Severe Atherosclerosis and Hypercholesterolemia in Mice Lacking Both the Melanocortin Type 4 Receptor and Low Density Lipoprotein Receptor

Dysfunction of the melanocortin system can result in severe obesity accompanied with dyslipidemia and symptoms of the metabolic syndrome but the effect on vascular atherogenesis is not known. To study the impact of obesity and dyslipidemia on the cardiovascular system, we generated mice double-deficient for the melanocortin type 4 receptor (Mc4r(mut) mice) and the LDL receptor (Ldlr(-/-) mice). Mc4r(mut) mice develop obesity due to hyperphagia. Double-mutant mice (Mc4r(mut);Ldlr(-/-)) exhibited massive increases in body weight, plasma cholesterol and triacylglycerol levels and developed atherosclerosis. Atherosclerotic lesion size was affected throughout the aortic root and brachiocephalic artery not only under semisynthetic, cholesterol-containing diet but also under cholesterol-free standard chow. The Mc4r(mut) mice developed a hepatic steatosis which contributes to increased plasma cholesterol levels even under cholesterol-free standard chow. Transcripts of cholesterol biosynthesis components and liver cholesterol levels did not significantly differ between wild-type and all mutant mouse strains but RNA sequencing data and biochemical measurements point to an altered bile acid elimination in Mc4r(mut);Ldlr(-/-). Therefore, the unchanged endogenous cholesterol biosynthesis together with a reduced hepatic VLDL and LDL-cholesterol clearance most likely led to increased plasma lipid levels and consequently to atherosclerosis in this animal model. Our data indicate that dysfunction of the melanocortin-regulated food intake and the resulting obesity significantly add to the proatherogenic lipoprotein profile caused by LDL receptor deficiency and, therefore, can be regarded as relevant risk factor for atherosclerosis

Growth and differentiation of primary and passaged equine bronchial epithelial cells under conventional and air-liquid-interface culture conditions

<p>Abstract</p> <p>Background</p> <p>Horses develop recurrent airway obstruction (RAO) that resembles human bronchial asthma. Differentiated primary equine bronchial epithelial cells (EBEC) in culture that closely mimic the airway cells <it>in vivo </it>would be useful to investigate the contribution of bronchial epithelium in inflammation of airway diseases. However, because isolation and characterization of EBEC cultures has been limited, we modified and optimized techniques of generating and culturing EBECs from healthy horses to mimic <it>in vivo </it>conditions.</p> <p>Results</p> <p>Large numbers of EBEC were obtained by trypsin digestion and successfully grown for up to 2 passages with or without serum. However, serum or ultroser G proved to be essential for EBEC differentiation on membrane inserts at ALI. A pseudo-stratified muco-ciliary epithelium with basal cells was observed at differentiation. Further, transepithelial resistance (TEER) was more consistent and higher in P₁cultures compared to P₀cultures while ciliation was delayed in P₁cultures.</p> <p>Conclusions</p> <p>This study provides an efficient method for obtaining a high-yield of EBECs and for generating highly differentiated cultures. These EBEC cultures can be used to study the formation of tight junction or to identify epithelial-derived inflammatory factors that contribute to lung diseases such as asthma.</p

The Role of Human-Automation Consensus in Multiple Unmanned Vehicle Scheduling

Objective: This study examined the impact of increasing automation replanning rates on operator performance and workload when supervising a decentralized network of heterogeneous unmanned vehicles. Background: Futuristic unmanned vehicles systems will invert the operator-to-vehicle ratio so that one operator can control multiple dissimilar vehicles connected through a decentralized network. Significant human-automation collaboration will be needed because of automation brittleness, but such collaboration could cause high workload. Method: Three increasing levels of replanning were tested on an existing multiple unmanned vehicle simulation environment that leverages decentralized algorithms for vehicle routing and task allocation in conjunction with human supervision. Results: Rapid replanning can cause high operator workload, ultimately resulting in poorer overall system performance. Poor performance was associated with a lack of operator consensus for when to accept the automation’s suggested prompts for new plan consideration as well as negative attitudes toward unmanned aerial vehicles in general. Participants with video game experience tended to collaborate more with the automation, which resulted in better performance. Conclusion: In decentralized unmanned vehicle networks, operators who ignore the automation’s requests for new plan consideration and impose rapid replans both increase their own workload and reduce the ability of the vehicle network to operate at its maximum capacity. Application: These findings have implications for personnel selection and training for futuristic systems involving human collaboration with decentralized algorithms embedded in networks of autonomous systems.Aurora Flight Sciences Corp.United States. Office of Naval Researc

Establishing a Large-Scale Field Experiment to Assess the Effects of Artificial Light at Night on Species and Food Webs

Artificial light at night (ALAN) is one of the most obvious hallmarks of human presence in an ecosystem. The rapidly increasing use of artificial light has fundamentally transformed nightscapes throughout most of the globe, although little is known about how ALAN impacts the biodiversity and food webs of illuminated ecosystems. We developed a large-scale experimental infrastructure to study the effects of ALAN on a light-naïve, natural riparian (i.e., terrestrial-aquatic) ecosystem. Twelve street lights (20 m apart) arranged in three rows parallel to an agricultural drainage ditch were installed on each of two sites located in a grassland ecosystem in northern Germany. A range of biotic, abiotic, and photometric data are collected regularly to study the short- and long-term effects of ALAN on behavior, species interactions, physiology, and species composition of communities. Here we describe the infrastructure setup and data collection methods, and characterize the study area including photometric measurements. None of the measured parameters differed significantly between sites in the period before illumination. Results of one short-term experiment, carried out with one site illuminated and the other acting as a control, demonstrate the attraction of ALAN by the immense and immediate increase of insect catches at the lit street lights. The experimental setup provides a unique platform for carrying out interdisciplinary research on sustainable lighting

HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis

Background &amp; aims: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated.Methods: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44.Results: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures.Conclusions: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell-mediated destruction of the intestinal epithelium in UC

HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44⁺ Natural Killer Cells in Ulcerative Colitis

Background &amp; Aims: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated. Methods: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44. Results: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401–NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures. Conclusions: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype–dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell–mediated destruction of the intestinal epithelium in UC.</p

Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

Peer reviewe

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

Außenanlagen in der Immobilienbewertung

Diese Abschlussarbeit beschäftigt sich mit dem Thema „Außenanlagen in der Immobilienbewertung“. Hiermit soll analysiert werden, inwieweit Außenanlagen einen Werteinfluss auf den Verkehrswert bebauter Grundstücke haben. Das Ziel dieser Studie ist herauszufinden, wie Außenanlagen bisher in der Immobilienbewertung berücksichtigt werden und wie ihr Potenzial als Werttreiber gemessen werden kann. Die Fragestellungen wurden auf Auswertungen geeigneter Fachliteratur aus den Bereichen der Immobilienbewertung sowie Garten- und Landschaftsbau untersucht. Darüber hinaus haben Gespräche mit Professoren und Mitarbeitern der Hochschule Osnabrück sowie mit Fachspezialisten aus der Immobilienbranche als auch ein Experten-Interview für aufschlussreiche Diskussionen gesorgt. Im Ergebnis wird deutlich, dass Außenanlagen durch Berührung gewisser wertbestimmender Parameter einen Einfluss auf den Marktwert von Immobilien ausüben. Wie die Studien zeigen, liegt dieser Wertanteil in einer Grauzone. Dies liegt vor allem an der unklaren Abgrenzung des Außenanlagenbegriffs in der Immobilienbewertung. Um den unbekannten Werteinfluss zu ermitteln, wird mit dieser Arbeit eine Möglichkeit für eine Datenerhebung erarbeitet. Die Evaluation soll in Form einer Befragung von Immobiliensachverständigen durchgeführt werden. Zur vergleichbaren Beurteilung dient ein erarbeiteter Kriterienkatalog. Auf diese Weise soll das wertsteigernde Potenzial von Außenanlagen auf den Ertragswert einer Immobilie gemessen werden können. In der Vergangenheit erstellte Ertragswertgutachten, die zu Verkaufstransaktionen geführt haben, sollen auf dieser Grundlage ausgewertet und verglichen werden. Das Endergebnis zeigt, wie mit dieser empirischen Datenerhebung ein Fazit bezüglich des tatsächlichen Wertanteils durch Außenanlagen am Immobilienwert bestimmt werden kann.This master’s thesis examines the impact of outdoor facilities on property value. It investigates how outdoor facilities have an influence on the market value of developed real estate. The aim of this thesis is to analyse the previous considerations on the impact of outdoor facilities upon value determination and how to calculate their potential as a value driver. The answer can be revealed through research of specialist landscape construction and real estate valuation literature. Additionally, conversations with my professors, specialists, and an interview with a real estate expert have provided supporting evidence for this thesis. The result shows that outdoor facilities do have influence over market value. They affect certain parameters of value determination, which affect the property values. It is, however, apparent that the value percentage is unknown. This is due to the unclear effect of outdoor facilities in real estate valuation. To identify the unknown influence on value, this paper aims to ascertain relevant data; a survey with experts forms the basis of this evaluation while a criteria catalogue will provide a comparable assessment. Therefore, the potential increase of value can be calculated and earnings can be capitalised. Previous expert reports based on sales transactions can be evaluated and compared. The result shows how the evaluation determines the value percentage of outdoor facilities