111 research outputs found
The significance of planning and management of the subsurface to achieve sustainable cities
Introduction: The subsurface is the foundation upon which all cities rest. But the subsurface is not only a construction basis which provide physical space for infrastructure and the possibility to create a better surface living environment: the subsurface is a multifunctional natural resource. Apart from physical space, it provides water, energy, materials, habitats for ecosystems, support for surface life, and a repository for cultural heritage and geological archives. Currently, the subsurface is often utilised according to the “first-come-first-served” principle, which hinders possibilities to take strategic decisions on prioritisation and optimisation of competing subsurface uses, as well as fair inter- and intragenerational distribution of limited natural resources. A great disadvantage is the invisibility of the subsurface and consequently a lack of understanding of it as a multifunctional resource: the recently launched concept of geosystem services could help mitigate its underrating. Methods: In order to better acknowledge and lift forward the significance of the subsurface in achieving a sustainable future, the 17 SDGs are scrutinized in relation to the resources of subsurface, and specifically how better planning and management of the subsurface can contribute in achieving the goals. Results: Subsurface planning and management is relevant to at least seven (3, 6, 7, 9, 11, 12, 13) out of seventeen SDGs. Although the subsurface is not explicitly mentioned in the SDGs (except for aquifers), the subsurface can significantly contribute in achieving several of these goals. Conclusions: Sound planning and management of the subsurface can support the achievement of the mapped SDGs in various ways. The subsurface must be recognised as a precious and multifunctional resource which require careful planning and sensitive management in accordance with its potential and its value to society.Grant support: Swedish Research Council Formas (942-2016-50), Swedish Rock Engineering Research Foundation (BeFo 385), Swedish Institute Visby Programme (23887/2017)
Subsurface planning: Towards a common understanding of the subsurface as a multifunctional resource
In response to powerful trends in technology, resource and land supply and demand, socioeconomics and geopolitics, cities are likely to increase use of the subsurface in the near future. Indeed, the subsurface and its appropriate use have been put forward as being of crucial importance if we are to achieve resilient and sustainable cities. In recent years, quite apart from being seen primarily as a construction basis to provide physical space for infrastructure and to create a better surface living environment, the subsurface has been recognised as a multifunctional natural resource, one which provides physical space, water, energy, materials, habitats for ecosystems, support for surface life, and a repository for cultural heritage and geological archives. Currently, the subsurface is often utilised according to the “first-come-first-served” principle, which hinders possibilities to take strategic decisions on prioritisation and optimisation of competing subsurface uses, as well as fair inter- and intragenerational distribution of limited natural resources. Taking a broad international perspective, this paper investigates the subsurface as a multifunctional resource from five focal points: (1) what professionals with different backgrounds mean when using different terms related to the subsurface; (2) how professionals describe the subsurface and its multiple resources, functions and services; (3) how planning of subsurface use is supported in policy and regulations; (4) how the subsurface is included in the planning process; and (5) frameworks that can support decision-making on responsible use of the subsurface. The study reveals that the subsurface must be recognised (not only by scientists but also by decision- and policy-makers and other stakeholders) as a precious and multifunctional resource requiring careful planning and sensitive management in accordance with its potential and its value to society. Utilisation of the different subsurface functions to yield services requires careful planning and a framework to support decision-makers in achieving a balance between utilisation and preservation, and between the subsurface functions themselves in the case of outright utilisation. Further, to facilitate the necessary change towards transdisciplinary work settings in the planning process and form a platform for knowledge exchange and capacity building, there is an urgent need for a common language, i.e. mutually understandable terminology, and a common understanding, i.e. an all-inclusive view on the subsurface as a complex multifunctional resource
MIR137 is an androgen regulated repressor of an extended network of transcriptional coregulators
Androgens and the androgen receptor (AR) play crucial roles in male development and the pathogenesis and progression of prostate cancer (PCa). The AR functions as a ligand dependent transcription factor which recruits multiple enzymatically distinct epigenetic coregulators to facilitate transcriptional regulation in response to androgens. Over-expression of AR coregulators is implicated in cancer. We have shown that over-expression of KDM1A, an AR coregulator, contributes to PCa recurrence by promoting VEGFA expression. However the mechanism(s) whereby AR coregulators are increased in PCa remain poorly understood. In this study we show that the microRNA hsa-miR-137 (miR137) tumor suppressor regulates expression of an extended network of transcriptional coregulators including KDM1A/LSD1/AOF1, KDM2A/JHDM1A/FBXL11, KDM4A/JMJD2A, KDM5B JARID1B/PLU1, KDM7A/JHDM1D/PHF8, MED1/TRAP220/DRIP205 and NCoA2/SRC2/TIF2. We show that expression of miR137 is increased by androgen in LnCaP androgen PCa responsive cells and that the miR137 locus is epigenetically silenced in androgen LnCaP:C4-2 and PC3 independent PCa cells. In addition, we found that restoration of miR137 expression down-regulates expression of VEGFA, an AR target gene, which suggests a role of miR137 loss also in cancer angiogenesis. Finally we show functional inhibition of mIR137 function enhanced androgen induction of PSA/KLK3 expression. Our data indicate that miR137 functions as an androgen regulated suppressor of androgen signaling by modulating expression of an extended network of transcriptional coregulators. Therefore, we propose that epigenetic silencing of miR137 is an important event in promoting androgen signaling during prostate carcinogenesis and progression
Use of sedimentary algal pigment analyses to infer past lake-water total phosphorus concentrations
AbstractWe tested the feasibility of using sedimentary algal pigment analyses by spectral deconvolution to infer past lake-water total phosphorus concentrations. We established equations that link lake-water nutrient concentrations and sediment pigment concentrations, using a combination of calibration in both space and time, with a training set of 31 Swedish lakes. The calibration dataset yielded a significant positive relationship between total carotenoid concentrations and lake-water total phosphorus concentrations. We also compared sediment-pigment-based nutrient inferences with time series of water column monitoring data to evaluate whether temporal changes in total phosphorus concentrations are well captured by analysis of sedimentary pigments. We found that changes in pigment preservation through time can alter the relationship between concentrations of lake-water nutrients and sedimentary pigments, thus limiting the reliability of historical ecological conditions inferred from pigments in the sediment. Our data suggested that ratios of Chlorophyll derivatives to total carotenoids (CD/TC ratio) and Chlorophyll a to Chlorophyll derivatives (CPI) can be used as proxies for pigment preservation. Using our approach, inferred temporal changes in water-column total phosphorus concentrations in lakes are promising, but require further development, specifically with respect to the influence of pigment degradation in both the water column and sediments, as well as the factors that control such degradation.</jats:p
Signature-Based Small Molecule Screening Identifies Cytosine Arabinoside as an EWS/FLI Modulator in Ewing Sarcoma
BACKGROUND: The presence of tumor-specific mutations in the cancer genome represents a potential opportunity for pharmacologic intervention to therapeutic benefit. Unfortunately, many classes of oncoproteins (e.g., transcription factors) are not amenable to conventional small-molecule screening. Despite the identification of tumor-specific somatic mutations, most cancer therapy still utilizes nonspecific, cytotoxic drugs. One illustrative example is the treatment of Ewing sarcoma. Although the EWS/FLI oncoprotein, present in the vast majority of Ewing tumors, was characterized over ten years ago, it has never been exploited as a target of therapy. Previously, this target has been intractable to modulation with traditional small-molecule library screening approaches. Here we describe a gene expression–based approach to identify compounds that induce a signature of EWS/FLI attenuation. We hypothesize that screening small-molecule libraries highly enriched for FDA-approved drugs will provide a more rapid path to clinical application. METHODS AND FINDINGS: A gene expression signature for the EWS/FLI off state was determined with microarray expression profiling of Ewing sarcoma cell lines with EWS/FLI-directed RNA interference. A small-molecule library enriched for FDA-approved drugs was screened with a high-throughput, ligation-mediated amplification assay with a fluorescent, bead-based detection. Screening identified cytosine arabinoside (ARA-C) as a modulator of EWS/FLI. ARA-C reduced EWS/FLI protein abundance and accordingly diminished cell viability and transformation and abrogated tumor growth in a xenograft model. Given the poor outcomes of many patients with Ewing sarcoma and the well-established ARA-C safety profile, clinical trials testing ARA-C are warranted. CONCLUSIONS: We demonstrate that a gene expression–based approach to small-molecule library screening can identify, for rapid clinical testing, candidate drugs that modulate previously intractable targets. Furthermore, this is a generic approach that can, in principle, be applied to the identification of modulators of any tumor-associated oncoprotein in the rare pediatric malignancies, but also in the more common adult cancers
Rapid Identification of Bio-Molecules Applied for Detection of Biosecurity Agents Using Rolling Circle Amplification
Detection and identification of pathogens in environmental samples for biosecurity applications are challenging due to the strict requirements on specificity, sensitivity and time. We have developed a concept for quick, specific and sensitive pathogen identification in environmental samples. Target identification is realized by padlock- and proximity probing, and reacted probes are amplified by RCA (rolling-circle amplification). The individual RCA products are labeled by fluorescence and enumerated by an instrument, developed for sensitive and rapid digital analysis. The concept is demonstrated by identification of simili biowarfare agents for bacteria (Escherichia coli and Pantoea agglomerans) and spores (Bacillus atrophaeus) released in field
The KDM5B and KDM1A lysine demethylases cooperate in regulating androgen receptor expression and signalling in prostate cancer
Histone H3 lysine 4 (H3K4) methylation is key epigenetic mark associated with active transcription and is a substrate for the KDM1A/LSD1 and KDM5B/JARID1B lysine demethylases. Increased expression of KDM1A and KDM5B is implicated in many cancer types, including prostate cancer (PCa). Both KDM1A and KDM5B interact with AR and promote androgen regulated gene expression. For this reason, there is great interested in the development of new therapies targeting KDM1A and KDM5B, particularly in the context of castrate resistant PCa (CRPC), where conventional androgen deprivation therapies and androgen receptor signalling inhibitors are no longer effective. As there is no curative therapy for CRPC, new approaches are urgently required to suppress androgen signalling that prevent, delay or reverse progression to the castrate resistant state. While the contribution of KDM1A to PCa is well established, the exact contribution of KDM5B to PCa is less well understood. However, there is evidence that KDM5B is implicated in numerous pro-oncogenic mechanisms in many different types of cancer, including the hypoxic response, immune evasion and PI3/AKT signalling. Here we elucidate the individual and cooperative functions of KDM1A and KDM5B in PCa. We show that KDM5B mRNA and protein expression is elevated in localised and advanced PCa. We show that the KDM5 inhibitor, CPI-455, impairs androgen regulated transcription and alternative splicing. Consistent with the established role of KDM1A and KDM5B as AR coregulators, we found that individual pharmacologic inhibition of KDM1A and KDM5 by namoline and CPI-455 respectively, impairs androgen regulated transcription. Notably, combined inhibition of KDM1A and KDM5 downregulates AR expression in CRPC cells. Furthermore, combined KDM1A and KDM5 inhibition impairs PCa cell proliferation and invasion more than individual inhibition of KDM1A and KDM5B. Collectively our study has identified individual and cooperative mechanisms involving KDM1A and KDM5 in androgen signalling in PCa. Our findings support the further development of KDM1A and KDM5B inhibitors to treat advanced PCa. Further work is now required to confirm the therapeutic feasibility of combined inhibition of KDM1A and KDM5B as a novel therapeutic strategy for targeting AR positive CRPC
Coffee consumption modifies risk of estrogen-receptor negative breast cancer
10.1186/bcr2879Breast Cancer Research133R4
Existential Loneliness and end-of-life care: A Systematic Review
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88662.pdf (publisher's version ) (Closed access)Patients with a life-threatening illness can be confronted with various types of loneliness, one of which is existential loneliness (EL). Since the experience of EL is extremely disruptive, the issue of EL is relevant for the practice of end-of-life care. Still, the literature on EL has generated little discussion and empirical substantiation and has never been systematically reviewed. In order to systematically review the literature, we (1) identified the existential loneliness literature; (2) established an organising framework for the review; (3) conducted a conceptual analysis of existential loneliness; and (4) discussed its relevance for end-of-life care. We found that the EL concept is profoundly unclear. Distinguishing between three dimensions of EL-as a condition, as an experience, and as a process of inner growth-leads to some conceptual clarification. Analysis of these dimensions on the basis of their respective key notions-everpresent, feeling, defence; death, awareness, difficult communication; and inner growth, giving meaning, authenticity-further clarifies the concept. Although none of the key notions are unambiguous, they may function as a starting point for the development of care strategies on EL at the end of life.1 april 201
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