GPNN: Power Studies and Applications of a Neural Network Method for Detecting Gene-Gene Interactions in Studies of Human Disease

The identification and characterization of genes that influence the risk of common, complex multifactorial disease primarily through interactions with other genes and environmental factors remains a statistical and computational challenge in genetic epidemiology. We have previously introduced a genetic programming optimized neural network (GPNN) as a method for optimizing the architecture of a neural network to improve the identification of gene combinations associated with disease risk. The goal of this study was to evaluate the power of GPNN for identifying high-order gene-gene interactions. We were also interested in applying GPNN to a real data analysis in Parkinson\u27s disease

Power of grammatical evolution neural networks to detect gene-gene interactions in the presence of error

<p>Abstract</p> <p>Background</p> <p>With the advent of increasingly efficient means to obtain genetic information, a great insurgence of data has resulted, leading to the need for methods for analyzing this data beyond that of traditional parametric statistical approaches. Recently we introduced Grammatical Evolution Neural Network (GENN), a machine-learning approach to detect gene-gene or gene-environment interactions, also known as epistasis, in high dimensional genetic epidemiological data. GENN has been shown to be highly successful in a range of simulated data, but the impact of error common to real data is unknown. In the current study, we examine the power of GENN to detect interesting interactions in the presence of noise due to genotyping error, missing data, phenocopy, and genetic heterogeneity. Additionally, we compare the performance of GENN to that of another computational method – Multifactor Dimensionality Reduction (MDR).</p> <p>Findings</p> <p>GENN is extremely robust to missing data and genotyping error. Phenocopy in a dataset reduces the power of both GENN and MDR. GENN is reasonably robust to genetic heterogeneity and find that in some cases GENN has substantially higher power than MDR to detect functional loci in the presence of genetic heterogeneity.</p> <p>Conclusion</p> <p>GENN is a promising method to detect gene-gene interaction, even in the presence of common types of error found in real data.</p

Sand dams as a potential solution to rural water security in drylands: Existing research and future opportunities

Sand dams, a rainwater harvesting technique, are small dams constructed across ephemeral streams. During the rainy season, water is stored in the sand that accumulates behind the dam. Sand dams provide communities in drylands with water during the dry season via scoop holes, pools, and shallow wells. Whilst many studies portray sand dams as a positive solution to the growing threat of dryland water insecurity, others highlight their challenges, including poor water quality, evaporation and leakage from some dams, and the contested failure rate and ability of dams to provide water year-round. This article reviews the peer-reviewed and gray literature on sand dams discovered through Scopus and Google Scholar searches, reference lists, and personal contacts. Findings from the collected literature were reviewed and categorized into sand dam hydrology, health and well-being impacts, economic cost and benefits, and water quality topics. In most numerical simulations, sand dams supply water to the local community throughout much of the dry season and exhibit a long-term positive impact on groundwater. Accounts of water storage and loss based on field measurements, conversely, often show that most water is lost due to evapotranspiration and seepage from the sand reservoir rather than community use. Furthermore, the positive impact on local groundwater storage, while variable, is likely seasonal. Sand dams are relatively affordable to build; construction estimates range from 6,000 to 8,500 EUR. However, existing literature suggests that sand dams are likely not a cost-efficient means of supplying water. Nevertheless, successful sand dams can significantly increase water availability and use, whilst reducing traveling time for water collection, subsequently providing a host of secondary benefits from improved hygiene, economic opportunity, and education. Positive impacts, however, are not equally shared and depend on variables, such as abstraction method, catchment, and household location. Furthermore, their water quality is variable, with high microbiological levels detected especially in scoop holes. Whilst sand dams can increase water security and resilience, they may not be an inclusive solution for all. More research is needed to assess the long-term sustainability of sand dams while accounting for the uncertainty of a changing climate

Boron Phosphate and Aluminum Phosphate Aerogels

Anhydrous sol-gel condensation of triethyl phosphate [(CH3CH2O)3PO] with boron trichloride (BCL3 ) or triethyl aluminum [(CH3CH2 ) 3A1] in organic solvents, led to formation of metallophosphate gels. The pore fluid of the gels was removed under supercritical conditions in a pressurized vessel to form aerogels. The aerogels were then calcined at progressively higher temperatures to produce high surface area phosphates. Since the initial gel reagent mixtures contained several NMR active nuclei, the condensation chemistry prior to the gel point was monitored by solution nB NMR. The surface areas, distribution of pore sizes, and total pore volumes of the aerogel products were determined using nitrogen gas physisorption methods

Synthesis of Passerini-3CR Polymers and Assembly into Cytocompatible Polymersomes

© 2020 The Authors. Published by Wiley-VCH GmbH The versatility of the Passerini three component reaction (Passerini-3CR) is herein exploited for the synthesis of an amphiphilic diblock copolymer, which self-assembles into polymersomes. Carboxy-functionalized poly(ethylene glycol) methyl ether is reacted with AB-type bifunctional monomers and tert-butyl isocyanide in a single process via Passerini-3CR. The resultant diblock copolymer (P1) is obtained in good yield and molar mass dispersity and is well tolerated in model cell lines. The Passerini-3CR versatility and reproducibility are shown by the synthesis of P2, P3, and P4 copolymers. The ability of the Passerini P1 polymersomes to incorporate hydrophilic molecules is verified by loading doxorubicin hydrochloride in P1DOX polymersomes. The flexibility of the synthesis is further demonstrated by simple post-functionalization with a dye, Cyanine-5 (Cy5). The obtained P1-Cy5 polymersomes rapidly internalize in 2D cell monolayers and penetrate deep into 3D spheroids of MDA-MB-231 triple-negative breast cancer cells. P1-Cy5 polymersomes injected systemically in healthy mice are well tolerated and no visible adverse effects are seen under the conditions tested. These data demonstrate that new, biodegradable, biocompatible polymersomes having properties suitable for future use in drug delivery can be easily synthesized by the Passerini-3CR

A 3D Heterotypic Breast Cancer Model Demonstrates a Role for Mesenchymal Stem Cells in Driving a Proliferative and Invasive Phenotype

Previous indirect 2D co-culture studies have demonstrated that mesenchymal stem cells (MSCs) promote breast cancer (BC) progression through secretion of paracrine factors including growth factors, cytokines and chemokines. In order to investigate this aspect of the tumour microenvironment in a more relevant 3D co-culture model, spheroids incorporating breast cancer cells (BCCs), both cell lines and primary BCCs expanded as patient-derived xenografts, and MSCs were established. MSCs in co-cultures were shown to enhance proliferation of estrogen receptor (ER)/progesterone receptor (PR)-positive BCCs. In addition, co-culture resulted in downregulation of E-cadherin in parallel with upregulation of the epithelial-mesenchymal transition (EMT)-relation transcription factor, SNAIL. Cytoplasmic relocalization of ski-related novel protein N (SnON), a negative regulator of transforming growth factor-beta (TGF-&beta;) signalling, and of &beta;-catenin, involved in a number of pathways including Wnt signalling, was also observed in BCCs in co-cultures in contrast to monocultures. In addition, the &beta;-catenin inhibitor, 3-[[(4-methylphenyl)sulfonyl]amino]-benzoic acid methyl ester (MSAB), mediated reduced growth and invasion in the co-cultures. This study highlights the potential role for SnON as a biomarker for BC invasiveness, and the importance of interactions between TGF-&beta; and Wnt signalling, involving SnON. Such pathways may contribute towards identifying possible targets for therapeutic intervention in BC patients

The Mental Health Benefits of Purposeful Activities in Public Green Spaces in Urban and Semi-Urban Neighbourhoods : A Mixed-Methods Pilot and Proof of Concept Study

Access and exposure to public green space might be critical to health promotion and prevention of mental ill health. However, it is uncertain if differential health and mental health benefits are associated with undertaking different activities in public green space. We evaluated the health and wellbeing benefits of different activities in different locations of public green spaces in urban and semi-urban areas. We used a mixed-methods before-and-after design. Volunteers at three conservation sites were recruited and took part in group guided walks, practical conservation tasks or citizen science. Repeated measures one-way ANOVAs with Bonferroni correction assessed the relationship between location and activity type on change in acute subjective mood from pre- to post-activity, measured with the UWIST Mood Adjective Checklist (UWIST-MACL). Qualitative semi-structured interviews were undertaken and analysed thematically to explore participants&rsquo; perceptions about the health and wellbeing benefits of activities in public green space. Forty-five participants were recruited, leading to 65 independent observations. Walking, conservation and citizen science in public green space were associated with improved mood. Across all participants acute subjective mood improved across all domains of the UWIST-MACL. There was a significant association between reduction in stress and location (p = 0.009). Qualitatively participants reported that conservation and citizen science conferred co-benefits to the environment and individual health and well-being and were perceived as purposeful. Undertaking purposeful activity in public green space has the potential to promote health and prevent mental ill health

Group interventions to improve health outcomes : a framework for their design and delivery

Peer reviewedPublisher PD

Modulation of the tumour promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma

Background and aims: Esophageal adenocarcinoma (EAC) is chemoresistant in the majority of cases. The tumor-promoting biology of cancer associated fibroblasts (CAF) make them a target for novel therapies. Phosphodiesterase type 5 inhibitors (PDE5i) have been shown to regulate the activated fibroblast phenotype in benign disease. We investigated the potential for CAF modulation in EAC using PDE5i to enhance the efficacy of chemotherapy. Methods: EAC fibroblasts were treated with PDE5i and phenotypic effects examined using immunoblotting, immunohistochemistry, gel contraction, transwell invasion, organotypics, single cell RNAseq and shotgun proteomics. The combination of PDE5i with standard-of-care chemotherapy (Epirubicin, 5-Fluorouracil and Cisplatin) was tested for safety and efficacy in validated near-patient model systems (3D tumor growth assays (3D-TGAs) and patient derived xenograft (PDX) mouse models). Results: PDE5i treatment reduced alpha-SMA expression in CAFs by 50% (p<0.05), associated with a significant reduction in the ability of CAFs to contract collagen-1 gels and induce cancer cell invasion, (p<0.05). RNAseq and proteomic analysis of CAF and EAC cell lines revealed PDE5i specific regulation of pathways related to fibroblast activation and tumor promotion. 3D-TGA assays confirmed the importance of stromal cells to chemoresistance in EAC, which could be attenuated by PDE5i. Chemotherapy+PDE5i in PDX-bearing mice was safe and significantly reduced PDX tumor volume (p<0.05). Conclusion: PDE5 is a candidate for clinical trials to alter the fibroblast phenotype in esophageal cancer. We demonstrate the specificity of PDE5i for fibroblasts to prevent transdifferentiation and revert the CAF phenotype. Finally, we confirm the efficacy of PDE5i in combination with chemotherapy in close-to-patient in vitro and in vivo PDX-based model systems