumetric BMD assessment can accurately predict the 2-year risk to sustain an osteoporosis-associated fracture in at-risk patients without requiring a calibration phantom. Lower DECT-based BMD values are strongly associated with an increased risk to sustain fragility fractures.
Key Points: Dual-energy CT–derived assessment of bone mineral density can identify patients at risk to sustain osteoporosis-associated fractures with a sensitivity of 85.45% and a specificity of 89.19%. The DECT-derived BMD threshold for identification of at-risk patients lies above the American College of Radiology (ACR) QCT guidelines for the identification of osteoporosis (93.70 mg/cm 3 vs 80 mg/cm 3 ).
To explore and describe attitudes and opinions towards suicidality in healthcare professionals (HCPs) working with oncological patients. Methods: A 48-item online questionnaire was developed and distributed to HCPs working with cancer patients. Three hundred fifty-four answered questionnaires were analyzed. Results: The majority of HCPs reported that they were able to understand why a cancer patient would commit suicide (87.8%) or would seek help from an assisted suicide organization (ASO; 83.9%). The understandable reasons were pain and physical impairments (51.4%), social isolation (19.8%), loss of control and autonomy (18.1%), terminal disease (17.2%), loss of meaning (15.3%), desperation (14.7%), and psychic distress (9.3%). Personal experiences with suicidality lead only 44.8% of HCPs to believe that thereby they would be better able to understand a patients’ wish for suicide. Religion was negatively associated with understanding of suicide and why a cancer patient would seek help from an ASO. Knowledge of suicidality was positively associated with why a cancer patient would seek help from an ASO. Conclusions: There is still little knowledge in oncology about the relation of HCPs’ attitudes toward suicidality in their patients and how those attitudes influence their behavior, especially care and treatment of patients. More research on this topic is needed. It stands to reason that more education about suicidality in cancer patients seems likely to improve understanding and attitudes and thereby influence care for cancer patients.
Objectives: Current treatments for chronic depression have focused on reducing interpersonal problems and negative affect, but paid little attention to promoting prosocial motivation and positive affect. Following this treatment focus, the objective of the present study was to examine whether the combination of metta (Loving Kindness) group meditation and subsequent tailored individual therapy focusing on kindness towards oneself and others (metta-based therapy, MBT) shows greater improvements in depressive symptoms than a wait list control group in patients with chronic depression. Methods: Forty-eight patients with DSM-5 persistent depressive disorder were randomly assigned to MBT or a wait list control condition. Outcome was assessed after group meditation, after subsequent individual therapy, and at 6-month follow-up. The primary outcome measure was an independent blind rating of depressive symptoms at post-test. Secondary outcome included changes in self-reported depression, behavioral activation, rumination, social functioning, mindfulness, compassion, and clinician-rated emotion regulation. Results: Mixed-design analyses showed significant differences between MBT and WLC in changes from pre- to post-test in clinician-rated and self-rated depression, behavioral activation, rumination, social functioning, mindfulness, and emotion regulation. Most of the changes occurred during group meditation and were associated with large effect sizes. Improvements were maintained at 6-month follow-up. Conclusions: The results provide preliminary support for the effectiveness of MBT in treating chronic depression. Trial Registration: ISRCTN, ISRCTN97264476.
When taking into consideration the demographic and socio-economic trends in most European countries, the demand for domestic services will be increasing in the next decades. This development could be used for creating formal employment opportunities in private households for unskilled and low-skilled labour. However, it is not an easy task since it entails devising a strategy for reducing the high share of informal labour in as well as overcoming the current fragmentation of the domestic services sector. Both on the national and EU level there is a need for policy advice on how to best integrate the diverse but yet interrelated needs and interests of the households, the employees and the firms as providers of domestic services into one coherent strategy. So far, such a comprehensive strategy can be found only in France where the BorlooPlan systematically integrated measures and tools from all relevant fields of politics. Thus it led to a significant growth of the domestic services sector and a substantial increase of formal employment. This brochure presents the Generalised Model, a tool for devising a similarly comprehensive and coherent strategy. It was constructed by drawing on the successful French strategy of creating more formal employment relationships through the systematic development of the domestic services sector. The brochure demonstrates how other countries can learn from the French experience by analysing their current situation and using the Generalised Model to create a strategy fitting their specific circumstances. By studying the situations in Germany, Austria, Italy and Poland and considering how to create strategies fitting the different national settings in these countries it is shown how the Generalised Model can put into practice. These case studies were conducted in the EU Project “Labour Market Instruments for Reducing Illegal Employment in Private Households of the Elderly”, supported by DG Employment, Social Affairs and Inclusion. The brochure intends to initiate and stimulate discourses on fostering the creation of formal employment in EU Member States. Therefore, it addresses different stakeholders such as policymakers on the national, regional and EU level, representatives of local administrations, providers of domestic services, domestic workers, trade unions or welfare associations, labour administration, placement services as well as providers of education and training.
Despite several decades of active research, there are still substantial gaps in the knowledge of parasitoid wasps in Australia, with many families and genera yet to be revised using modern approaches and only a fraction of the estimated fauna currently described. The genus Glyptapanteles Ashmead, 1904 is a member of the subfamily Microgastrinae (Hymenoptera: Braconidae) and all species in the subfamily are lepidopteran parasitoids. The genus previously contained only three species known from Australia: G. deliasa Austin & Dangerfield, 1992, G. drioplanetus Fagan-Jeffries & Austin, 2021 and G. mnesampela Austin, 2000. To undertake a revision of this morphologically-conserved group in Australia, we used a combination of molecular (cytochrome oxidase subunit one (COI) and wingless genes) and minimal morphological data to delimit and describe an additional 31 species: G. austini Fagan-Jeffries & Bird sp. nov. and the following 30 species all authored by Fagan-Jeffries, Bird & Austin: G. albigena sp. nov., G. andamookaensis sp. nov., G. arcanus sp. nov., G. aspersus sp. nov., G. austrinus sp. nov., G. baylessi sp. nov., G. bradfordae sp. nov., G. cooperi sp. nov., G. doreyi sp. nov., G. dowtoni sp. nov., G. eburneus sp. nov., G. erucadesolator sp. nov., G. ferrugineus sp. nov., G. foraminous sp. nov., G. goodwinnoakes sp. nov., G. guzikae sp. nov., G. harveyi sp. nov., G. kingae sp. nov., G. kittelae sp. nov., G. kurandaensis sp. nov., G. lambkinae sp. nov., G. lessardi sp. nov., G. mouldsi sp. nov., G. niveus sp. nov., G. rixi sp. nov., G. rodriguezae sp. nov., G. ruhri sp. nov., G. sanniopolus sp. nov., G. vergrandiacus sp. nov. and G. wrightae sp. nov. We provide a key to species groups and to the species able to be identified on morphological characters alone. Additionally, we provide a brief discussion of the difficulties in describing small, morphologically conserved wasps and the challenges associated with revising the taxonomy of hyperdiverse taxa in the context of the planned mission of Taxonomy Australia to accelerate the documentation of Australia’s biodiversity.
Five new and six known species belonging to the genus Basirotyleptus collected from the Western Ghats, India, are described and illustrated. Basirotyleptus conicaudatus sp. nov. is characterized by having 0.42–0.44 mm long body; odontostyle 9.5–10.0 μm, odontophore 11.5–12.0 μm; pharyngeal bulb pear-shaped, 14–15% of total neck length; female genital system mono-opisthodelphic; tail conoid with acute terminus. Basirotyleptus constrictus sp. nov. is characterized by having 0.38–0.49 mm long body; perioral disc distinct; odontostyle 9–10 μm, odontophore 14–15 μm; pharyngeal bulb pear-shaped, 15–17% of total neck length; female genital system mono-opisthodelphic; tail rounded to conoid. Basirotyleptus goaensis sp. nov. is characterized by having 0.73–0.87 mm long body; odontostyle 13.0–14.5 μm, odontophore 15.0–17.5 μm; pharyngeal bulb pyriform, 16–18% of total neck length; female genital system mono-opisthodelphic; tail rounded. Basirotyleptus neocaudatus sp. nov. is characterized by having 0.31–0.44 mm long body; odontostyle 7.5–9.5 μm, odontophore 10–13 μm; pharyngeal bulb pear-shaped, 14–19% of total neck length; female genital system mono-opisthodelphic; tail conoid with acute terminus. Basirotyleptus siddiqii sp. nov. is characterized by having 0.36 mm long body; odontostyle 7.5–8.0 μm, odontophore 10.0–10.5 μm; pharyngeal bulb pear-shaped, 15–16% of total neck length; female genital system mono-opisthodelphic; tail conoid. Six known species viz., B. basiri, B. pini, B. nindei, B. ethiopicus, B. acus, B. minutus are also described and illustrated. Along with light microscopic study, line drawings, compendium and key to species of Basirotyleptus are also provided.
We describe and illustrate eight new species of chewing lice in the genus Philopterus Nitzsch, 1818, parasitic on hosts in the bird families Cardinalidae, Chloropseidae, Hirundinidae, Icteridae, Motacillidae, Paridae, and Vangidae from China, Peru, South Africa, Thailand, and the USA. They are: Philopterus coriaceus sp. nov. from Molothrus oryzivorus oryzivorus (Gmelin, 1788); P. hebes sp. nov. from Chloropsis aurifrons inornata Kloss, 1918 and C. cochinchinensis kinneari Hall & Deignan, 1956; P. micropunctatus sp. nov. from Anthus hodgsoni Richmond, 1907; P. afropari sp. nov. from Melaniparus cinerascens cinerascens (Vieillot, 1818); P. pseudhirundo sp. nov. from Pseudhirundo griseopyga Sundevall, 1850; P. sinensis sp. nov. from Hemipus picatus capitalis (Horsfield, 1840); P. stansburyensis sp. nov. from Pheucticus melanocephalus melanocephalus (Swainson, 1827); and P. trepostephanus sp. nov. from Tephrodornis virgatus fretensis Robinson & Kloss, 1920 and T. v. mekongensis Meyer de Schauensee, 1946. Philopterus hebes sp. nov. constitutes the first record of the genus Philopterus from the Chloropseidae. We also provide some notes on the morphology and status of Cypseloecus Conci, 1941.
The original description of Rivudiva trichobasis Lugo-Ortiz & McCafferty, 1998 is short, with few illustrations. The lack of information resulted in a broad specific diagnosis, with emphasis on the spine-like setae on the antenna. Our hypothesis is that the lack of information resulted in many species being hidden behind R. trichobasis name. We evaluated the species R. coveloae (Traver, 1971) and R. venezuelensis (Traver, 1943) considering the new evidence. After analyzing the paratype of R. trichobasis and records of the species in Brazil, the hidden-species hypothesis was corroborated. Five new species were identified among the published records of R. trichobasis of which four are described here: R. amazona sp. nov. (Roraima State), R. oxum sp. nov. (Rondônia State), R. uiara sp. nov. (Amazonas State), R. naia sp. nov. (Roraima State). The fifth species, Rivudiva sp. X from Maranhão State, could not be described due to the poor conservation of the specimen and is therefore left in open nomenclature. Records from Espírito Santo State (Brazil) and from Paraguay are treated as putative and must be evaluated considering the new evidence. Rivudiva venezuelensis and Rivudiva coveloae are diagnosed and illustrated based on type material. After analyzing these two species, we hypothesize that only R. coveloae likely belongs to the genus Rivudiva. However, information on the nymphal stage is needed to corroborate this hypothesis.
Für jeden Betroffenen ist die Diagnose Krebs ein schwerwiegender Einschnitt in der Lebensqualität und -führung, da die Behandlung oftmals mit langen Chemotherapien einhergeht. Moderne Durchbrüche in der Krebsbehandlung stammen aus dem Forschungsbereich der zielgerichteten Molekulartherapie oder aus dem Gebiet der Immuntherapien, die zu beachtlichen Erfolgen bei der Behandlung von Krebspatienten führten. Trotzdem bleiben auf dem Gebiet der Onkologie weiterhin Fragen zu den grundlegenden biologischen Prozessen unbeantwortet.
Zu den Onkoproteinen, die das Tumorwachstum in Leukemiezellen stark beeinflussen, gehören die Proteine der Klasse der mixed lineage leukemia (MLL) Histonmethyltransferasen. Genetische Fusionen des mll Gens, sogenannte Rearragments, führen zu MLL-fusion Produkten, die erheblich zum Verlauf der aggressiven akuten myeloischen Leukämie (AML) beitragen. Ein weiteres Onkoprotein, das für den Krankheitsverlauf vieler Krebsarten relevant ist, ist die Transkriptionsfaktorfamilie MYC. Überexprimierung von MYC wurde in einem Drittel aller humanen Tumore beobachtet. Zahlreiche Studien belegen, dass hohe MYC Level die Expression von Genen regulieren, die essentiell für den Transformationsprozess und somit das Tumorwachstum sind. Da der Transkriptionsfaktor weder eine sabile tertiäre Proteinstruktur noch eine für Inhibitoren adressierbare Bindetasche aufweist, gilt MYC bis heute als undruggable.
Sowohl die Histonmethyltransferase MLL1, als auch der Transkriptionsfaktor MYC interagieren mit einem ca. 37 kDa Protein namens WD40-repeat containing Protein 5 (WDR5), das durch seine propellerförmige Struktur eine Oberfläche mit insgesamt zwei Bindestellen aufweist. Mehrere Studien zeigten, dass WDR5 die Stabilität und somit die Funktion epigenetischer Proteinkomplexe wie SET/ MLL und NSL gewährleistet. In diesem Kontext wurde WDR5 als relevantes Target für die MLL-rearragend akute lymphatische Leukämie (ALL) postuliert. Weitere Studien zeigten zusätzliche Rollen von WDR5, wie die Interaktion zwischen WDR5 und dem Onkoprotein MYC sowie dessen Rekrutierung zum Chromatin. Seit 2015 wurden erfolgreich mehrere niedermolekulare Wirkstoffe für die Inhibierung von WDR5 entwickelt. Dabei zielten die meisten der literaturbekannten Inhibitoren auf die Argininmotiv-erkennende WDR5-interacting (Win) Bindestelle, eine große, hydrophobe Bindetasche im Zentrum des WDR5-Propellers. Die Resultate der besser erforschten Win Inhibitoren zeigten, dass WDR5 ein erfolgsversprechendes Target zur Inhibierung von leukämischen (MLL-r-abhängigen) und neuroblastomatischen (MYC-abhängigen) Zellwachstum ist.
Da beide Bindestellen des WDR5 Proteins Interaktionen mit onkologisch bedeutsamen Faktoren eingehen, würde eine einseitige Inhibierung nur die Effekte der jeweiligen Bindestelle aufzeigen. Diese Limitierung könnte jedoch durch die Entwicklung von WDR5 PROTACs (Proteolysis targeting chimeras) aufgehoben werden, da alle Gerüstfunktionen des Proteins und Protein-Protein-Interaktionen durch die Degradierung von WDR5 entfernt werden würden. Dabei induzieren die heterobifunktionellen Moleküle den Abbau des Zielproteins über das zelleigene Ubiquitin-Proteasom-System, statt die Enzymfunktion zu inhibieren. Nach dem zelleigenen Abbau des Zielproteins wird der PROTAC freigesetzt und kann einen neuen Zyklus der Proteindegradation einleiten, was die erforderliche Menge an Wirkstoff verringert.
Diese Dissertation beschäftigte sich mit dem Design, der Synthese sowie der biophysikalischen und biologischen Evaluierung von WDR5 PROTACs. Ausgehend von literaturbekannten WDR5 Liganden wurden zwei verschiedene PROTAC Typen entworfen. Diese beiden Molekültypen besitzen einen unterschiedlichen geometrischen Austrittswinkel, wodurch die Chance auf eine erfolgreiche Komplexbildung zwischen WDR5, PROTAC und E3 Ligase erhöht wird. Als Leitstruktur fungierten die Verbindungen OICR-9429 sowie DDO-2117 und ausgehend von Ligand (6d) wurden heterobifunktionelle Moleküle mit verschiedenen Linkersystemen ([PEG]- und alkyl-basiert, sowie aromatisch verbrückt) und verschiedenen E3 Ligase Liganden (Cereblon, VHL und MDM2) synthetisiert. Die anschließenden biochemischen und biophysikalischen Evaluierungen der verschiedenen PROTACs durch Thermofluor (DSF) und ITC zeigten eine hohe in vitro Affinität einiger Moleküle. Die zelluläre Permeabilität der großen Moleküle wurde in einem hier etablierten BRET Assay untersucht. Zur Assay-Etablierung wurden drei Tracer (21a-c), basierend auf BODIPY Konjugaten, synthetisiert und getestet, bevor die PROTACs in intakten und lysierten Zellen vermessen wurden. Während die zellulären Affinitäten von Cereblon- und VHL-adressierenden PROTACs sich im niedrigen μM Bereich bewegten, wurden die nicht zellgängigen MDM2 PROTACs von weiteren Experimenten ausgeschlossen.
Die Degradierungeffizienz der WDR5 PROTACs (7a-e) und (8a-j) wurden in der Leukämie Zellinie MV4-11 untersucht, da diese die am meisten auftretende MLL fusion Mutation AF4 birgt. Dabei wurde der Proteinabbau von WDR5 über den HiBiT Assay sowie Western Blots nachgewiesen. ...
There have been numerous attempts to reform the Economic and Monetary Union (EMU) after the Great Recession, however the reform success varies greatly among sub-fields. Additionally, the political science research community has engaged a diverse set of theory- driven explanations, causal mechanisms, and variables to explain respective reform success. This article takes stock of reform policies in the EMU from two angles. First, it outlines distinct theoretical approaches that seek to explain success and failure of reform proposals and second, it surveys how they explain policy output and policy outcome in four policy subfields: financial stabilization, economic governance, financial solidarity, and cooperative dissolution. Finally, the article develops a set of explanatory factors from the existing literature that will be used for a Qualitative Comparative Analysis (QCA).
Benthic samples were collected during two expeditions near the Antarctic Peninsula and in the South-Eastern Weddell Sea. During these studies, a new species of Ampharetidae Malmgren, 1867, Anobothrus konstantini Säring & Bick sp. nov., was found. Here we present a detailed description of this species. We used the traditional light microscope and scanning electron microscope (SEM) to identify and describe the diagnostic characters: a circular glandular band on segment 6; an elongate ridge between the notopodia on segment 12 and modified notochaetae on this segment; 16 thoracic, two intermediate and ten abdominal segments. For the first time, micro-computed tomography (micro-CT) was used for a species description of Anobothrus. Micro-CT provided information on the shape of the prostomium (Ampharete-type) and the arrangement of branchiae (four pairs in two rows, without a gap). In addition, we provide quantitative information on the environmental niche based on sediment parameters (chlorophyll a content, organic matter content, chloroplast equivalent, grain size) for the new Anobothrus species, relevant for, e.g., species distribution modelling. Finally, an identification key for all Anobothrus species is provided.
Inducing cell death in tumor cells is a major goal of anti-cancer therapy. However, the preferable mode of cell death to induce is under debate. Apoptosis is known to be an anti-inflammatory and pro-resolving type of programmed cell death, whereas necroptosis results in the release of danger-associated molecular patterns (DAMPs) and is pro-inflammatory. Efferocytosis of apoptotic cells by macrophages results in a pro-resolving switch of macrophages polarization and is required to induce resolution of inflammation. This impact of apoptotic cells on macrophages is a non-desired consequence of cell death in tumors, which are often characterized by an overshooting wound healing response. Moreover, apoptosis resistance is frequently observed in cancer cells. To overcome apoptosis resistance in cancer cells, necroptosis can be induced as an alternative mechanism for cancer treatment. Interferons (IFNs) play an important role in tumor immune responses and act by inducing the expression of IFN-stiumlated genes (ISGs). Furthermore, IFNs were shown to be able to induce necroptosis together with Smac-mimetics when caspases are inhibited in different cancer cell lines. Necroptosis is induced by phosphorylation and activation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1), RIPK3 and pseudokinase mixed lineage kinase domain-like (MLKL).
In my thesis, we first identified MLKL as an ISG in various cancer cell lines. MLKL upregulation was found to be a general feature of IFN signaling since both type I and type II IFNs increase the expression of MLKL. IFNy was able to upregulate MLKL at messenger ribonucleic acid (mRNA) and protein level indicating that MLKL is elevated transcriptionally. Indeed, Actinomycin D chase experiments showed that inhibition of transcription abolished MLKL upregulation upon IFN treatment. Both, knockdown of the IFNy-activated transcription factors interferon regulatory factor 1 (IRF1) and signal transducer and activator of transcription 1 (STAT1) as well as knockout of IRF1 significantly dampened MLKL mRNA upregulation, demonstrating that STAT1 and especially IRF1 are necessary to induce MLKL expression. This first part of the study highlights the upregulation of MLKL by IFNy as valuable tool to sensitize cells towards necroptosis and by that overcome apoptosis resistance in cancers.
When compared to apoptosis, the immune response to necroptotic cells and the polarization of macrophages phagocytosing necroptotic cells is not well studied. In most studies, cell death was induced by biological or chemical compounds, which may lead to artifacts by affecting the macrophages and triggering of unrelated signaling pathways. Therefore, in the second part of my thesis we used a pure cell death system of NIH 3T3 cells expressing either dimerizable caspase 8 or oligomerizable RIPK3 to induce cell death. Addition of B/B-Homodimerizer (dimerizer) to the cells resulted in apoptosis or necroptosis, which was confirmed by caspase 3/7 activation, phosphorylation of MLKL and inhibitor experiments, respectively. We analyzed the effect of dying cells on peritoneal macrophages by establishing a co-culture in a transwell system. The genetic profile of macrophages co-cultured with dying cells was evaluated by whole transcriptome RNA sequencing. In macrophages co-cultured with necroptotic cells genes corresponding to chemotaxis and hypoxia pathways were upregulated. A significant proportion of hypoxia-related pathways are mediated by hypoxia-inducible factor 1-alpha (HIF-1α), which also induces metabolic changes in polarized macrophages. We could show that macrophages co-cultured with necroptotic cells showed a decreased mitochondrial respiration, indicating an inflammatory (M1) polarization. Protein levels of chemokine C-X-C motif ligand 1 (CXCL1), which was increased in the RNA sequencing data, were also upregulated in supernatant of co-cultured macrophages and of necroptotic cells, demonstrating that necroptotic cells both secrete CXCL1 and induce gene expression of CXCL1 in peritoneal macrophages. This may influence the recruitment of neutrophils as inhibition of necroptosis during Zymosan-A-induced peritonits in mice decreased the levels of neutrophils at day 1 of this model of self-resolving inflammation.
Furthermore, RNA sequencing revealed an unexpected impact of apoptotic cells on macrophage biology as cell cycle and cell division pathways were increased. Enhanced proliferation of macrophages was confirmed by two functional assay with peritoneal macrophages isolated from mice and IC-21 macrophages. Inhibition of apoptosis during Zymosan-A-induced peritonits in mice demonstrated decreased mRNA levels of cell cycle mediators in peritoneal macrophages. Simultaneously with cell cycle activation, gene sets of prostaglandin E2 (PGE2) signaling were upregulated during RNA sequencing. In the second part of my thesis we could demonstrate, that apoptotic cells induce transcription of cell cycle genes and proliferation of macrophages and necroptotic cells are able to influence the chemokine profile of macrophages and thereby the recruitment of neutrophils.
Master of science in international economics and economic policy : guidelines winter term 2017/2018
(2017)
Master of science in international economics and economic policy : guidelines winter term 2021/22
(2021)
Early Carboniferous coiled nautiloids from North Africa are virtually unknown. An assemblage of nine species, all from the family Trigonoceratidae, from the Dalle à Merocanites (Tournaisian-Viséan boundary interval) of Timimoun in western Algeria is described, being the most diverse Carboniferous nautiloid assemblage known from North Africa but much less diverse than the time-equivalent assemblages from Belgium and Ireland. The assemblage consists of the species Maccoyoceras pentagonum sp. nov., Lispoceras orbis sp. nov., Thrincoceras devolvere sp. nov., Rineceras multituberculatum sp. nov., Rineceras rectangulatum sp. nov., Vestinautilus padus sp. nov., Vestinautilus concinnus sp. nov., Planetoceras destrictum sp. nov. and Planetoceras transforme sp. nov. A morphometric analysis of Maccoyoceras pentagonum sp. nov. and Lispoceras orbis sp. nov. shows that the intraspecific variation in these species is within rather narrow limits.
Challenges of FAIR phase 0
(2018)
After two-year's shutdown, the GSI accelerators plus the latest addition of storage ring CRYRING, will be back into operation in 2018 as the FAIR phase 0 with the goal to fulfill the needs of scientific community and the FAIR accelerators and detector development. Even though GSI has been well known for its operation of a variety of ion beams ranging from proton up to uranium for multi research areas such as nuclear physics, astrophysics, biophysics, material science, the upcoming beam time faces a number of challenges in re-commissioning its existing circular accelerators with brand new control system and upgrade of beam instrumentations, as well as in rising failures of dated components and systems. The cycling synchrotron SIS18 has been undergoing a set of upgrade measures for fulfilling future FAIR operation, among which many measures will also be commissioned during the upcoming beam time. This paper presents the highlights of the challenges such as re-establishing the high intensity heavy ion operation as well as parallel operation mode for serving multi users. The status of preparation including commissioning results will also be reported.
HADES is a fixed target experiment using SIS18 heavy-ion beams. It investigates the microscopic properties of matter formed in heavy-ion, proton and pion - induced reactions in the 1-3.5 GeV/u energy regime. In 2014 HADES used a secondary pion beam produced by interaction between high-intensity nitrogen primary beam and a beryllium target. In these conditions beam losses, generated by slow extraction and beam transport to the experimental area, led to activation of the beam line elements and triggered radiation alarms. The primary beam intensity had to be reduced and the beam optics modified in order to keep radiation levels within the allowed limits. Similar beam conditions are requested by HADES experiment for upcoming run in 2018 and in the following years. Therefore, a number of measures have been proposed to improve beam transmission and quality. These measures are: additional shielding, additional beam instrumentation, modification of beam optics and increase of vacuum chambers' apertures in critical locations. The optics study and preliminary results of FLUKA simulations for optimization of location of loss detectors are presented.
GSI High Energy Beam Transfer lines (HEST) link the SIS18 synchrotron with two storage rings (Experimental Storage Ring and Cryring) and six experimental caves. The recent upgrades to HEST beam instrumentation enables precise measurements of beam properties along the lines and allow for faster and more precise beams setup on targets. Preliminary results of some of the measurements performed during runs in 2018 and 2019 are presented here. The focus is on response matrix measurements and quadrupole scans performed on HADES beam line. The errors and future improvements are discussed.
An automated beam-setting optimization application has been implemented on top of FAIR’s control system software stack based on CERN’s LSA framework. The optimization functionality is built using the Jenetics software library implemented in Java. Tests of the software with beam have been performed at the CRYRING@ESR ion storage ring.
The present study focuses on the beam line optimization from the heavy-ion synchrotron SIS18 to the HADES experiment. BOBYQA (Bound Optimization BY Quadratic Approximation) solves bound constrained optimization problems without using derivatives of the objective function. The Bayesian optimization is another strategy for global optimization of costly, noisy functions without using derivatives. A python programming interface to MADX allow the use of the python implementation of BOBYQA and Bayesian method. This gave the possibility to use tracking simulation with MADX to determine the loss budget for each lattice setting during the optimization and compare both optimization methods.
Due to the massive parallel operation modes at GSI accelerators, a lot of accelerator setup and re-adjustment has to be made by operators during a beam time. This is typically done manually using potentiometers and is very time-consuming. With the FAIR project the complexity of the accelerator facility increases further and for efficiency reasons it is recommended to establish a high level of automation for future operation. Modern Accelerator Control Systems allow a fast access to both, accelerator settings and beam diagnostics data. This provides the opportunity to implement algorithms for automated adjustment of e.g. magnet settings to maximize transmission and optimize required beam parameters. The fast-switching magnets in GSI-beamlines are an optimal basis for an automatic exploration of the parameter-space. The optimization of the parameters for the SIS18 multi-turn-injection using a genetic algorithm has already been simulated*. The first results of our automatized online parameter optimization at the CRYRING@ESR injector are presented here.
Since the last 20 years, modern heuristic algorithms and machine learning have been increasingly used for several purposes in accelerator technology and physics. Since computing power has become less and less of a limiting factor, these tools have become part of the physicist community's standard toolkit [1][2] [3] [4] [5]. This paper describes the construction of an algorithm that can be used to generate an optimised lattice design for transfer lines under the consideration of restrictions that usually limit design options in reality. The developed algorithm has been applied to the existing SIS18 to HADES transfer line in GSI.
Metacyclops sakaeratensis sp. nov. and M. brancelji sp. nov. are described as being present in the mountainous areas of Northeastern and Southern Thailand, respectively. Two new species resemble M. woni in both sexes, but they are easily distinguished from their Cambodian relative by having: 1) transverse suture on the dorsal surface of the genital double-somite, 2) serrated hyaline frill on the posterior margin of third pedigerous somite, 3) different length / width ratio of caudal ramus, and 4) a row of spinule on caudal surface of intercoxal sclerite of the third swimming legs. The significant differences between M. sakaeratensis sp. nov. and M. brancelji sp. nov. are present in both sexes, including the body size, integumental ornamentation of the body surface, length / width ratio of caudal ramus, armature of the fifth swimming leg, and the male sixth swimming leg. In addition, an up-to-date key to the female of all fifteen species of Metacyclops recorded in Asia is provided.
Perinereis anderssoni Kinberg, 1865 originally described from Brazil has been attributed with a wide distribution on the American Atlantic coasts, ranging from Brazil to Bermuda, due to the synonymy of Nereis bairdii Webster, 1884 and Nereis (Perinereis) melanocephala McIntosh, 1885. In this paper, the synonymy of Nereis bairdii with Perinereis anderssoni is rejected based on a re-examination of the syntypes of N. bairdii which are found to contain two species requiring designation of a lectotype and paralectotypes here redescribed as Perinereis bairdii (Webster, 1884) and the remaining specimens are here described as Perinereis websteri sp. nov. The synonymy of Nereis (Perinereis) melanocephala with P. anderssoni is rejected and the synonymy with P. bairdii proposed by previous authors is accepted here. A description of P. anderssoni, a redescription of P. floridana, and a description of the males of P. cariboea with additional material are provided for comparison. A key to identifying all Atlantic Perinereis species is also included.
A new genus, Thaicypris gen. nov., in the tribe Herpetocypridini Kaufmann, 1900 of the subfamily Herpetocypridinae Kaufmann, 1900 is established to accommodate a new species from Thailand. The present contribution deals with the description of a new genus and species, Thaicypris panhai gen. et sp. nov., which is mainly characterized by the distinctive and raised, inwardly displaced selvage at the postero-ventral part of the right valve (RV) that is not parallel to the valve margin, the absence of an anterior inner list on the RV, the prominent and elevated double inner list on the posterior part of the left valve, the small and three-segmented Rome organ on the first antenna (A1), the spatulated terminal segment of the maxillular (Mx1) palp, the slender caudal ramus (CR) with long and thin Sp seta, the presence of basal triangle on the CR attachment, and the pointed projection at the terminal segment base of the prehensile palps. The hemipenis of the new genus and species is outstanding, especially the medial lateral shield which has a long, beak-shaped protrusion on the distal part. The discovery of this Thai taxon is the first record of the tribe Herpetocypridini in Thailand and the second species of the tribe in Southeast Asia.
Two new species of Ageniella Banks, 1912 (Hymenoptera: Pompilidae) from Brazil and updated keys
(2022)
Ageniella Banks, 1912 is a paraphyletic group exclusive to the Nearctic and Neotropical regions. The genus has a remarkable morphological diversity among species and strong sexual dimorphism, hampering taxonomic studies of it. Herein, we add two new species to the Neotropical fauna of Ageniella: A. caerulea sp. nov. belonging to the subgenus Ameragenia and A. ruschi sp. nov. belonging to the subgenus Priophanes; both species are described and illustrated. A brief discussion of subgeneric characters and an updated taxonomic key to the species of Ageniella known from Brazil are provided.
This work comprises the investigation of four different biosynthesis gene clusters from Xenorhabdus. Xenorhabdus is an entomopathogenic bacterium that lives in mutualistic symbiosis with its Steinernema nematode host and together they infect and kill insect larvae. Xenorhabdus is well known for the production of so-called specialised metabolites and many of these compounds are synthesised by non-ribosomal peptide synthetases (NRPSs) or NRPS-polyketide synthase (PKS)-hybrids. These enzymes are organised in a modular manner and produce structurally very diverse molecules, often with the help of modifying domains and tailoring enzymes. In general, the genes involved in the biosynthesis are organised in so-called biosynthetic gene clusters (BGCs) in the genome of the producing strain. Exchanging the native promoter with an inducible promoter, e.g. PBAD, allows the targeted activation of the BGC and in turn the analysis of the biosynthesis product via LC-MS analysis.
The first BGC investigated in this work is responsible for the biosynthesis of xenofuranones. Based on gene deletions, this work shows that the NRPS-like enzyme XfsA produces a carboxylated furanone intermediate which is subsequently decarboxylated by XfsB to yield xenofuranone B. The next step in xenofuranone biosynthesis is the O-methylation of xenofuranone B to yield xenofuranone A. A comparative proteomics approach allowed the identification of four methyltransferase candidates and subsequent gene deletions confirmed one of the candidates to be responsible for methylation of xenofuranone B. The proteome analysis was based on the comparison of X. szentirmaii WT and X. szentirmaii Δhfq because distinct levels of the methylated xenofuranone A were observed when the xfs BGC was activated in either WT or Δhfq strain. Hfq is a global transcriptional regulator whose deletion is associated with the down regulation of natural product biosynthesis in Xenorhabdus. The strong PBAD activation of the xfs BGC also allowed the detection of two novel xenofuranone derivatives which arise from incorporation of one 4-hydroxyphenylpyruvic acid as first or second building block, respectively.
PBAD based activation of the second BGC addressed in this work lead to the detection of a novel metabolite and compound purification allowed NMR-based structure elucidation. The molecule exhibits two pyrrolizidine moieties and was named pyrrolizwilline (pyrrolizidine + twin (German: “Zwilling”)). The BGC comprises seven genes and single gene deletions as well as heterologous expression in E. coli and NRPS engineering were conducted to investigate the biosynthesis. The first two genes xhpA and xhpB encode a bimodular NRPS and a monooxygenase which synthesise a pyrrolizixenamide-like structure, similar to PxaA and PxaB in pyrrolizixenamide biosynthesis. It is suggested that the acyl side chain incorporated by XhpA is removed by the α,β-hydrolase XhpG. The keto function is then reduced by two subsequent two electron reductions catalysed by XhpC and XhpD. One of these two reduced pyrrolizidine units most likely is extended with glyoxalate prior to non-enzymatic dimerisation with the second pyrrolizidine moiety. To finally yield pyrrolizwilline, L-valine is incorporated, probably by the free-standing condensation domain XhpF.
The third BGC investigated is responsible for the production of a tripeptide composed of β-D-homoserine, α-hydroxyglycine and L-valine and is referred to as glyoxpeptide. This work demonstrates that the previously observed glyoxpeptide derivative is derived from glycerol present in the culture medium. Furthermore, this work shows that the monooxygenase domain, which is found in an unusual position between motifs A8 and A9 within the adenylation domain, is responsible for the α-hydroxylation of glycine. It is suggested that the α-hydroxylation of glycine renders the tripeptide prone to hydrolysis via hemiacetal formation. Hence, the XgsC_MonoOx domain might be an interesting candidate for further NRPS engineering.
The fourth BGC addressed is responsible for the production of xildivalines and this work describes two additional derivatives which are detected only when the promoter is exchanged and activated in the X. hominickii WT strain but not in X. hominickii Δhfq. Deletion of the methyltransferase encoding gene xisE results in the production of non-methylated xildivalines. It remains to be determined when the N-methylation of L-valine takes place. It is discussed that the methyltransferase could act on the NRPS released product but also during the assembly. The peptide deformylase is not involved in the proposed biosynthesis as xildivaline production is detected in a ΔxisD strain. The PKS XisB features two adjacent, so-called tandem T domains. The inactivation of the first or the second T domain by point mutation causes decreased production titres of detected xildivalines in the respective mutant strain when compared to the wild type.
Six new species of Amblypsilopus Bigot, 1888 from the Afrotropical region are described and illustrated: A. gabonensis sp. nov. from Gabon, A. martini sp. nov., A. mufindiensis sp. nov. and A. udzungwensis sp. nov. from Tanzania, A. milleri sp. nov. from South Africa, and A. spiniscapus sp. nov. from Ivory Coast. Amblypsilopus gabonensis sp. nov. and A. spiniscapus sp. nov. are remarkable in having a setose antennal scape. Amblypsilopus martini sp. nov. and A. mufindiensis sp. nov. are peculiar in bearing very long setae on the antennal pedicel, mesonotum and scutellum. Amblypsilopus milleri sp. nov. is considered a member of the South African A. fasciatus species group despite its unmodified wing venation. The new species differ also from other similar representatives of the genus in the morphology of the male cercus and the male secondary sexual characters on the legs. The male of A. bevisi (Curran, 1927) is described for the first time. The following species described from females are considered doubtful (nomina dubia): A. flavicollis (Becker, 1923), A. rectangularis (Parent, 1937), A. sudanensis (Parent, 1939) and A. tropicalis (Parent, 1933). Amblypsilopus subfascipennis (Curran, 1926) has a strongly sinuate wing vein dm-m and is transferred to Chrysosoma Guérin-Méneville, 1831 (comb. nov.). Chrysosoma ungulatum Parent, 1941 from Príncipe with an almost straight vein dm-m is transferred to Amblypsilopus (comb. nov.). Chrysosoma centrale Becker, 1923 from Tanzania also has a straight wing vein dm-m and modified fore tarsus, being very close in habitus to A. steelei Grichanov, 1996, and is also transferred to Amblypsilopus (comb. nov.). Chrysosoma asperum Parent, 1933 from South Africa has the same characters, is almost identical to South African A. bevisi and is also transferred here to Amblypsilopus (comb. nov.) and newly synonymized with A. bevisi (syn. nov.). Presently, 66 reliable species of Amblypsilopus are known from the Afrotropical region, including 37 from the Afrotropical mainland. A revised identification key to males of species of the Afrotropical mainland is provided. New records are given for some known species. The species diversity of the Afrotropical fauna and variability of morphological characters in the genus Amblypsilopus are briefly discussed.
We describe and delimit with integrative taxonomy the new springtail species Desoria calderonis sp. nov. (Collembola: Isotomidae). This cryophilic species is strictly linked to the supraglacial stony debris of the isolated Calderone glacier (Central Apennines, Italy), one of the southernmost glaciers of Europe. Desoria calderonis sp. nov. could belong to the nivalis-complex, a group of European mountain species included in the violacea-group. Genetic analysis (COI mtDNA barcoding) confirms the morphological attribution to the genus Desoria Nicolet in Desor, 1841, but highlights that the genus, in its current definition, is polyphyletic. We specify the peculiar micro-habitat preferences and highlight the threat of extinction for this cryophilic species in the context of the ongoing climate change and subsequent risk of complete disappearance of the glacier.
We describe and delimit with integrative taxonomy the new springtail species Desoria calderonis sp. nov. (Collembola: Isotomidae). This cryophilic species is strictly linked to the supraglacial stony debris of the isolated Calderone glacier (Central Apennines, Italy), one of the southernmost glaciers of Europe. Desoria calderonis sp. nov. could belong to the nivalis-complex, a group of European mountain species included in the violacea-group. Genetic analysis (COI mtDNA barcoding) confirms the morphological attribution to the genus Desoria Nicolet in Desor, 1841, but highlights that the genus, in its current definition, is polyphyletic. We specify the peculiar micro-habitat preferences and highlight the threat of extinction for this cryophilic species in the context of the ongoing climate change and subsequent risk of complete disappearance of the glacier.
Natural products (NPs) from microorganisms have been important sources for discovering new therapeutic and chemical entities. While their corresponding biosynthetic gene clusters (BGCs) can be easily identified by gene-sequence-similarity-based bioinformatics strategies, the actual access to these NPs for structure elucidation and bioactivity testing remains difficult. Deletion of the gene encoding the RNA chaperone, Hfq, results in strains losing the production of most NPs. By exchanging the native promoter of a desired BGC against an inducible promoter in Δhfq mutants, almost exclusive production of the corresponding NP from the targeted BGC in Photorhabdus, Xenorhabdus and Pseudomonas was observed including the production of several new NPs derived from previously uncharacterized non-ribosomal peptide synthetases (NRPS). This easyPACId approach (easy Promoter Activated Compound Identification) facilitates NP identification due to low interference from other NPs. Moreover, it allows direct bioactivity testing of supernatants containing secreted NPs, without laborious purification.
Proteins encoded by small open reading frames (sORFs) have a widespread occurrence in diverse microorganisms and can be of high functional importance. However, due to annotation biases and their technically challenging direct detection, these small proteins have been overlooked for a long time and were only recently rediscovered. The currently rapidly growing number of such proteins requires efficient methods to investigate their structure–function relationship. Herein, a method is presented for fast determination of the conformational properties of small proteins. Their small size makes them perfectly amenable for solution-state NMR spectroscopy. NMR spectroscopy can provide detailed information about their conformational states (folded, partially folded, and unstructured). In the context of the priority program on small proteins funded by the German research foundation (SPP2002), 27 small proteins from 9 different bacterial and archaeal organisms have been investigated. It is found that most of these small proteins are unstructured or partially folded. Bioinformatics tools predict that some of these unstructured proteins can potentially fold upon complex formation. A protocol for fast NMR spectroscopy structure elucidation is described for the small proteins that adopt a persistently folded structure by implementation of new NMR technologies, including automated resonance assignment and nonuniform sampling in combination with targeted acquisition.
Acetogenic bacteria are a group of strictly anaerobic bacteria that may have been first life forms on Earth since they employ an ancient pathway for CO2 fixation into acetyl-CoA that is coupled to the synthesis of ATP, the Wood–Ljungdahl pathway. Electrons for CO2 reduction are derived from oxidation of H2 or CO and thus, these bacteria can grow lithotrophically on gases present on early Earth. Among the organic molecules present on early Earth is acetaldehyde, a highly volatile C2 compound. Here, we demonstrate that the acetogenic model bacterium Acetobacterium woodii grows on acetaldehyde. Acetaldehyde is dismutated to ethanol and acetyl-CoA, most likely by the bifunctional alcohol dehydrogenase AdhE. Acetyl-CoA is converted to acetate by two subsequent enzymes, phosphotransacetylase and acetate kinase, accompanied by the synthesis of ATP by substrate-level phosphorylation. Apparently, growth on acetaldehyde does not employ the Wood–Ljungdahl pathway. Our finding opens the possibility of a simple and ancient metabolic pathway with only three enzymes that allows for biomass (acetyl-CoA) and ATP formation on early Earth.
Photobleaching is a major challenge in fluorescence microscopy, in particular if high excitation light intensities are used. Signal-to-noise and spatial resolution may be compromised, which limits the amount of information that can be extracted from an image. Photobleaching can be bypassed by using exchangeable labels, which transiently bind to and dissociate from a target, thereby replenishing the destroyed labels with intact ones from a reservoir. Here, we demonstrate confocal and STED microscopy with short, fluorophore-labeled oligonucleotides that transiently bind to complementary oligonucleotides attached to protein-specific antibodies. The constant exchange of fluorophore labels in DNA-based STED imaging bypasses photobleaching that occurs with covalent labels. We show that this concept is suitable for targeted, two-color STED imaging of whole cells.