Developing a novel 3D model of the intestinal epithelium as a tool to study the pharmacokinetics of new chemical entities

New chemical entities (NCE) are in continuous development in pharmaceutical companies across the globe, in a never-ending arms race of human ingenuity against human disease. Methods for the testing of NCEs in the past have relied on the widespread use of basic cellular epithelial equivalents, generally made by culturing a single epithelial cell line on a 2D permeable plastic membrane, and animal models for the validation of NCEs. These techniques are utilised before progression onto animal and human trials and eventual commercial availability after thorough efficacy and safety testing. The use of cell lines to create two-dimensional (2D) models of the intestinal epithelium have been the gold standard since the 1980’s. These models benefit as both a cost saving exercise due to their simplicity and in reducing the need to use animals in research. which then, as today, is both ethically important and physiologically justified because animal models are often unreliable models of human anatomy, tissue and function. However, 2D models are unable to recreate complex structural variations present in vivo, usually incorporating a single cell phenotype in a non-physiologically based system. Whilst these simple models are cheap and mass producible, their use for NCEs analysis leads to progression of poor clinical candidates to later phases of development which fail due to in vivo functional irrelevance, toxicity or poor pharmacokinetics. Newer methods have been developed which improve the in vivo characteristics of 2D models, often through inclusion of additional cells lineages, such as goblet cells to make use of their distinct functions. Likewise, paracrine effects of fibroblasts or immune cells are increasingly shown to have critical functions in directing epithelial homeostasis and development. Three-dimensional (3D) tissue equivalents, are an emerging technology able to model a number of systems in vitro, bridging the gap between 2D models and human tissues. Ultimately however, conventional 2D monoculture models such as Caco-2 remain the gold standard for pharmacokinetic and toxicity analysis of NCE. It was hypothesised that Caco-2 model phenotypes can be improved through the use of fibroblast conditioned medias and application of cell lines into a 3D model. The aim was to develop a more developed understanding of the effect of the paracrine microenvironment and 3D culture on epithelial, specifically Caco-2, phenotype. 4 Through utilisation of the Caco-2 cell line along with fibroblast cells of varying origin (Colon carcinoma, normal small intestine and skin) this study was able to create both 2D Transwell paracrine cultures and 3D models of both the intestinal epithelium and mucosae respectively. Colon derived fibroblast cells were shown to secrete significant concentrations of Keratinocyte Growth Factor (KGF) into media under normal 2D culture conditions. Moreover, the addition of paracrine factors released by fibroblast cells into culture and direct 3D co-culture allows for the creation of models with enhanced structural characteristics over Caco-2 monolayers with distinct epithelial and sub-epithelial compartmentalisation and similar structural morphologies as seen in in vivo tissues. Functionally, models were tested for their pharmacokinetic capability to a number of model compounds. Comparison of model functional between models and reported literature values for tissues and Caco-2 controls suggests that paracrine fibroblast secretome and 3D cells culture has a significant effect on Caco-2 function. Significant variation between models was observed in this study suggesting further research into the mechanistic actions behind the morphological changes seen is required

Estimating the influence of different urban canopy cover types on atmospheric particulate matter (PM10) pollution abatement in London UK

In the urban environment atmospheric pollution by PM10 (particulate matter with a diameter less than 10 x 10-6 m) is a problem that can have adverse effects on human health, particularly increasing rates of respiratory disease. The main contributors to atmospheric PM10 in the urban environment are road traffic, industry and powerproduction. The urban tree canopy is a receptor for removing PM10s from the atmosphere due to the large surface areas generated by leaves and air turbulence created by the structure of the urban forest. In this context urban greening has long been known as a mechanism to contribute towards PM10 removal from the air, furthermore, tree canopy cover has a role in contributing towards a more sustainable urban environment.The work reported here has been carried out within the BRIDGE project (SustainaBle uRban plannIng Decision support accountinG for urban mEtabolism). The aim of this project is to assess the fluxes of energy, water, carbon dioxide and particulates within the urban environment and develope a DSS (Decision Support System) to aid urban planners in sustainable development. A combination of published urban canopy cover data from ground, airborne and satellite based surveys was used. For each of the 33 London boroughs the urban canopy was classified to three groups, urban woodland, street trees and garden trees and each group quantified in terms of ground cover. The total [PM10] for each borough was taken from the LAEI (London Atmospheric Emissions Inventory 2006) and the contribution to reducing [PM10] was assessed for each canopy type. Deposition to the urban canopy was assessed using the UFORE (Urban Forest Effects Model) approach. Deposition to the canopy, boundary layer height and percentage reduction of the [PM10] in the atmosphere was assessed using both hourly meterological data and [PM10] and seasonal data derived from annual models. Results from hourly and annual data were compared with measured values. The model was then applied to future predictions of annual [PM10] and future canopy cover scenarios for London. The contribution of each canopy type subjected to the different atmospheric [PM10] of the 33 London boroughs now and in the future will be discussed. Implementing these findings into a decision support system (DSS) for sustainable urban planning will also be discussed<br/

Development of a mammalian neurosensory full‐thickness skin equivalent and its application to screen sensitizing stimuli

Human skin equivalents (HSEs) are an increasingly popular research tool due to limitations associated with animal testing for dermatological research. They recapitulate many aspects of skin structure and function, however, many only contain two basic cell types to model dermal and epidermal compartments, which limits their application. We describe advances in the field skin tissue modeling to produce a construct containing sensory-like neurons that is responsive to known noxious stimuli. Through incorporation of mammalian sensory-like neurons, we were able to recapitulate aspects of the neuroinflammatory response including secretion of substance P and a range of pro-inflammatory cytokines in response to a well-characterized neurosensitizing agent: capsaicin. We observed that neuronal cell bodies reside in the upper dermal compartment with neurites extending toward the keratinocytes of the stratum basale where they exist in close proximity to one another. These data suggest that we are able to model aspects of the neuroinflammatory response that occurs during exposure to dermatological stimuli including therapeutics and cosmetics. We propose that this skin construct can be considered a platform technology with a wide range of applications including screening of actives, therapeutics, modeling of inflammatory skin diseases, and fundamental approaches to probe underlying cell and molecular mechanisms

Cross Sector Partnerships – Development of the Chicago Region Trees Initiative

The Chicago Region Trees Initiative (CRTI) is a partnership of more than 200 organizations across the seven county Chicago metro region. The CRTI believes that trees are critical to our quality of life, and its mission is to ensure that trees are more healthy, abundant, diverse, and equitably distributed to provide needed benefits to all people and communities in the Chicago region. Our key goals are to inspire people to value trees, increase the Chicago region’s tree canopy, reduce threats to trees, and enhance oak ecosystems. The CRTI has built upon the work and programs of others, and the experience of partners to shape the urban forest in the Chicago region by 2050

Prioritization and Planning to Improve Urban Tree Health in the Chicago Region

The Chicago Region Trees Initiative (CRTI) has collected one of the largest data sets on urban forestry in the United States. This data informs where and how CRTI prioritizes its work and capacity building. This data has been incorporated into interactive online resources that communities and neighborhoods can access to help decision makers, landowners, and managers understand where and what to plant, the value of the urban forest, impacts of woody invasive species, heat island challenges, and where opportunities exist for oak ecosystem enhancement. This data helps CRTI and its partners to prioritize action

A scaling law for monocrystalline PV/T modules with CCPC and comparison with triple junction PV cells

Scaling laws serve as a tool to convert the five parameters in a lumped one-diode electrical model of a photovoltaic (PV) cell/module/panel under indoor standard test conditions (STC) into the parameters under any outdoor conditions. By using the transformed parameters, a current-voltage curve can be established under any outdoor conditions to predict the PV cell/module/panel performance. A scaling law is developed for PV modules with and without crossed compound parabolic concentrator (CCPC) based on the experimental current-voltage curves of six flat monocrystalline PV modules collected from literature at variable irradiances and cell temperatures by using nonlinear least squares method. Experiments are performed to validate the model and method on a monocrystalline PV cell at various irradiances and cell temperatures. The proposed scaling law is compared with the existing one, and the former exhibits a much better accuracy when the cell temperature is higher than 40 °C. The scaling law of a triple junction flat PV cell is also compared with that of the monocrystalline cell and the CCPC effects on the scaling law are investigated with the monocrystalline PV cell. It is identified that the CCPCs impose a more significant influence on the scaling law for the monocrystalline PV cell in comparison with the triple junction PV cell. The proposed scaling law is applied to predict the electrical performance of PV/thermal modules with CCPC

Duke Activity Status Index and Liver Frailty Index predict mortality in ambulatory patients with advanced chronic liver disease:A prospective, observational study

BACKGROUND: There remains a lack of consensus on how to assess functional exercise capacity and physical frailty in patients with advanced chronic liver disease (CLD) being assessed for liver transplantation (LT). Aim To investigate prospectively the utility of the Duke Activity Status Index (DASI) and Liver Frailty Index (LFI) in ambulatory patients with CLD.AIM: To investigate prospectively the utility of the Duke Activity Status Index (DASI) and Liver Frailty Index (LFI) in ambulatory patients with CLD.METHODS: We recruited patients from outpatient clinics at University Hospitals Birmingham, UK (2018-2019). We prospectively collated the DASI and LFI to identify the prevalence of, respectively, functional capacity and physical frailty, and to evaluate their accuracy in predicting overall and pre-LT mortality.RESULTS: We studied 307 patients (57% male; median age 54 years; UKELD 52). Median DASI score was 28.7 (IQR 16.2-50.2), mean LFI was 3.82 (SD = 0.72), and 81% were defined either 'pre-frail' or 'frail'. Female sex and hyponatraemia were significant independent predictors of both DASI and LFI. Age and encephalopathy were significant independent predictors of LFI, while BMI significantly predicted DASI. DASI and LFI were significantly related to overall (HR 0.97, p = 0.001 [DASI], HR 2.04, p = 0.001 [LFI]) and pre-LT mortality (HR 0.96, p = 0.02 [DASI], HR 1.94, p = 0.04 [LFI]).CONCLUSIONS: Poor functional exercise capacity and physical frailty are highly prevalent among ambulatory patients with CLD who are being assessed for LT. The DASI and LFI are simple, low-cost tools that predict overall and pre-LT mortality. Implementation of both should be considered in all outpatients with CLD to highlight those who may benefit from targeted nutritional and exercise interventions.</p

Duke Activity Status Index and Liver Frailty Index predict mortality in ambulatory patients with advanced chronic liver disease:A prospective, observational study

BACKGROUND: There remains a lack of consensus on how to assess functional exercise capacity and physical frailty in patients with advanced chronic liver disease (CLD) being assessed for liver transplantation (LT). Aim To investigate prospectively the utility of the Duke Activity Status Index (DASI) and Liver Frailty Index (LFI) in ambulatory patients with CLD.AIM: To investigate prospectively the utility of the Duke Activity Status Index (DASI) and Liver Frailty Index (LFI) in ambulatory patients with CLD.METHODS: We recruited patients from outpatient clinics at University Hospitals Birmingham, UK (2018-2019). We prospectively collated the DASI and LFI to identify the prevalence of, respectively, functional capacity and physical frailty, and to evaluate their accuracy in predicting overall and pre-LT mortality.RESULTS: We studied 307 patients (57% male; median age 54 years; UKELD 52). Median DASI score was 28.7 (IQR 16.2-50.2), mean LFI was 3.82 (SD = 0.72), and 81% were defined either 'pre-frail' or 'frail'. Female sex and hyponatraemia were significant independent predictors of both DASI and LFI. Age and encephalopathy were significant independent predictors of LFI, while BMI significantly predicted DASI. DASI and LFI were significantly related to overall (HR 0.97, p = 0.001 [DASI], HR 2.04, p = 0.001 [LFI]) and pre-LT mortality (HR 0.96, p = 0.02 [DASI], HR 1.94, p = 0.04 [LFI]).CONCLUSIONS: Poor functional exercise capacity and physical frailty are highly prevalent among ambulatory patients with CLD who are being assessed for LT. The DASI and LFI are simple, low-cost tools that predict overall and pre-LT mortality. Implementation of both should be considered in all outpatients with CLD to highlight those who may benefit from targeted nutritional and exercise interventions.</p

Powering West Midlands Growth: A Regional Approach to Clean Energy Innovation

The West Midlands is uniquely positioned to lead the UK in taking advantage of the economic opportunities arising from the global transition to a clean energy system. The region’s strengths include: strong and coherent political leadership committed to sustainability; the diversity of economic needs and scale of demand required to build competitive markets to support radical innovation; a world-class concentration of both academic and commercial expertise in the low-carbon energy sector; a massive programme of public and private investment in infrastructure planned for the next decade, and above all, the determination to secure long-term economic benefit from clean energy innovation. This report makes the case for the creation of a small number of Energy Innovation Zones (EIZs) across the region, acting as pathfinders for an approach that might subsequently be adopted across the country as a whole. EIZs enable barriers – such as powerful institutional silos separating transport, digital, planning and energy – to be overcome within designated geographies. They create a risk-managed and commercial-scale context for the development of new local clean energy markets. They also provide a practical mechanism to help attract investment and muster local political support. At a national level, they can help ensure innovation is built into the government’s strategic sector deals and other large scale public investment projects

Deep Underground Science and Engineering Laboratory - Preliminary Design Report

The DUSEL Project has produced the Preliminary Design of the Deep Underground Science and Engineering Laboratory (DUSEL) at the rehabilitated former Homestake mine in South Dakota. The Facility design calls for, on the surface, two new buildings - one a visitor and education center, the other an experiment assembly hall - and multiple repurposed existing buildings. To support underground research activities, the design includes two laboratory modules and additional spaces at a level 4,850 feet underground for physics, biology, engineering, and Earth science experiments. On the same level, the design includes a Department of Energy-shepherded Large Cavity supporting the Long Baseline Neutrino Experiment. At the 7,400-feet level, the design incorporates one laboratory module and additional spaces for physics and Earth science efforts. With input from some 25 science and engineering collaborations, the Project has designed critical experimental space and infrastructure needs, including space for a suite of multidisciplinary experiments in a laboratory whose projected life span is at least 30 years. From these experiments, a critical suite of experiments is outlined, whose construction will be funded along with the facility. The Facility design permits expansion and evolution, as may be driven by future science requirements, and enables participation by other agencies. The design leverages South Dakota's substantial investment in facility infrastructure, risk retirement, and operation of its Sanford Laboratory at Homestake. The Project is planning education and outreach programs, and has initiated efforts to establish regional partnerships with underserved populations - regional American Indian and rural populations