The Neuropeptide Alpha-Melanocyte-Stimulating Hormone Is Critically Involved in the Development of Cytotoxic CD8+ T Cells in Mice and Humans

BACKGROUND: The neuropeptide alpha-melanocyte-stimulating hormone is well known as a mediator of skin pigmentation. More recently, it has been shown that alpha-melanocyte-stimulating hormone also plays pivotal roles in energy homeostasis, sexual function, and inflammation or immunomodulation. Alpha-melanocyte-stimulating hormone exerts its antiinflammatory and immunomodulatory effects by binding to the melanocortin-1 receptor, and since T cells are important effectors during immune responses, we investigated the effects of alpha-melanocyte-stimulating hormone on T cell function. METHODOLOGY/PRINCIPAL FINDINGS: T cells were treated with alpha-melanocyte-stimulating hormone, and subsequently, their phenotype and function was analyzed in a contact allergy as well as a melanoma model. Furthermore, the relevance of alpha-melanocyte-stimulating hormone-mediated signaling for the induction of cytotoxicity was assessed in CD8(+) T cells from melanoma patients with functional and nonfunctional melanocortin-1 receptors. Here we demonstrate that the melanocortin-1 receptor is expressed by murine as well as human CD8(+) T cells, and we furthermore show that alpha-melanocyte-stimulating hormone/melanocortin-1 receptor-mediated signaling is critical for the induction of cytotoxicity in human and murine CD8(+) T cells. Upon adoptive transfer, alpha-melanocyte-stimulating hormone-treated murine CD8(+) T cells significantly reduced contact allergy responses in recipient mice. Additionally, the presented data indicate that alpha-melanocyte-stimulating hormone via signaling through a functional melanocortin-1 receptor augmented antitumoral immunity by up-regulating the expression of cytotoxic genes and enhancing the cytolytic activity in tumor-specific CD8(+) T cells. CONCLUSIONS/SIGNIFICANCE: Together, these results point to an important role of alpha-melanocyte-stimulating hormone in MHC class I-restricted cytotoxicity. Therefore, treatment of contact allergies or skin cancer with alpha-melanocyte-stimulating hormone or other more stable agonists of melanocortin-1 receptor might ameliorate disease or improve antitumoral immune responses

From Pixels to Planning: Large-scale Mapping of Urban Morphology and Population Distribution with the World Settlement Footprint 3D

Urban morphology and human population distribution are two interrelated aspects of our urbanization that play a critical role in shaping the sustainability, resilience and liveability of cities. In recent years, the advent of global datasets with 3D information derived from Earth Observation (EO) technologies has revolutionised our ability to study and analyse these two aspects of urbanisation, providing information that is essential for designing cities that can accommodate the needs of their residents while minimizing their environmental impact. One such dataset is the novel World Settlement Footprint 3D (WSF3D) produced by the German Aerospace Center (DLR). The WSF3D was the first global dataset providing detailed information of the fraction, area, average height and total volume of buildings, at unprecedented spatial resolution, coverage and consistency. Since its development, researchers from different organizations (e.g. WorldBank, United Nations, WorldPop) have employed the dataset as input data for large-scale studies in urban morphology and population distribution, with a level of detail that was previously impossible. In this paper we present a selection of WSF3D-driven applications with the objective of demonstrating how the new data can be used to support urban planning and management. First, the WSF3D has been employed to demonstrate how the four layers of the dataset can be used to determine a building's functional use, and how this information can be leveraged to improve large-scale models of population distribution at large-scale. Thereafter, the WSF3D has been used to determine the relationships among building height/volume, population density and income, which can provide insights into the efficient use of space (e.g. crowding vs layering) on the one hand, and shed light into infrastructure disparities and variations, on the other. With that being said, due to the global nature of the WSF3D dataset, the previous analyses were conducted from local to regional scales, which can also help identify opportunities for interventions that can be replicated across different locations. Overall, with the results of this research, the authors aim to provide planners and policy-makers with valuable insights into usability of the globally available WSF3D dataset. By demonstrating its potential as reliable and robust input data, this study seeks not only to empower evidence-based decision-making, but also to advocate for the widespread adoption of geospatial layers in the implementation of strategies towards sustainable development strategies of the built environment

From Pixels to Planning: Large-scale Mapping of Urban Morphology and Population Distribution with the World Settlement Footprint 3D

Urban morphology and human population distribution are two interrelated aspects of our urbanization that play a critical role in shaping the sustainability, resilience and liveability of cities. In recent years, the advent of global datasets with 3D information derived from Earth Observation (EO) technologies has revolutionised our ability to study and analyse these two aspects of urbanisation, providing information that iS essential for designing cities that can accommodate the needs of their residents while minimizing their environmental impact. One such dataset is the novel World Settlement Footprint 3D (WSF3D) produced by the German Aerospace Center (DLR). The WSF3D was the first global dataset providing detailed information of the fraction, area, average height and total volume of buildings, at unprecedented spatial resolution, coverage and consistency. Since its development, researchers from different organizations (e.g. WorldBank, United Nations, WorldPop) have employed the dataset as input data for large-scale studies in urban morphology and population distribution, with a level of detail that was previously impossible. In this paper we present a selection of WSF3D-driven applications with the objective of demonstrating how the new data can be used to support urban planning and management. First, the WSF3D has been employed to demonstrate how the four layers of the dataset can be used to determine a building's functional use, and how this information can be leveraged to improve large-scale models of population distribution at large-scale. Thereafter, the WSF3D has been used to determine the relationships among building height/volume, population density and income, which can provide insights into the efficient use of space (e.g. crowding vs layering) on the one hand, and shed light into infrastructure disparities and variations, on the other. With that being said, due to the global nature of the WSF3D dataset, the previous analyses were conducted from local to regional scales, which can also help identify opportunities for interventions that can be replicated across different locations. Overall, with the results of this research, the authors aim to provide planners and policy-makers with valuable insights into usability of the globally available WSF3D dataset. By demonstrating its potential as reliable and robust input data, this study seeks not only to empower evidence-based decision-making, but also to advocate for the widespread adoption of geospatial layers in the implementation of strategies towards sustainable development strategies of the built environment

World Settlement Footprint 3D - A first three-dimensional survey of the global building stock

Settlements, and in particular cities, are at the center of key future challenges related to global change and sustainable development. Widely used indicators to assess the efficiency and sustainability of settlement development are the compactness and density of the built-up area. However, at global scale, a temporally consistent and spatially detailed survey of the distribution and concentration of the building stock – meaning the total area and volume of buildings within a defined spatial unit or settlement, commonly referred to as building density – does not yet exist. To fill this data and knowledge gap, an approach was developed to map key characteristics of the world’s building stock in a so far unprecedented level of spatial detail for every single settlement on our planet. The resulting World Settlement Footprint 3D dataset quantifies the fraction, total area, average height, and total volume of buildings for a measuring grid with 90 m cell size. The World Settlement Footprint 3D is generated using a modified version of the World Settlement Footprint human settlements mask derived from Sentinel-1 and Sentinel-2 satellite imagery at 10 m spatial resolution, in combination with 12 m digital elevation data and radar imagery collected by the TanDEM-X mission. The underlying, automated processing framework includes three basic workflows: one estimating the mean building height based on an analysis of height differences along potential building edges, a second module determining the building fraction and total building area within each 90 m cell, and a third part combining the height information and building area in order to determine the average height and total built-up volume at 90 m gridding. Optionally, a simple 3D building model (level of detail 1) can be generated for regions where data on the building footprints is available. A comprehensive validation campaign based on 3D building models obtained for 19 regions (~86,000 km2) and street-view samples indicating the number of floors for >130,000 individual buildings in 15 additional cities documents that the novel World Settlement Footprint 3D data provides valuable and, for the first time, globally consistent information on key characteristics of the building stock in both, large urban agglomerations as well as small-scale rural settlements. Thus, the new dataset represents a promising baseline dataset for a wide range of previously impossible environmental, socioeconomic, and climatological studies worldwide

Large-scale 3D Modelling of the Built Environment - Joint Analysis of TanDEM-X, Sentinel-2 and Open Street Map Data

Continental to global scale mapping of the human settlement extent based on earth observation satellite data has made considerable progress. Nevertheless, the current approaches only provide a two-dimensional representation of the built environment. Therewith, a full characterization is restricted in terms of the urban morphology and built-up density, which can only be gained by a detailed examination of the vertical settlement extent. This paper introduces a methodology for the extraction of three-dimensional (3D) information on human settlements by analyzing the digital elevation and radar intensity data collected by the German TanDEM-X satellite mission in combination with multispectral Sentinel-2 imagery and data from the Open Street Map initiative and the Global Urban Footprint human settlement mask. The first module of the underlying processor generates a normalized digital surface model from the TanDEM-X digital elevation model for all regions marked as a built-up area by the Global Urban Footprint. The second module generates a building mask based on a joint processing of Open Street Map, TanDEM-X/TerraSAR-X radar images, the calculated normalized digital surface model and Sentinel-2 imagery. Finally, a third module allocates the local relative heights of the normalized digital surface model to the building structures provided by the building mask. The outcome of the procedure is a 3D map of the built environment showing the estimated local height for all identified vertical building structures at 12 m spatial resolution. The results of a first validation campaign based on reference data collected for the seven cities of Amsterdam (NL), Indianapolis (US), Kigali (RW), Munich (DE), New York (US), Vienna (AT), and Washington (US) indicate the potential of the proposed methodology to accurately estimate the distribution of building heights within the built-up area

Rehabilitative Versorgung und gesundheitsbedingte Frühberentung von Personen mit Migrationshintergrund in Deutschland: Abschlussbericht

Dieser Abschlussbericht stellt die Ergebnisse des Projektes "Rehabilitative Versorgung und gesundheitsbedingte Frühberentung von Personen mit Migrationshintergrund in Deutschland" vor. Auf Basis eines quantitativen und qualitativen Forschungszugangs wurde untersucht, inwiefern sich einzelne Gruppen von ausländischen Staatsangehörigen bzw. Menschen mit Migrationshintergrund hinsichtlich der Häufigkeit von Arbeitsunfällen und Berufskrankheiten, der Inanspruchnahme beruflicher und medizinischer Rehabilitationsmaßnahmen, des Rehabilitationserfolges und der Frühberentung von Deutschen bzw. Menschen ohne Migrationshintergrund unterscheiden. Unter Bezugnahme auf Prozess- und Individualdaten unterschiedlicher Rehabilitationsträger zeigt der Bericht, dass Menschen mit Migrationshintergrund im Durchschnitt weniger häufig Maßnahmen der medizinischen Rehabilitation in Anspruch nehmen sowie einen geringeren Rehabilitationserfolg und höhere Frühberentungsquoten aufweisen als die Mehrheitsbevölkerung. Auf Basis einer systematischen Literaturrecherche und mittels qualitativer Experten- und Fokusgruppeninterviews werden darüber hinaus unterschiedliche Zugangs-, Durchführungs- und Wirksamkeitsbarrieren in der Rehabilitation von Menschen mit Migrationshintergrund identifiziert, welche die quantitativen Ergebnisse zumindest teilweise erklären können. Handlungsempfehlungen für die Verbesserung der rehabilitativen Versorgung von Menschen mit Migrationshintergrund werden abgeleitet

Tumor Transcriptome Sequencing Reveals Allelic Expression Imbalances Associated with Copy Number Alterations

Due to growing throughput and shrinking cost, massively parallel sequencing is rapidly becoming an attractive alternative to microarrays for the genome-wide study of gene expression and copy number alterations in primary tumors. The sequencing of transcripts (RNA-Seq) should offer several advantages over microarray-based methods, including the ability to detect somatic mutations and accurately measure allele-specific expression. To investigate these advantages we have applied a novel, strand-specific RNA-Seq method to tumors and matched normal tissue from three patients with oral squamous cell carcinomas. Additionally, to better understand the genomic determinants of the gene expression changes observed, we have sequenced the tumor and normal genomes of one of these patients. We demonstrate here that our RNA-Seq method accurately measures allelic imbalance and that measurement on the genome-wide scale yields novel insights into cancer etiology. As expected, the set of genes differentially expressed in the tumors is enriched for cell adhesion and differentiation functions, but, unexpectedly, the set of allelically imbalanced genes is also enriched for these same cancer-related functions. By comparing the transcriptomic perturbations observed in one patient to his underlying normal and tumor genomes, we find that allelic imbalance in the tumor is associated with copy number mutations and that copy number mutations are, in turn, strongly associated with changes in transcript abundance. These results support a model in which allele-specific deletions and duplications drive allele-specific changes in gene expression in the developing tumor

Nanomaterials for Neural Interfaces

This review focuses on the application of nanomaterials for neural interfacing. The junction between nanotechnology and neural tissues can be particularly worthy of scientific attention for several reasons: (i) Neural cells are electroactive, and the electronic properties of nanostructures can be tailored to match the charge transport requirements of electrical cellular interfacing. (ii) The unique mechanical and chemical properties of nanomaterials are critical for integration with neural tissue as long-term implants. (iii) Solutions to many critical problems in neural biology/medicine are limited by the availability of specialized materials. (iv) Neuronal stimulation is needed for a variety of common and severe health problems. This confluence of need, accumulated expertise, and potential impact on the well-being of people suggests the potential of nanomaterials to revolutionize the field of neural interfacing. In this review, we begin with foundational topics, such as the current status of neural electrode (NE) technology, the key challenges facing the practical utilization of NEs, and the potential advantages of nanostructures as components of chronic implants. After that the detailed account of toxicology and biocompatibility of nanomaterials in respect to neural tissues is given. Next, we cover a variety of specific applications of nanoengineered devices, including drug delivery, imaging, topographic patterning, electrode design, nanoscale transistors for high-resolution neural interfacing, and photoactivated interfaces. We also critically evaluate the specific properties of particular nanomaterials—including nanoparticles, nanowires, and carbon nanotubes—that can be taken advantage of in neuroprosthetic devices. The most promising future areas of research and practical device engineering are discussed as a conclusion to the review.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64336/1/3970_ftp.pd

Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial

Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council