Search

On the backdrop of the numerous proposals for the reform of the electoral law in recent years here variations of multi-member regional constituencies are inspected, each of which elect several representatives to the German parliament (Bundestag) . This way, a stable size of parliament and proportional distribution of seats among parties can be guaranteed . Moreover, participation of electors on selecting personnel for the parliament can be intensi- fied . The authors prefer simple and efficient casting of four votes for individual candidates or one general vote for a party’s list in a regional constituency . Their specific proposal is to establish 43 regional multi-member constituencies that simultaneously are present or former administrative districts (“Regierungsbezirke”) and in case of Länder of small populations, congruent to the Land . Such a structure of constituencies aligns with people’s psychological identification with their home districts, which in many cases have existed f or centuries within the same or similar borders .

Background: There is similarity in schizophrenia and methamphetamine-induced psychosis neurobiology. Few studies have directly compared neurometabolites in thalamo-cortical circuitry across these disorders or assessed the relationship with peripheral cytokines. This study compared neurometabolites and neuronal integrity in thalamo-cortical circuitry, and investigated associations with peripheral cytokine levels in both disorders. Methods: Ninety-five participants were recruited – 36 with schizophrenia, 27 with methamphetamine-induced psychosis, and 32 healthy controls. All participants underwent a magnetic resonance imaging scan, which included magnetic resonance spectroscopy. Glutamatergic and neuroinflammatory neurometabolites were examined. Serum cytokine concentrations included Interleukin 1-beta, Interleukin-8, Interleukin-10, Tumor Necrosis Factor alpha and Interferon gamma. Parametric data were analyzed with one-way analysis of variance and non-parametric data were analyzed with Kruskal Wallis tests. Associations were determined using Spearman’s rank-order coefficient. Results: The methamphetamine-induced psychosis group had lower n-acetyl aspartate with n-acetyl-aspartyl glutamate in left dorsolateral prefrontal cortex and left frontal white matter, compared to controls. In schizophrenia, positive associations were found between glutamate and n-acetyl aspartate and n-acetyl aspartate with n-acetyl-aspartyl glutamate in the anterior cingulate cortex. In the methamphetamine-induced psychosis group, positive relationships were found between myo-inositol in the left thalamus and bilateral anterior cingulate cortex. Conclusion: In schizophrenia, there is suggestion of dysfunction in neuronal tissues in the glutamate-glutamine cycle within the thalamo-cortical circuit. In methamphetamine-induced psychosis, there is evidence of compromised neuronal integrity associated with chronic disease progression, and suggestion of aberrant neuroinflammatory regulation in the thalamus-ACC circuit. This study highlights similarities and differences in the psychobiology of the two disorders

Idiopathic pulmonary fibrosis (IPF) is a lethal and chronic lung disease characterized by aberrant intercellular communication, increased extracellular matrix (ECM) deposition, and destruction of functional lung tissue. Extracellular vesicles (EVs) accumulate within the lung in IPF, but their cargo and biological effects remain unclear. Here, we provide the entire the proteome of EV and non-EV fraction during pulmonary fibrosis, and functionally characterize their contribution to fibrosis. EVs were isolated by differential ultracentrifugation of bronchoalveolar lavage fluid (BALF) collected from mice challenged with bleomycin (or PBS as control) or culture supernatants from primary mouse lung fibroblasts. EVs were characterized by nanoparticle tracking analysis, Western Blotting, and quantitative mass spectrometry to define their proteome. EVs accumulation peaked at 14 days post-bleomycin instillation and correlated with decreased lung function. Label-free proteomics identified 107 proteins specific to fibrotic BALF-EVs. This signature was associated with wound healing, extracellular matrix organization, and cell motility. BALF-EVs from fibrotic lungs promoted fibrogenesis, including induction of ECM proteins in precision cut lung slicesex vivoand impaired alveolar epithelial cell stem cell function. Deconvolution using single cell RNA sequencing datasets revealed that fibroblasts are the major cellular source of BALF-EVs. EVs from fibroblasts were significantly enriched in Secreted Frizzled Related Protein 1 (SFRP1). In the lungs of patients with IPF, SFRP1 was significantly increased in mesenchymal cells.Sfrp1deficiency reduced the ability of fibroblast-derived EVs to potentiate bleomycin-induced lung fibrosisin vivoand led to a reduction in fibrosis marker gene expression. In sum, EVs carry specific protein cargos, such as SFRP1, to contribute to organ remodeling during fibrosis. Our data identified EVs transporting SFRP1 as a potential therapeutic target for IPF.

Kirsten rat sarcoma virus (KRAS)-mutant cancers are frequent, metastatic, lethal, and largely undruggable. While interleukin (IL)-1β and nuclear factor (NF)-κB inhibition hold promise against cancer, untargeted treatments are not effective. Here, we show that human KRAS-mutant cancers are addicted to IL-1β via inflammatory versican signaling to macrophage inhibitor of NF-κB kinase (IKK) β. Human pan-cancer and experimental NF-κB reporter, transcriptome, and proteome screens reveal that KRAS-mutant tumors trigger macrophage IKKβ activation and IL-1β release via secretory versican. Tumor-specific versican silencing and macrophage-restricted IKKβ deletion prevents myeloid NF-κB activation and metastasis. Versican and IKKβ are mutually addicted and/or overexpressed in human cancers and possess diagnostic and prognostic power. Non-oncogene KRAS/IL-1β addiction is abolished by IL-1β and TLR1/2 inhibition, indicating cardinal and actionable roles for versican and IKKβ in metastasis.

Description, Innovative high-content screening platform identified N-(2-butoxyphenyl)-3-(phenyl)acrylamides as novel antifibrotics., Fibrogenic processes instigate fatal chronic diseases leading to organ failure and death. Underlying biological processes involve induced massive deposition of extracellular matrix (ECM) by aberrant fibroblasts. We subjected diseased primary human lung fibroblasts to an advanced three-dimensional phenotypic high-content assay and screened a repurposing drug library of small molecules for inhibiting ECM deposition. Fibrotic Pattern Detection by Artificial Intelligence identified tranilast as an effective inhibitor. Structure-activity relationship studies confirmed N-(2-butoxyphenyl)-3-(phenyl)acrylamides (N23Ps) as a novel and highly potent compound class. N23Ps suppressed myofibroblast transdifferentiation, ECM deposition, cellular contractility, and altered cell shapes, thus advocating a unique mode of action. Mechanistically, transcriptomics identified SMURF2 as a potential therapeutic target network. Antifibrotic activity of N23Ps was verified by proteomics in a human ex vivo tissue fibrosis disease model, suppressing profibrotic markers SERPINE1 and CXCL8. Conclusively, N23Ps are a novel class of highly potent compounds inhibiting organ fibrosis in patients.

SummaryProtein degradation by proteasomes is important for the immune response against tumors. Antigens generated by the proteasome promote immune cell infiltration into tumors and improve tumors’ responses to immunotherapy. For example, immunoproteasomes – a subset of proteasomes induced by inflammatory signals – may improve the response of melanomas to immune checkpoint inhibitors (ICI) by eliciting tumor inflammation. Yet, it is unclear whether and how protein degradation by proteasomes impacts cancer progression and contributes to immune evasion and resistance. Here, we profile the proteasome-cleaved peptides in lung cancers and find that PSME4 serves as a novel inhibitory regulator of the immunoproteasome, playing an anti-inflammatory role in cancer. Biochemical assays combined with scRNA-seq, immunopeptidomics and in vivo analyses demonstrate that PSME4 promotes an immunosuppressive environment around the tumor and abrogates anti-tumor immunity by inhibiting antigen presentation and attenuating tumor inflammation. Furthermore, we find that PSME4 expression is correlated with responsiveness to ICI across several cancer types. Our findings suggest that PSME4-mediated regulation of proteasome activity is a novel mechanism of immune evasion in non-small-cell lung carcinoma and may be targeted therapeutically for restoring anti-tumor immunity.Graphical AbstractHighlightsMapping the degradation landscape in Non-Small Cell Lung Cancer (NSCLC) uncovers altered proteasome activity and compositionProteasome regulator PSME4 plays an anti-inflammatory role in NSCLC by attenuating immunoproteasome activityPSME4 restricts tumor antigen presentation and cytokine secretion, defining a ‘cold’ tumor environmentPSME4 drives tumor immune evasion and is associated with resistance to immunotherapy

A 52-year-old woman, who had previous bilateral subpectoral breast augmentation, underwent thoracotomy for a right upper lobe pulmonary adenocarcinoma. Seven years after her thoracic surgery, the patient noticed a reduction in her right breast volume, with shortness of breath and cough. A computed tomography study of the chest revealed intrathoracic migration of her right breast implant with no sing of capsule rupture. Subsequent video-assisted thoracoscopy confirmed this diagnosis.

BackgroundSurvival after curative resection of early-stage lung adenocarcinoma (LUAD) varies and prognostic biomarkers are urgently needed.MethodsLarge-format tissue samples from a prospective cohort of 200 patients with resected LUAD were immunophenotyped for cancer hallmarks TP53, NF1, CD45, PD-1, PCNA, TUNEL and FVIII, and were followed for a median of 2.34 (95% CI 1.71–3.49) years.ResultsUnsupervised hierarchical clustering revealed two patient subgroups with similar clinicopathological features and genotype, but with markedly different survival: “proliferative” patients (60%) with elevated TP53, NF1, CD45 and PCNA expression had 50% 5-year overall survival, while “apoptotic” patients (40%) with high TUNEL had 70% 5-year survival (hazard ratio 2.23, 95% CI 1.33–3.80; p=0.0069). Cox regression and machine learning algorithms including random forests built clinically useful models: a score to predict overall survival and a formula and nomogram to predict tumour phenotype. The distinct LUAD phenotypes were validated in The Cancer Genome Atlas and KMplotter data, and showed prognostic power supplementary to International Association for the Study of Lung Cancer tumour–node–metastasis stage and World Health Organization histologic classification.ConclusionsTwo molecular subtypes of LUAD exist and their identification provides important prognostic information.

Zusammenfassung Hintergrund Die hypertherme intrathorakale Chemotherapie (HITOC) wird bereits seit einigen Jahren in mehreren thoraxchirurgischen Kliniken angewendet. Diese Expertenempfehlung soll nun basierend auf der klinischen Erfahrung und der vorhandenen Literatur grundlegende Empfehlungen für eine standardisierte Durchführung der HITOC liefern. Material und Methode Im Zeitraum von Oktober bis Dezember 2018 wurden Empfehlungen zur Anwendung der HITOC in Deutschland durch eine Gruppe von Experten aus 5 thoraxchirurgischen Kliniken erarbeitet. Die Auswahl der Experten mit den meisten Operationen mit HITOC erfolgte anhand einer deutschlandweiten HITOC-Umfrage aus dem Jahr 2017. Die Empfehlungen basieren auf den klinischen Erfahrungen sowie wissenschaftlichen Arbeiten bzw. Daten der einzelnen Kliniken und einer aktuellen Literaturrecherche zur HITOC. Ergebnis Die Empfehlungen wurden durch alle 5 teilnehmenden Kliniken in einer Konsensusumfrage bewertet. Hieraus ergaben sich 6 Schwerpunkte mit insgesamt 17 Empfehlungen. Bei jeder Empfehlung wurde eine Konsensstärke in Prozent berechnet. Eine 100%ige Konsensstärke wurde bei der Nomenklatur (HITOC), der technischen Durchführung, dem Chemotherapeutikum, dem perioperativen Management, den Schutzmaßnahmen und den Indikationen erreicht. Als Basis-Chemotherapeutikum für die HITOC wird von allen Experten Cisplatin empfohlen, da hier die meisten klinischen Erfahrungen und Daten vorliegen. Die Dosierung von Cisplatin wird in mg/m2 Körperoberfläche (KOF) angegeben und sollte zwischen 150 und 175 mg/m2 KOF betragen. Die zusätzliche Angabe des Perfusionsvolumens (ca. 4 – 5 l) scheint für den intrathorakalen Konzentrationsgradienten eine Rolle zu spielen und sollte mit beachtet werden. Schlussfolgerung Diese Expertenempfehlungen zeigen eine standardisierte und einheitliche Durchführung der HITOC. Hierdurch sollen postoperative Komplikationen durch die HITOC vermindert und eine bessere Vergleichbarkeit der Ergebnisse ermöglicht werden.

Animal studies have shown that the striatal cholinergic system plays a role in behavioral flexibility but, until recently, this system could not be studied in humans due to a lack of appropriate noninvasive techniques. Using proton magnetic resonance spectroscopy, we recently showed that the concentration of dorsal striatal choline (an acetylcholine precursor) changes during reversal learning (a measure of behavioral flexibility) in humans. The aim of the present study was to examine whether regional average striatal choline was associated with reversal learning. A total of 22 participants (mean age = 25.2 years, range = 18–32 years, 13 female) reached learning criterion in a probabilistic learning task with a reversal component. We measured choline at rest in both the dorsal and ventral striatum using magnetic resonance spectroscopy. Task performance was described using a simple reinforcement learning model that dissociates the contributions of positive and negative prediction errors to learning. Average levels of choline in the dorsal striatum were associated with performance during reversal, but not during initial learning. Specifically, lower levels of choline in the dorsal striatum were associated with a lower number of perseverative trials. Moreover, choline levels explained interindividual variance in perseveration over and above that explained by learning from negative prediction errors. These findings suggest that the dorsal striatal cholinergic system plays an important role in behavioral flexibility, in line with evidence from the animal literature and our previous work in humans. Additionally, this work provides further support for the idea of measuring choline with magnetic resonance spectroscopy as a noninvasive way of studying human cholinergic neurochemistry. SIGNIFICANCE STATEMENT Behavioral flexibility is a crucial component of adaptation and survival. Evidence from the animal literature shows that the striatal cholinergic system is fundamental to reversal learning, a key paradigm for studying behavioral flexibility, but this system remains understudied in humans. Using proton magnetic resonance spectroscopy, we showed that choline levels at rest in the dorsal striatum are associated with performance specifically during reversal learning. These novel findings help to bridge the gap between animal and human studies by demonstrating the importance of cholinergic function in the dorsal striatum in human behavioral flexibility. Importantly, the methods described here cannot only be applied to furthering our understanding of healthy human neurochemistry, but also to extending our understanding of cholinergic disorders.

Strontium was found to be a growth-promoting additive during the precipitation of calcite from aqueous solution. This raises the question of whether growth of the isostructural magnesite is promoted by aqueous strontium ions as well. For this, the influence of Sr2+ on magnesite growth was investigated by macroscopic mixed-flow reactor experiments and hydrothermal atomic force microscopy at 100 °C. It was found that neither growth rates nor molecular step morphologies are affected by the presence of strontium. The partition coefficient of strontium between magnesite and aqueous solution K d Sr mgs = X Sr X Mg / m Sr m Mg was determined to be 50 μM and Mg:Sr ratios ≤ 60, strontianite precipitation limited Sr incorporation into growing magnesite to ~0.5 mol%. Similar amounts of Sr incorporation into calcite were reported in literature, although the partition coefficient of Sr between calcite and solution is lower than between magnesite and solution. The slow growth rates of magnesite, however, imply the use of high solution supersaturations. These conditions inevitably promote strontianite precipitation depleting the solution of Sr. In the case of calcite, fast growth rates can be achieved at low supersaturations. Such solutions are permissive of high Sr concentrations without strontianite precipitation. The magnesite growth rates measured here complete the literature data, now spanning a range of supersaturation states of more than one order of magnitude (Ω ≈ 20–240). The completed data allow for a refinement of the kinetic constants of magnesite precipitation. The fit of all rates to the function R = k (Ω − 1)n yielded the reaction order n = 1.76 ± 0.03 and the growth rate constant k = 0.015 ± 0.002 nmol m−2 s−1.

International audience; A comprehensive characterization of lung adenocarcinoma (LADC) clinical features is currently missing. We prospectively evaluated Caucasian patients with early-stage LADC. Patients with LADC diagnosed between 2011 and 2015 were prospectively assessed for lung resection with curative intent. Fifty clinical, pathologic, radiologic, and molecular variables were recorded. Patients were followed till death/study conclusion. The main findings were compared to a separate cohort from France. Of 1943 patients evaluated, 366 were enrolled (18.8%; 181 female; 75 never-smokers; 28% of registered Bavarian cases over the study period). Smoking and obstruction were significantly more prevalent in GLAD compared with adult Bavarians (P < 0.0001). Ever-smoker tumors were preferentially localized to the upper lobes. We observed 120 relapses and 74 deaths over 704 cumulative follow-up years. Median overall and disease-free survival were >7.5 and 3.6 years, respectively. Patients aged 65 years, resected >60 days postdiagnosis, with abnormal FVC/DLCO VA , N2/N3 stage, or solid histology had significantly decreased survival estimates. These were fit into a weighted locoregional LADC death risk score that outperformed pTNM7 in predicting survival in the GLAD and in our second cohort. We define the clinical gestalt of locoregional LADC and provide a new clinical tool to predict survival, findings that may aid future management and research design

Rationale: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease characterized by lung epithelial cell injury, increased (myo) fibroblast activation, and extracellular matrix deposition. Extracellular vesicles (EVs) regulate intercellular communication by carrying a variety of signaling mediators, including WNT (wingless/integrated) proteins. The relevance of EVs in pulmonary fibrosis and their potential contribution to disease pathogenesis, however, remain unexplored.Objectives: To characterize EVs and study the role of EV-bound WNT signaling in IPF.Methods: We isolated EVs from BAL fluid (BALF) from experimental lung fibrosis as well as samples from IPF, non-IPF interstitial lung disease (ILD), non-ILD, and healthy volunteers from two independent cohorts. EVs were characterized by transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. Primary human lung fibroblasts (phLFs) were used for EV isolation and analyzed by metabolic activity assays, cell counting, quantitative PCR, and Western blotting upon WNT gain- and loss-of-function studies.Measurements and Main Results: We found increased EVs, particularly exosomes, in BALF from experimental lung fibrosis as well as from patients with IPF. WNT5A was secreted on EVs in lung fibrosis and induced by transforming growth factor-beta in primary human lung fibroblasts. The phLF-derived EVs induced phLF proliferation, which was attenuated by WNT5A silencing and antibody-mediated inhibition and required intact EV structure. Similarly, EVs from IPF BALF induced phLF proliferation, which was mediated by WNT5A.Conclusions: Increased EVs function as carriers for signaling mediators, such as WNT5A, in IPF and thus contribute to disease pathogenesis. Characterization of EV secretion and composition may lead to novel approaches to diagnose and develop treatments for pulmonary fibrosis.

The mechanisms tumor cells use to hijack the immune system are largely uncharted. Here we used bioluminescent nuclear factor (NF)-κB reporter mice and macrophages to discover that metastatic tumors trigger NF-κB activation in host macrophages, dependent on mutant KRAS signaling and delivered via secretory versican. Versican activates NF-κB in tumor-associated macrophages via inhibitor of NF-κB kinase (IKK) β, resulting in release of interleukin (IL)-1β into the tumor microenvironment. Versican silencing in cancer cells or conditional IKKβ deletion in macrophages prevents myeloid NF-κB activation and metastasis. Versican is overexpressed and/or mutated in human cancers and metastatic effusions with KRAS mutations, predicts poor survival, can aid in the development of diagnostic platforms for pleural metastasis, and is druggable via toll-like receptor (TLR) 1/2 inhibition. The data indicate a cardinal role for tumor-derived versican in establishing cross-talk with macrophage IKKβ during metastasis and may foster the development of new therapies and diagnostic tools.

Dorsolateral prefrontal cortex (dlPFC) is proposed to drive brain-wide focus by biasing processing in favour of task-relevant information. A longstanding debate concerns whether this is achieved through enhancing processing of relevant information and/or by inhibiting irrelevant information. To address this, we applied transcranial magnetic stimulation (TMS) during fMRI, and tested for causal changes in information coding. Participants attended to one feature, whilst ignoring another feature, of a visual object. If dlPFC is necessary for facilitation, disruptive TMS should decrease coding of attended features. Conversely, if dlPFC is crucial for inhibition, TMS should increase coding of ignored features. Here, we show that TMS decreases coding of relevant information across frontoparietal cortex, and the impact is significantly stronger than any effect on irrelevant information, which is not statistically detectable. This provides causal evidence for a specific role of dlPFC in enhancing task-relevant representations and demonstrates the cognitive-neural insights possible with concurrent TMS-fMRI-MVPA., Jade Jackson et al. use fMRI concurrent with transcranial magnetic stimulation (TMS) in an attention task to evaluate whether the right dorsolateral prefrontal cortex (dlPFC) is involved in facilitation of relevant information, or suppression of irrelevant information. Their results suggest that the dlPFC is causally involved in processing relevant information in an attention task and highlight the utility of a dual fMRI-TMS approach.

Lung cancer is the leading cause of death among all cancer types with the most common incidence and mortality rates. The proteasome is a well-identified therapeutic target for cancer treatment. It acts as the main protein degradation system in the cell and degrades key mediators of cell growth, migration and survival. In this study, we analyzed non-tumorous and tumor tissues of patients suffering from different types of lung cancers. We observed significant upregulation of proteasome activator 200 (PA200) in tumor tissues compared to non-tumor lung samples of the same patient (Mann-Whitney U test, n=6). We also analyzed tumor tissue sections of lung cancer patients by immunohistochemistry and showed that PA200 was strongly induced in cancer cells. However, neither tumor stroma nor necrotic areas indicated expression of the activator. Importantly, PA200 is significantly increased in lung adenocarcinoma (LUAD), squamous cell lung cancer (SQCLC) compared to small cell lung cancer (SCLC) and correlated with significantly diminished survival in non-small cell lung cancer patients. Silencing of PA200 in the lung adenoma cell line A549 resulted in concerted downregulation of invasion, proliferation and metastasis-related gene expression. Our future experiments will focus on the function of PA200 in lung cancer cell growth, migration and invasion using CRISPR/Cas9 PA200 depleted A549 and H1299 cell lines. We will investigate the cellular function of modified PA200/proteasome complexes by analyzing RNA and protein signatures via RNA sequencing and mass spectrometry, respectively. We will use the power of functional assays (migration and invasion assay, colony formation assay) and address the functional role of PA200 as an oncogenic regulator in lung tumor growth and metastasis in vitro.

The airway epithelium is constantly exposed to noxious substances and respiratory disease is among the major leading causes of death worldwide. Upon airway injury, restoration of the normal lung architecture would be desirable, but the mechanisms involved in human adult lung regeneration are poorly understood. Notably, most mechanistic studies have been performed in mouse models where exposition to chemicals, most frequently naphthalene (NP) or polidocanol (PL), causes depletion of bronchial epithelial cells followed by subsequent epithelial regeneration. Given the major differences in cellular composition in the upper respiratory epithelium between humans and mice, we have set out to develop a human in vitro model for the analysis of lung injury and regeneration using primary human bronchial epithelial cells (phBECs) cultured at the air-liquid interface. In contrast to the mouse model, NP treatment in human bronchial epithelium in vitro did not induce cell death, let alone specifically deplete club cells. PL treatment, however, led to a dose-dependent loss of epithelial cells with an IC50 of 0.047% PL. Furthermore, loss of differentiated cell types such as goblet, ciliated and club cells were observed post PL treatment followed by subsequent regeneration of the human bronchial epithelium with the appearance of differentiated cell types at the expense of basal cells within two weeks. During regeneration phase, an increase in cell count was observed based on DAPI count from immunofluorescence analysis indicates proliferation. For proof-of-concept, we will next use this human in-vitro model to assess modulation of bronchial epithelial regeneration by Notch signaling.

The correspondence of cell state changes in diseased organs to peripheral protein signatures is currently unknown. Here, we generated and integrated single‐cell transcriptomic and proteomic data from multiple large pulmonary fibrosis patient cohorts. Integration of 233,638 single‐cell transcriptomes (n = 61) across three independent cohorts enabled us to derive shifts in cell type proportions and a robust core set of genes altered in lung fibrosis for 45 cell types. Mass spectrometry analysis of lung lavage fluid (n = 124) and plasma (n = 141) proteomes identified distinct protein signatures correlated with diagnosis, lung function, and injury status. A novel SSTR2+ pericyte state correlated with disease severity and was reflected in lavage fluid by increased levels of the complement regulatory factor CFHR1. We further discovered CRTAC1 as a biomarker of alveolar type‐2 epithelial cell health status in lavage fluid and plasma. Using cross‐modal analysis and machine learning, we identified the cellular source of biomarkers and demonstrated that information transfer between modalities correctly predicts disease status, suggesting feasibility of clinical cell state monitoring through longitudinal sampling of body fluid proteomes., Multi‐modal integration of single‐cell RNA‐seq data from lung tissue and proteomic data from body fluids across independent lung fibrosis patient cohorts revealed biomarker signatures that correspond with cell state changes during disease progression.

The prediction of dynamical stability of power grids becomes more important and challenging with increasing shares of renewable energy sources due to their decentralized structure, reduced inertia and volatility. We investigate the feasibility of applying graph neural networks (GNN) to predict dynamic stability of synchronisation in complex power grids using the single-node basin stability (SNBS) as a measure. To do so, we generate two synthetic datasets for grids with 20 and 100 nodes respectively and estimate SNBS using Monte-Carlo sampling. Those datasets are used to train and evaluate the performance of eight different GNN-models. All models use the full graph without simplifications as input and predict SNBS in a nodal-regression-setup. We show that SNBS can be predicted in general and the performance significantly changes using different GNN-models. Furthermore, we observe interesting transfer capabilities of our approach: GNN-models trained on smaller grids can directly be applied on larger grids without the need of retraining., Comment: 17 pages, 25 pages including appendix, 18 pictures plus tikz pictures

RATIONALE: The bronchial epithelium is constantly challenged by inhalative insults including cigarette smoke (CS), a key risk factor for lung disease. In vitro exposure of bronchial epithelial cells using CS extract (CSE) is a widespread alternative to whole CS (wCS) exposure. However, CSE exposure protocols vary considerably between studies, precluding direct comparison of applied doses. Moreover, they are rarely validated in terms of physiological response in vivo and the relevance of the findings is often unclear. METHODS: We tested six different exposure settings in primary human bronchial epithelial cells (phBECs), including five CSE protocols in comparison with wCS exposure. We quantified cell-delivered dose and directly compared all exposures using expression analysis of 10 well-established smoke-induced genes in bronchial epithelial cells. CSE exposure of phBECs was varied in terms of differentiation state, exposure route, duration of exposure, and dose. Gene expression was assessed by quantitative Real-Time PCR (qPCR) and Western Blot analysis. Cell type-specific expression of smoke-induced genes was analyzed by immunofluorescent analysis. RESULTS: Three surprisingly dissimilar exposure types, namely chronic CSE treatment of differentiating phBECs, acute CSE treatment of submerged basal phBECs, and wCS exposure of differentiated phBECs performed best, resulting in significant upregulation of seven (chronic CSE) and six (acute wCS, acute submerged CSE exposure) out of 10 genes. Acute apical or basolateral exposure of differentiated phBECs with CSE was much less effective despite similar doses used. CONCLUSIONS: Our findings provide guidance for the design of human in vitro CS exposure models in experimental and translational lung research.

BlockSystems.jl and NetworkDynamics.jl are two novel software packages which facilitate highly efficient transient stability simulations of power networks. Users may specify inputs and power system design in a convenient modular and equation-based manner without compromising on speed or model detail. Written in the high-level, high-performance programming language Julia a rich open-source package ecosystem is available, which provides state-of-the-art solvers and machine learning algorithms. Motivated by the recent interest in the Nordic inertia challenge we have implemented the Nordic5 test case and tuned its control parameters by making use of the machine learning and automatic differentiation capabilities of our software stack.