Partikelaufnahme in der Hühnerlunge

Der Aufnahmemechanismus, Weitertransport sowie Abbau von inhalierten Partikeln in der Vogellunge sind im Vergleich zur Säugerlunge weitgehend unverstanden. Dies liegt zum einen an den anatomischen Unterschieden und zum anderen an der geringeren Verfügbarkeit spezifischer Marker, insbesondere für aviäre antigenpräsentierende Zellen. Von bestimmten Bereichen der Vogellunge, wie dem follikelassoziierten Epithel (FAE) des Bronchus-assoziierten lymphatischen Gewebes (BALT) oder den Atrienepithelien, wird die Fähigkeit zur Phagozytose angenommen. Umfassende histologische Untersuchungen zur Partikelaufnahme, die dies belegen, sind jedoch nicht vorhanden. Diese Arbeit setzt sich anhand von unterschiedlichen histologischen Techniken umfassend mit der Partikelaufnahme in der Hühnerlunge auseinander. Die Versuche stellen eine histologische Annäherung an das Thema Partikelaufnahme in der Vogellunge dar und dienen als Grundlage für die Etablierung von geeigneten in vivo-Versuchs-modellen für die histologische Analyse. Aus diesem Grund – und insbesondere aus Tierschutzgründen – wurde die Applikation in Anlehnung an beschriebene Infektionsversuche kurze Zeit post mortem durchgeführt. Um die Heterogenität der Partikel in der Stallluft abzubilden, wurden unterschiedliche Partikel tracheal appliziert (Tusche, Latex-Beads, Fluoresceinisothiocyanat, Neutralrot, E. coli). Die Vitalität des Gewebes wurde anhand von Vitalitätsfärbungen bestätigt. Die Ergebnisse dieser Arbeit zeigen deutlich, dass alle eingegebenen Partikel sowie E. coli-Bakterien durch das Atrienepithel aufgenommen werden und belegen damit dessen postulierte Phagozytosefähigkeit. Entgegen den Forschungs-ergebnissen beim Säuger ist im Bereich des FAE des Hühner-BALT nur eine geringe Aufnahmekapazität für Tusche und Beads darstellbar, wohingegen FITC (Fluoresceinisothiocyanat) effektiv durch das gesamte FAE aufgenommen wird. Hinweise zum Abtransport der Partikel lassen sich aus den histologischen Befunden ableiten. Sowohl Tusche als auch Beads sind vermehrt in den interparabronchialen Septen und teilweise in der Nähe extrabronchialer germinaler Zentren (GCs) sowie den Blutgefäßen darstellbar. In den GCs älterer Tiere finden sich regelmäßig Partikelablagerungen, die teilweise positiv mit dem anti Pan-Zytokeratin-Antikörper reagieren und Federstaub entsprechen können. Die GCs können somit einen Ablageort für inhalierte Partikel darstellen, ähnlich wie dies bei Säugerlymphknoten beschrieben ist. Aufgrund dieser Ergebnisse und zum besseren Verständnis der pulmonalen GCs wurde eine dreidimensionale Rekonstruktion der GCs erstellt. Diese zeigte, dass sich die GCs der Lunge von den typisch kugeligen Milz-GCs unterscheiden und an die strukturellen Besonder-heiten der Lunge angepasst sind. Neutralrot, Kohlenstoffpartikel aus der Tusche und Beads werden den Ergebnissen der Arbeit nach durch Makrophagen bzw. dendritische Zellen im Bereich der Atriensepten aufgenommen und somit möglicherweise zellulär zu den Blutgefäßen und interparabronchialen Septen transportiert. Die interparabronchialen Septen können eine lymphatische Drainage der Lunge darstellen, der Nachweis von Lymphendothelzellen gelang mit den zur Verfügung stehenden Antikörpern allerdings nicht. Allein FITC reichert sich in den Epithelien des Primärbronchus und der Atrien an und findet sich nur vereinzelt im Bindegewebe. Die Identifizierung der FITC-assoziierten Zellen gelang mit den derzeit verfügbaren Markern jedoch nicht. Die antigenspezifische Immunantwort wurde im Rahmen einer Impfung mit dem Newcastle Disease Virus durch Genexpressionsanalysen in Abhängigkeit der verschiedenen Kompartimente der Lunge (Primärbronchus, Parenchym, Trachea) und der Milz untersucht. Die konjunktivale Impfung führt sowohl zu einer systemischen als auch pulmonalen Immunantwort in Form eines Anstiegs der B Zellen und des Enzyms AID (activation induced cytidine deaminase), das im Rahmen der germinalen Zentrumsreaktion exprimiert wird. Immunhisto-chemische Untersuchungen als Ansatz eines histologischen Verständnisses der immunologischen Vorgänge weisen hierbei sowohl auf eine Beteiligung des BALT (Anstieg der GC-Zahl) als auch auf eine schleimhautassoziierte Immunität hin (Anstieg der IgA-Sekretion). Auf den hier etablierten Versuchsmodellen aufbauend, kann der Weg inhalierter Partikel durch in vivo-Studien gezielt analysiert und die Frage nach dem Abtransport aus der Lunge nach Aufnahme durch das Atrienepithel bzw. das FAE weiterverfolgt werden.In contrast to the mammalian lung comparatively little is known about the avian respiratory immune system and the mechanisms by which inhaled particles are taken up, transported and degraded. The anatomical differences compared to the mammalian lung as well as the scarcity of known immune cell markers are complicating the analysis. Some pulmonary structures like the atrial and the follicle associated epithelium (FAE) of the bronchus associated lymphoid tissue (BALT) are suspected to be capable of endocytosis. But extensive histological studies focusing on the particle uptake in the avian lung are missing to this day. Therefore this work’s aim is to analyze the route of tracheally applied particles and to characterize the cells involved in particle uptake by histological and immunohistochemical methods. The experiments of this work represent a histological approach towards the understanding of particle uptake in the avian lung and help to establish a suitable experimental design for further histological studies on the chicken lung. Taking this into account and due to animal welfare reasons the experiments were performed post mortem on the basis of infection models of cultured lung tissue. To imitate the heterogeneity of dust particles inhaled by chickens under conventional housing conditions different types of particles were used (ink, beads, fluorescein isothiocyanate, neutral red, E. coli). The viability of the lung tissue was confirmed by neutral red as a viability marker. This work’s detailed histological study clearly shows the uptake of all applied particles, chemicals and the E. coli bacteria by the atrial epithelium, confirming its postulated phagocytic capacity. In contrast to research results concerning the mammalian BALT there is only little uptake of ink (approx. 2 µm) and latex beads (1 µm) by the FAE of the avian BALT, whereas FITC (fluorescein isothiocyanate) is taken up effectively. There is histological evidence of a possible path of particle transport after entering the lung. The carbon particles of the ink as well as the latex beads can be found in increased number inside the inter-parabronchial septa and also partly near extrabronchial germinal centers (GC) or inside the pulmonary blood vessels. GCs of older animals regularly show deposition of heterogeneous particles, which partly can be stained by the anti pan cytokeratin antibody and therefore could represent feather keratins. This finding suggests that the GCs play a role as a place of antigen presentation and deposition similar to the mammalian pulmonary lymph nodes. Furthermore neutral red, carbon particles and latex beads are taken up by macrophages and dendritic cells respectively localized within the atrial septa. Therefore the particle transport towards the interparabronchial septa, GCs or blood vessels could take place by cellular mechanisms. The interparabronchial septa could function as lymphatic vessels of the lung, though the existence of lymphatic endothelial cells could not be proven by currently available antibodies. FITC is found mainly inside the epithelium of the primary bronchus and the atria, while there is only little FITC within the connective tissue, but currently available antibodies failed to characterize the FITC associated cells. The antigen specific immune response was investigated by NDV-vaccination in consideration of the different bronchial and extrabronchial compartments (primary bronchus, parenchyma, trachea) and the spleen. The conjunctival vaccination leads both to a systemic and local immune response in terms of an increase of the gene expression of B cells and the enzyme AID (activation induced cytidine deaminase) as a marker of the germinal center reaction. Immunohistochemical analysis as a step towards understanding the pulmonary immune reaction indicates a participation of the BALT (increase of number of GCs) as well as a mucosal immunity (increase of IgA secretion). The experimental design established in this work can be used to analyze the particle uptake in the avian lung by in vivo studies and thus helps to answer the question how and where particles are transported after uptake by the atrial or follicle associated epithelium

Make Exarcheia’s Housing Affordable Again

The economic crisis that affected Greece since 2011 and European Austerity politics led to considerable cuts in the Greek public budget and shortcomings of social welfare (VAIOU & KALANDIDIS 2016: p. 462). The reduction or loss of income afflicted prosperity and pushed great parts of the population into poverty. The impacts also arose regarding housing affordability (MALOUTAS 2014: p. 159). Originally, the percentage of private ownership was higher than the share of tenants (EUROSTAT 2018). However, the crisis increased the dependence on loans and slowed down purchasing activity at the mortgage market (SABANIOTIS & HARDOUVELIS 2012: p. 3). Moreover, during the crisis, the housing taxation was raised while salaries decreased, which impeded the affordability of housing for the common people. Generally, there is no comprehensive housing policy in Greece that could support people who were not any more able to afford their homes (MALOUTAS 2014: p. 159). This is an extraordinarily relevant topic in Exarcheia, an area that can be considered as a residential neighbourhood. Still, homelessness is a significant problem as becomes apparent in the streetscape. However, there are numerous abandoned houses that form a potential that could be used for the implementation of a higher stock of affordable housing. Furthermore, the area accounts for several listed - thus protected - buildings, whose renovation underlies strict regulations, and which can hence not be adjusted for social housing. Nevertheless, an increasing share of recently opened short-time rentals (e.g. AirBnB) have also appeared for touristic reasons and have been discussed to be one cause for the withdrawal of affordable buildings from the housing market (HOST COMPLIANCE 2018). These contradictory developments affect the housing situation in Exarcheia and can thus be interpreted as a danger for affordability in the area. In this context, affordable housing is defined as “social rented, affordable rented and intermediate housing, provided to eligible households whose needs are not met by the market” (GOVERNMENT DIGITAL SERVICE 2018) with a focus on particularly vulnerable groups like low income or homeless people. The emerging questions are, why affordable housing is particularly relevant for Exarcheia and how the matter could be solved with regard to the particularity of the area. Thus, the present article shows an overview of the housing market and ongoing changes in Exarcheia (See Chapter 2). A SWOT analysis (see Chapter 3) was conducted to identify the potentials and risks for the neighbourhood of a more intense use as an affordable residential area. However, the expansion of a supply with affordable housing requires the involvement of different stakeholders which will be reflected by different scenarios of development which were considered as realistic (see Chapter 4). As to this, possible approaches will be presented in Chapter 5

Forecasting Brain Activity Based on Models of Spatio-Temporal Brain Dynamics: A Comparison of Graph Neural Network Architectures

Comprehending the interplay between spatial and temporal characteristics of neural dynamics can contribute to our understanding of information processing in the human brain. Graph neural networks (GNNs) provide a new possibility to interpret graph structured signals like those observed in complex brain networks. In our study we compare different spatio-temporal GNN architectures and study their ability to model neural activity distributions obtained in functional MRI (fMRI) studies. We evaluate the performance of the GNN models on a variety of scenarios in MRI studies and also compare it to a VAR model, which is currently often used for directed functional connectivity analysis. We show that by learning localized functional interactions on the anatomical substrate, GNN based approaches are able to robustly scale to large network studies, even when available data are scarce. By including anatomical connectivity as the physical substrate for information propagation, such GNNs also provide a multi-modal perspective on directed connectivity analysis, offering a novel possibility to investigate the spatio-temporal dynamics in brain networks

SPR biosensor based on polymer multi-mode optical waveguide and nanoparticle signal enhancement

We present a surface plasmon resonance (SPR) biosensor that is based on a planar-optical multi-mode (MM) polymer waveguide structure applied for the detection of biomolecules in the lower nano-molar (nM) range. The basic sensor shows a sensitivity of 608.6 nm/RIU when exposed to refractive index changes with a measurement resolution of 4.3 × 10−3 RIU. By combining the SPR sensor with an aptamer-functionalized, gold-nanoparticle (AuNP)-enhanced sandwich assay, the detection of C-reactive protein (CRP) in a buffer solution was achieved with a response of 0.118 nm/nM. Due to the multi-mode polymer waveguide structure and the simple concept, the reported biosensor is well suited for low-cost disposable lab-on-a-chip applications and can be used with rather simple and economic devices. In particular, the sensor offers the potential for fast and multiplexed detection of several biomarkers on a single integrated platform

Quantum field theoretic approach to neutrino oscillations in matter

We consider neutrino oscillations in non-uniform matter in a quantum field theoretic (QFT) approach, in which neutrino production, propagation and detection are considered as a single process. We find the conditions under which the oscillation probability can be sensibly defined and demonstrate how the properly normalized oscillation probability can be obtained in the QFT framework. We derive the evolution equation for the oscillation amplitude and discuss the conditions under which it reduces to the standard Schr\"odinger-like evolution equation. It is shown that, contrary to the common usage, the Schr\"odinger-like evolution equation is not applicable in certain cases, such as oscillations of neutrinos produced in decays of free pions provided that sterile neutrinos with $\Delta m^2\gtrsim 1$ eV$^2$ exist.Comment: LaTeX, 24 pages + 16 pages of appendices, 1 figure. V2: typos correcte

A search for spectral hysteresis and energy-dependent time lags from X-ray and TeV gamma-ray observations of Mrk 421

Blazars are variable emitters across all wavelengths over a wide range of timescales, from months down to minutes. It is therefore essential to observe blazars simultaneously at different wavelengths, especially in the X-ray and gamma-ray bands, where the broadband spectral energy distributions usually peak. In this work, we report on three "target-of-opportunity" (ToO) observations of Mrk 421, one of the brightest TeV blazars, triggered by a strong flaring event at TeV energies in 2014. These observations feature long, continuous, and simultaneous exposures with XMM-Newton (covering X-ray and optical/ultraviolet bands) and VERITAS (covering TeV gamma-ray band), along with contemporaneous observations from other gamma-ray facilities (MAGIC and Fermi-LAT) and a number of radio and optical facilities. Although neither rapid flares nor significant X-ray/TeV correlation are detected, these observations reveal subtle changes in the X-ray spectrum of the source over the course of a few days. We search the simultaneous X-ray and TeV data for spectral hysteresis patterns and time delays, which could provide insight into the emission mechanisms and the source properties (e.g. the radius of the emitting region, the strength of the magnetic field, and related timescales). The observed broadband spectra are consistent with a one-zone synchrotron self-Compton model. We find that the power spectral density distribution at $\gtrsim 4\times 10^{-4}$ Hz from the X-ray data can be described by a power-law model with an index value between 1.2 and 1.8, and do not find evidence for a steepening of the power spectral index (often associated with a characteristic length scale) compared to the previously reported values at lower frequencies.Comment: 45 pages, 15 figure

New Raffaelea species (Ophiostomatales) from the USA and Taiwan associated with ambrosia beetles and plant hosts

Raffaelea (Ophiostomatales) is a genus of more than 20 ophiostomatoid fungi commonly occurring in symbioses with wood-boring ambrosia beetles. We examined ambrosia beetles and plant hosts in the USA and Taiwan for the presence of these mycosymbionts and found 22 isolates representing known and undescribed lineages in Raffaelea. From 28S rDNA and β-tubulin sequences, we generated a molecular phylogeny of Ophiostomatales and observed morphological features of seven cultures representing undescribed lineages in Raffaelea s. lat. From these analyses, we describe five new species in Raffaelea s. lat.: R. aguacate, R. campbellii, R. crossotarsa, R. cyclorhipidia, and R. xyleborina spp. nov. Our analyses also identified two plantpathogenic species of Raffaelea associated with previously undocumented beetle hosts: (1) R. quercivora, the causative agent of Japanese oak wilt, from Cyclorhipidion ohnoi and Crossotarsus emancipatus in Taiwan, and (2) R. lauricola, the pathogen responsible for laurel wilt, from Ambrosiodmus lecontei in Florida. The results of this study show that Raffaelea and associated ophiostomatoid fungi have been poorly sampled and that future investigations on ambrosia beetle mycosymbionts should reveal a substantially increased diversity.The United States Department of Agriculture (USDA) Forest Service (FS)-SRS Coop agreement 14-CA-11330130-032, USDA-FS-FHP Coop agreement 12-CA-11420004-042, USDA Farm Bill agreement 12-8130-0377- CA, National Science Foundation grant DEB 1256968 and the Department of Science and Technology/ National Research Foundation Centre of Excellence in Tree Health Biotechnology (CTHB), South Africa.http://www.imafungus.orgam2017Forestry and Agricultural Biotechnology Institute (FABI)Microbiology and Plant Patholog

Free-Circulating Methylated DNA in Blood for Diagnosis, Staging, Prognosis, and Monitoring of Head and Neck Squamous Cell Carcinoma Patients: An Observational Prospective Cohort Study

Abstract BACKGROUND Circulating cell-free DNA methylation testing in blood has recently received regulatory approval for screening of colorectal cancer. Its application in other clinical settings, including staging, prognosis, prediction, and recurrence monitoring is highly promising, and of particular interest in head and neck squamous cell carcinomas (HNSCCs) that represent a heterogeneous group of cancers with unsatisfactory treatment guidelines. METHODS Short stature homeobox 2 (SHOX2) and septin 9 (SEPT9) DNA methylation in plasma from 649 prospectively enrolled patients (training study: 284 HNSCC/122 control patients; testing study: 141 HNSCC/102 control patients) was quantified before treatment and longitudinally during surveillance. RESULTS In the training study, 59% of HNSCC patients were methylation-positive at 96% specificity. Methylation levels correlated with tumor and nodal category (P &amp;lt; 0.001). Initially increased methylation levels were associated with a higher risk of death [SEPT9: hazard ratio (HR) = 5.27, P = 0.001; SHOX2: HR = 2.32, P = 0.024]. Disease recurrence/metastases were detected in 47% of patients up to 377 days earlier compared to current clinical practice. The onset of second cancers was detected up to 343 days earlier. In the testing study, sensitivity (52%), specificity (95%), prediction of overall survival (SEPT9: HR = 2.78, P = 0.022; SHOX2: HR = 2.50, P = 0.026), and correlation with tumor and nodal category (P &amp;lt;0.001) were successfully validated. CONCLUSIONS Methylation testing in plasma is a powerful diagnostic tool for molecular disease staging, risk stratification, and disease monitoring. Patients with initially high biomarker levels might benefit from intensified treatment and posttherapeutic surveillance. The early detection of a recurrent/metastatic disease or a second malignancy could lead to an earlier consecutive treatment, thereby improving patients' outcomes. </jats:sec

Hematopoietic cell transplantation in severe combined immunodeficiency : The SCETIDE 2006-2014 European cohort

Publisher Copyright: © 2021 The AuthorsBackground: Hematopoietic stem cell transplantation (HSCT) represents a curative treatment for patients with severe combined immunodeficiency (SCID), a group of monogenic immune disorders with an otherwise fatal outcome. Objective: We performed a comprehensive multicenter analysis of genotype-specific HSCT outcome, including detailed analysis of immune reconstitution (IR) and the predictive value for clinical outcome. Methods: HSCT outcome was studied in 338 patients with genetically confirmed SCID who underwent transplantation in 2006-2014 and who were registered in the SCETIDE registry. In a representative subgroup of 152 patients, data on IR and long-term clinical outcome were analyzed. Results: Two-year OS was similar with matched family and unrelated donors and better than mismatched donor HSCT (P 0.5 × 10e3/μL at +1 year were identified as independent predictors of favorable clinical and immunologic outcome. Conclusion: Recent advances in HSCT in SCID patients have resulted in improved OS and EFS in all genotypes and donor types. To achieve a favorable long-term outcome, treatment strategies should aim for optimal naive CD4 T lymphocyte regeneration.Peer reviewe

Treatment and Outcome Analysis of 639 Relapsed Non-Hodgkin Lymphomas in Children and Adolescents and Resulting Treatment Recommendations.

Despite poor survival, controversies remain in the treatment for refractory or relapsed pediatric non-Hodgkin lymphoma (r/r NHL). The current project aimed to collect international experience on the re-induction treatment of r/r NHL, hematopoietic stem cell transplantation (HSCT), risk factors associated with outcome, and to suggest treatment recommendations. Inclusion criteria were (i) refractory disease, disease progression or relapse of any NHL subtype except anaplastic large cell lymphoma, (ii) age < 18 years at initial diagnosis, (iii) diagnosis in/after January 2000. Data from 639 eligible patients were evaluable. The eight-year probability of overall survival was 34 ± 2% with highly significant differences according to NHL subtypes: 28 ± 3% for 254 Burkitt lymphoma/leukemia, 50 ± 6% for 98 diffuse large B-cell lymphomas, 57 ± 8% for 41 primary mediastinal large B-cell lymphomas, 27 ± 3% for 177 T-lymphoblastic lymphomas, 52 ± 10% for 34 precursor-B-cell lymphoblastic lymphomas and 30 ± 9% for 35 patients with rare NHL subtypes. Subtype-specific factors associated with survival and treatment recommendations are suggested. There were no survivors without HSCT, except in few very small subgroups. Conclusions: There is an urgent need to further improve survival in r/r NHL. The current study provides the largest real-world series, which underlines the role of HSCT and suggests treatment recommendations