Modeling Stem/Progenitor Cell-Induced Neovascularization and\ud Oxygenation around Solid Implants

Tissue engineering constructs and other solid implants with biomedical applications, such as drug delivery devices or bioartificial organs, need oxygen (O2) to function properly. To understand better the vascular integration of such devices, we recently developed a novel model sensor containing O2-sensitive crystals, consisting of a polymeric capsule limited by a nano-porous filter. The sensor was implanted in mice with hydrogel alone (control) or hydrogel embedded with mouse CD117/c-kit+ bone marrow progenitor cells (BMPC) in order to stimulate peri-implant neovascularization. The sensor provided local partial O2 pressure (pO2) using non-invasive electron paramagnetic resonance (EPR) signal measurements. A consistently higher level of per-implant oxygenation was observed in the cell-treatment case as compared to the control over a 10-week period. In order to provide a mechanistic explanation of these experimental observations, we present in this paper a mathematical model, formulated as a system of coupled partial differential equations, that simulates peri-implant vascularization. In the control case, vascularization is considered to be the result of a Foreign Body Reaction (FBR) while in the cell-treatment case, adipogenesis in response to paracrine stimuli produced by the stem cells is assumed to induce neovascularization. The model is validated by fitting numerical predictions of local pO2 to measurements from the implanted sensor. The model is then used to investigate further the potential for using stem cell treatment to enhance the vascular integration of biomedical implants. We thus demonstrate how mathematical modeling combined with experimentation can be used to infer how vasculature develops around biomedical implants in control and stem celltreated cases

Oscillatory dynamics in a model of vascular tumour growth -- implications for chemotherapy

Background\ud \ud Investigations of solid tumours suggest that vessel occlusion may occur when increased pressure from the tumour mass is exerted on the vessel walls. Since immature vessels are frequently found in tumours and may be particularly sensitive, such occlusion may impair tumour blood flow and have a negative impact on therapeutic outcome. In order to study the effects that occlusion may have on tumour growth patterns and therapeutic response, in this paper we develop and investigate a continuum model of vascular tumour growth.\ud Results\ud \ud By analysing a spatially uniform submodel, we identify regions of parameter space in which the combination of tumour cell proliferation and vessel occlusion give rise to sustained temporal oscillations in the tumour cell population and in the vessel density. Alternatively, if the vessels are assumed to be less prone to collapse, stable steady state solutions are observed. When spatial effects are considered, the pattern of tumour invasion depends on the dynamics of the spatially uniform submodel. If the submodel predicts a stable steady state, then steady travelling waves are observed in the full model, and the system evolves to the same stable steady state behind the invading front. When the submodel yields oscillatory behaviour, the full model produces periodic travelling waves. The stability of the waves (which can be predicted by approximating the system as one of λ-ω type) dictates whether the waves develop into regular or irregular spatio-temporal oscillations. Simulations of chemotherapy reveal that treatment outcome depends crucially on the underlying tumour growth dynamics. In particular, if the dynamics are oscillatory, then therapeutic efficacy is difficult to assess since the fluctuations in the size of the tumour cell population are enhanced, compared to untreated controls.\ud Conclusions\ud \ud We have developed a mathematical model of vascular tumour growth formulated as a system of partial differential equations (PDEs). Employing a combination of numerical and analytical techniques, we demonstrate how the spatio-temporal dynamics of the untreated tumour may influence its response to chemotherapy.\ud Reviewers\ud \ud This manuscript was reviewed by Professor Zvia Agur and Professor Marek Kimmel

The FHD/ε\boldsymbol{\varepsilon}ppsilon Epoch of Reionization Power Spectrum Pipeline

Epoch of Reionization data analysis requires unprecedented levels of accuracy in radio interferometer pipelines. We have developed an imaging power spectrum analysis to meet these requirements and generate robust 21 cm EoR measurements. In this work, we build a signal path framework to mathematically describe each step in the analysis, from data reduction in the FHD package to power spectrum generation in the $\varepsilon$ppsilon package. In particular, we focus on the distinguishing characteristics of FHD/$\varepsilon$ppsilon: highly accurate spectral calibration, extensive data verification products, and end-to-end error propagation. We present our key data analysis products in detail to facilitate understanding of the prominent systematics in image-based power spectrum analyses. As a verification to our analysis, we also highlight a full-pipeline analysis simulation to demonstrate signal preservation and lack of signal loss. This careful treatment ensures that the FHD/$\varepsilon$ppsilon power spectrum pipeline can reduce radio interferometric data to produce credible 21 cm EoR measurements.Comment: 21 pages, 10 figures, accepted by PAS

Inference of the genetic network regulating lateral root initiation in Arabidopsis thaliana

Regulation of gene expression is crucial for organism growth, and it is one of the challenges in Systems Biology to reconstruct the underlying regulatory biological networks from transcriptomic data. The formation of lateral roots in Arabidopsis thaliana is stimulated by a cascade of regulators of which only the interactions of its initial elements have been identified. Using simulated gene expression data with known network topology, we compare the performance of inference algorithms, based on different approaches, for which ready-to-use software is available. We show that their performance improves with the network size and the inclusion of mutants. We then analyse two sets of genes, whose activity is likely to be relevant to lateral root initiation in Arabidopsis, by integrating sequence analysis with the intersection of the results of the best performing methods on time series and mutants to infer their regulatory network. The methods applied capture known interactions between genes that are candidate regulators at early stages of development. The network inferred from genes significantly expressed during lateral root formation exhibits distinct scale-free, small world and hierarchical properties and the nodes with a high out-degree may warrant further investigation

Short-term fluctuations in heavy metal concentrations during flood events through abandoned metal mines, with implications for aquatic ecology and mine water treatment

The variability in heavy metal concentrations and physico-chemical parameters during rain-fed river floods that pass through abandoned metal mines is poorly understood due to the difficulties of sampling these events. Such information is essential for the characterisation of contaminant dynamics and for investigations of contaminant/ecosystem relations and the effectiveness of remediation. This study investigates the role of flood flows in contaminant mobilisation and temporary increases in toxicity at an abandoned metal mine in central Wales, UK. Flood events substantially increase the potential toxicity of river water. The principal contaminants are dissolved Pb, mobilized by increased acidity resulting from the dissolution and flushing of efflourescent salts accumulated on the surface of mine spoil. The implications of flood runoff and contaminant mobilisation for aquatic ecology and mine water treatment are discussed

Stormflow hydrochemistry in a river draining an abandoned metal mine: the Afon Twymyn, central Wales

Contaminated drainage from metal mines is a serious water-quality problem facing nations that exploit metal mineral resources. Measurements of river hydrochemistry during baseflow are common at mine sites, whilst detailed hydrochemical information regarding stormflow is limited and often confined to a single event. This study investigates the seasonal evolution of stormflow hydrochemistry at an abandoned metal mine in central Wales, UK, and the possible sources and mechanisms of metal release. Significant flushing of metals was observed during stormflow events, resulting in concentrations that severely exceeded water-quality guidelines. The relationship between metal concentrations and river discharge suggests dissolution of efflorescent metal sulphates on the surface of the mine spoil as the principal source of the contamination. High fluxes of Pb during stormflows are linked to extended periods of dry weather prior to storm events that produced water table drawdown and encouraged oxidation of Pb sulphide in the mine spoil. However, some Pb flushing also occurred following wet antecedent conditions. It is suggested that Fe oxide reduction in mine spoil and translatory flows involving metal-rich pore waters results in flushing during wetter periods. Detailed measurements of stormflow hydrochemistry at mine sites are essential for accurate forecasting of long-term trends in metals flux to understand metal sources and mechanisms of release, to assess potential risks to water quality and instream ecology, and to gauge the potential effectiveness of remediation. In order to protect riverine and riparian ecosystems, it is suggested that routine monitoring of stormflows becomes part of catchment management in mining-impacted regions

Self-harm, substance use and psychological distress in the Australian general population

AIMS: To examine predictors of self-harm, especially substance use and psychological distress, in an Australian adult general population sample. DESIGN: Sequential-cohort design with follow-up every four years. SETTING: Australian general population. PARTICIPANTS: A random sample of adults aged 20-24 and 40-44 years (at baseline) living in and around the Australian Capital Territory. MEASUREMENTS: Self-report survey including items on four common forms of self-harm. Psychological distress was indexed by the combined Goldberg Anxiety and Depression scale scores and alcohol problems by the Alcohol Use Disorders Identification Test (AUDIT). FINDINGS: 4,160 people (84% of baseline) were re-interviewed at eight years: 4126 reported their self-harm status. Past year self-harm was reported by 8.2% (95% CI 7.4-9.0%) of participants (males: 9.3% (8.0-10.6%), females: 7.3% (6.2-8.4%)). Several forms of substance use – smoking (odds ratio = 1.52), marijuana use (odds ratio = 1.77), and drinking alcohol at a level likely to cause dependence (AUDIT score > 20) (odds ratio = 2.08) – were independently predictive of past year self-harm. Additional key risk factors for self-harm in the past year were childhood sexual abuse by a parent (odds ratio = 3.07), bisexual orientation (odds ratio = 2.65), younger age (odds ratio = 2.23) and male gender (odds ratio = 1.86). Other independent predictors were years of education, adverse life events, psychological distress and financial strain. CONCLUSIONS: Self-harm in young and middle-aged adults appears to be associated with current smoking, marijuana and “dependent†alcohol use. Other independent predictors include younger age, male gender, bisexual orientation, financial strain, education level, psychological distress, adverse life events and sexual abuse by a parent

The Chromospheric Activity and Ages of M Dwarf Stars in Wide Binary Systems

We investigate the relationship between age and chromospheric activity for 139 M dwarf stars in wide binary systems with white dwarf companions. The age of each system is determined from the cooling age of its white dwarf component. The current limit for activity-age relations found for M dwarfs in open clusters is 4 Gyr. Our unique approach to finding ages for M stars allows for the exploration of this relationship at ages older than 4 Gyr. The general trend of stars remaining active for a longer time at later spectral type is confirmed. However, our larger sample and greater age range reveals additional complexity in assigning age based on activity alone. We find that M dwarfs in wide binaries older than 4 Gyr depart from the log-linear relation for clusters and are found to have activity at magnitudes, colors and masses which are brighter, bluer and more massive than predicted by the cluster relation. In addition to our activity-age results, we present the measured radial velocities and complete space motions for 161 white dwarf stars in wide binaries.Comment: 22 pages including 9 figures and 5 tables. Accepted for publication in The Astronomical Journa