River and Ridge: Eco-Revelatory Design at Seven Islands Wildlife Refuge

Eco-revelatory design (ERD) emerged in 1998 as a reaction to polarity within the field of landscape architecture. Two predominant schools of thought, one insistently cultural and the other assertively ecological, reigned over the conceptual and theoretical dialog in landscape design and planning. The authors of ERD proposed a design theory in which landscape architecture is “intended to reveal and interpret ecological phenomena, processes and relationships” (Brown, Harkness, Johnston, 1998). Proponents of ERD recognized that landscape architecture alters and directs both cultural and ecological systems. Furthermore, they acknowledged landscape architects’ capacity to direct human experience and reveal, through design, aspects of ecology and culture. This integrated approach provides opportunity for people to place themselves in and as part of an interconnected socio-ecologic world, reinforcing the relationships between humans and the bio-geosphere. In this thesis I explore phenomenological design as a method to reveal ecological systems and comment on the cultural systems impacting them. The intention is to reveal, through design, the cultural relevance of ecological imperatives at multiple spatial and temporal scales. In design, phenomenology is a method used to understand place as a gestalt of concrete, qualitative phenomena. Phenomenological design methods will be used to explore a series of eco-revelatory design interventions along a transect loop path. The interventions seek to translate seven process indices of the sedimentary rock cycle: weathering, erosion, transport, deposition, lithification, collision, and uplift. Seven Islands Wildlife Refuge (SIWR) is the site and lens with which I will explore these concepts over a period of three seasons. SIWR is an ecologically managed peninsula along the floodplain of the French Broad River in east Knox County, TN. The site provides an uncommon opportunity to explore a landscape that appears natural, but is managed for surrounding human development and habitat

The blood vasculature instructs lymphatic patterning in a SOX7-dependent manner

Despite a growing catalog of secreted factors critical for lymphatic network assembly, little is known about the mechanisms that modulate the expression level of these molecular cues in blood vascular endothelial cells (BECs). Here, we show that a BEC-specific transcription factor, SOX7, plays a crucial role in a non-cell-autonomous manner by modulating the transcription of angiocrine signals to pattern lymphatic vessels. While SOX7 is not expressed in lymphatic endothelial cells (LECs), the conditional loss of SOX7 function in mouse embryos causes a dysmorphic dermal lymphatic phenotype. We identify novel distant regulatory regions in mice and humans that contribute to directly repressing the transcription of a major lymphangiogenic growth factor (Vegfc) in a SOX7-dependent manner. Further, we show that SOX7 directly binds HEY1, a canonical repressor of the Notch pathway, suggesting that transcriptional repression may also be modulated by the recruitment of this protein partner at Vegfc genomic regulatory regions. Our work unveils a role for SOX7 in modulating downstream signaling events crucial for lymphatic patterning, at least in part via the transcriptional repression of VEGFC levels in the blood vascular endothelium.Peer reviewe

FSP1 is a glutathione-independent ferroptosis suppressor

Ferroptosis is an iron-dependent form of necrotic cell death marked by oxidative damage to phospholipids1,2. To date, ferroptosis has been believed to be controlled only by the phospholipid hydroperoxide-reducing enzyme glutathione peroxidase 4 (GPX4)3,4 and radical-trapping antioxidants5,6. However, elucidation of the factors that underlie the sensitivity of a given cell type to ferroptosis7 is critical to understand the pathophysiological role of ferroptosis and how it may be exploited for the treatment of cancer. Although metabolic constraints8 and phospholipid composition9,10 contribute to ferroptosis sensitivity, no cell-autonomous mechanisms have been identified that account for the resistance of cells to ferroptosis. Here we used an expression cloning approach to identify genes in human cancer cells that are able to complement the loss of GPX4. We found that the flavoprotein apoptosis-inducing factor mitochondria-associated 2 (AIFM2) is a previously unrecognized anti-ferroptotic gene. AIFM2, which we renamed ferroptosis suppressor protein 1 (FSP1) and which was initially described as a pro-apoptotic gene11, confers protection against ferroptosis elicited by GPX4 deletion. We further demonstrate that the suppression of ferroptosis by FSP1 is mediated by ubiquinone (also known as coenzyme Q10 (CoQ10)): the reduced form, ubiquinol, traps lipid peroxyl radicals that mediate lipid peroxidation, whereas FSP1 catalyses the regeneration of CoQ10 using NAD(P)H. Pharmacological targeting of FSP1 strongly synergizes with GPX4 inhibitors to trigger ferroptosis in a number of cancer entities. In conclusion, the FSP1–CoQ10–NAD(P)H pathway exists as a stand-alone parallel system, which co-operates with GPX4 and glutathione to suppress phospholipid peroxidation and ferroptosis

New Insights into the Phylogeny and Molecular Classification of Nicotinamide Mononucleotide Deamidases

Nicotinamide mononucleotide (NMN) deamidase is one of the key enzymes of the bacterial pyridine nucleotide cycle (PNC). It catalyzes the conversion of NMN to nicotinic acid mononucleotide, which is later converted to NAD+ by entering the Preiss-Handler pathway. However, very few biochemical data are available regarding this enzyme. This paper represents the first complete molecular characterization of a novel NMN deamidase from the halotolerant and alkaliphilic bacterium Oceanobacillus iheyensis (OiPncC). The enzyme was active over a broad pH range, with an optimum at pH 7.4, whilst maintaining 90 % activity at pH 10.0. Surprisingly, the enzyme was quite stable at such basic pH, maintaining 61 % activity after 21 days. As regard temperature, it had an optimum at 65 °C but its stability was better below 50 °C. OiPncC was a Michaelian enzyme towards its only substrate NMN, with a Km value of 0.18 mM and a kcat/Km of 2.1 mM-1 s-1. To further our understanding of these enzymes, a complete phylogenetic and structural analysis was carried out taking into account the two Pfam domains usually associated with them (MocF and CinA). This analysis sheds light on the evolution of NMN deamidases, and enables the classification of NMN deamidases into 12 different subgroups, pointing to a novel domain architecture never before described. Using a Logo representation, conserved blocks were determined, providing new insights on the crucial residues involved in the binding and catalysis of both CinA and MocF domains. The analysis of these conserved blocks within new protein sequences could permit the more efficient data curation of incoming NMN deamidases

MaterialDigital

The MaterialDigital or BWMD dataset is an RDF data repository generated by the Use Case Metals within the framework of the MaterialDigital project. It showcases the digitalization of the aluminum permanent mold casting process, followed by a two-stage heat treatment, involving solution annealing and artificial aging by means of ontology based semantic data structures. For the purposes of the study, the casting alloy AlSi10Mg was used. In two casting campaigns, project-specific databases were established using test bars, which were subjected to mechanical and analytical material characterization. A demonstrator casting was also cast, and subjected to static bending stress on a laboratory test rig. For both casting campaigns, variations in chemical composition of the AlSi10Mg alloy were introduced with respect to the silicon and magnesium content. Accompanying the casting campaigns were casting simulations to refine model parameters through temperature measurements in the test bar mold. There were two primary objectives of the project. The first aim was to leverage the digital workflow to structure the data from the test bar characterization campaign. Individual data sets from each process step were linked together to create a comprehensive and coherent knowledge graph of the process chain, which was then transferred to a graph database. The development of a domain ontology for the process chain allowed the extraction of expert knowledge on the impact of chemical composition and heat treatment parameters on various mechanical properties from the material data space. Beyond querying metadata, the heterogeneous raw data sets could also be accessed by machines, as evidenced by tensile tests. This technology is thus transformative in its ability to capture material- and process-specific expert knowledge, serving as the basis for further data-based analyses. In practical terms, this can guide decision-making regarding the ideal heat treatment parameters given the chemical composition that will ensure the attainment of specific material strength.Fördermittelgeber: Ministerium für Wirtschaft, Arbeit und Wohnungsbau Baden-Württemberg -WM BW-In order to work with this dataset download and unzip the folder BWMD_Dataset.zip. The dataset includes the BWMD Ontology file (BWMD_Ontologie_2020-08-12.owl) in non modularized version (as legacy of the MaterialDigital project), which can be opened e.g. with the free software Protégé (https://protege.stanford.edu/about.php). The process semantic data model or generic process graph template (Graph-ProcessTemplate-bwmd-2020-05-15.kdb) is included as well and can be visualized and edited with the Inforapid KnowledgeBase Builder software (https://www.inforapid.com/en-us/). However, the main feature of the uploaded dataset is the complete BWMD RDF graph database (BWMD_full_DB_Anonymized.ttl) generated based on the generic graph template pattern for all the semantically modeled processes. Note that this file contains as well the BWMD Ontology and all the inferred generated statements with the reasoner OWL2-2RL (Optimized) from the Graph DB Free Software. To work with the BWMD RDF graph database import the file BWMD_full_DB_Anonymized.ttl in a graph instance (e.g. Graph DB Free). Once the RDF graph is imported in a local repository it is possible to further work with it and to run SPARQL queries to extract information. To facilitate the user the knowledge extraction process, two Jupyter Notebooks are included (query_mdbw.ipynb and plot_tensile_tests.ipynb) with integrated SPARQL queries. To run these Jupyter Notebooks locally, please keep in mind to download the necessary Python packages and to update the SPARQL endpoint with your own one a the name of the repository you created to import the RDF BWMD database (BWMD_full_DB_Anonymized.ttl)

The transcription factor NRF2 enhances melanoma malignancy by blocking differentiation and inducing COX2 expression

The transcription factor NRF2 is the major mediator of oxidative stress responses and is closely connected to therapy resistance in tumors harboring activating mutations in the NRF2 pathway. In melanoma, such mutations are rare, and it is unclear to what extent melanomas rely on NRF2. Here we show that NRF2 suppresses the activity of the melanocyte lineage marker MITF in melanoma, thereby reducing the expression of pigmentation markers. Intriguingly, we furthermore identified NRF2 as key regulator of immune-modulating genes, linking oxidative stress with the induction of cyclooxygenase 2 (COX2) in an ATF4-dependent manner. COX2 is critical for the secretion of prostaglandin E2 and was strongly induced by H$_2$O$_2$ or TNFα only in presence of NRF2. Induction of MITF and depletion of COX2 and PGE2 were also observed in NRF2-deleted melanoma cells in vivo. Furthermore, genes corresponding to the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coincided with immune evasion parameters in human melanoma datasets. Even in vitro, NRF2 activation or prostaglandin E2 supplementation blunted the induction of the innate immune response in melanoma cells. Transcriptome analyses from lung adenocarcinomas indicate that the observed link between NRF2 and the innate immune response is not restricted to melanoma

Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice

Ferroptosis is a non-apoptotic form of cell death induced by small molecules in specific tumour types, and in engineered cells overexpressing oncogenic RAS. Yet, its relevance in non-transformed cells and tissues is unexplored and remains enigmatic. Here, we provide direct genetic evidence that the knockout of ​glutathione peroxidase 4 (​Gpx4) causes cell death in a pathologically relevant form of ferroptosis. Using inducible ​Gpx4−/− mice, we elucidate an essential role for the glutathione/​Gpx4 axis in preventing lipid-oxidation-induced acute renal failure and associated death. We furthermore systematically evaluated a library of small molecules for possible ferroptosis inhibitors, leading to the discovery of a potent spiroquinoxalinamine derivative called ​Liproxstatin-1, which is able to suppress ferroptosis in cells, in ​Gpx4−/− mice, and in a pre-clinical model of ischaemia/reperfusion-induced hepatic damage. In sum, we demonstrate that ferroptosis is a pervasive and dynamic form of cell death, which, when impeded, promises substantial cytoprotection