An Investigation Of Gene Networks Influenced By Low Dose Ionizing Radiation Using Statistical And Graph Theoretical Algorithms

Increased application of radiation in health and security sectors has raised concerns about its deleterious effects. Ionizing radiation (IR) less than 10cGys is considered low dose ionizing radiation (LDIR) by the National Research Committee to assess health risks from exposure to low levels of IR. It is hard to extract the effects of mild stimulus such as LDIR on gene expression profiles using simple differential expression. We hypothesized that differential correlation instead would capture the effects of LDIR on mutual relationships between genes. We tested this hypothesis on expression profiles from five inbred strains of mice treated with LDIR. Whereas ANOVA detected little effect of LDIR on gene expression, a differential correlation graph generated by a two stage statistical filter revealed gene networks enriched with genes implicated in radiation response, DNA damage repair, apoptosis, cancer and immune system. To mimic the effects of radiation on human populations, we profiled baseline expression of recombinant inbred strains of BXD mice derived from a cross between C57BL/6J and DBA/2J standard inbred strains. To establish a threshold for extraction of gene networks from the baseline expression profiles, we compared gene enrichment in paracliques obtained at different absolute Pearson correlations (APC) using graph algorithms. Gene networks extracted at statistically significant APC (r≈0.41) exhibited even better enrichment of genes participating in common biological processes than networks extracted at higher APCs from 0.6 to 0.875. Since immune response is influenced by LDIR, we investigated the effects of genetic background on variability of immune system in a population of BXD mice. Considering immune response as a complex trait, we identified significant QTLs explaining the ratio of CD8+ and CD4+ T-cells. Multiple regression modeling of genes neighboring statistically significant QTLs identified three candidate genes (Ptprk,Acp1 and Lamb1-1) explaining 61% variance of ratio of CD4+ and CD8+ T cells. Expression profiling of parental strains of BXD mice also revealed effects of LDIR and LDIR*strain on expression of genes related to immune response. Thus using an integrated approach involving transcriptomic, SNP and immunological data, we have developed novel methods to pinpoint candidate gene networks putatively influenced by LDIR

Rule-Based Cell Systems Model of Aging using Feedback Loop Motifs Mediated by Stress Responses

Investigating the complex systems dynamics of the aging process requires integration of a broad range of cellular processes describing damage and functional decline co-existing with adaptive and protective regulatory mechanisms. We evolve an integrated generic cell network to represent the connectivity of key cellular mechanisms structured into positive and negative feedback loop motifs centrally important for aging. The conceptual network is casted into a fuzzy-logic, hybrid-intelligent framework based on interaction rules assembled from a priori knowledge. Based upon a classical homeostatic representation of cellular energy metabolism, we first demonstrate how positive-feedback loops accelerate damage and decline consistent with a vicious cycle. This model is iteratively extended towards an adaptive response model by incorporating protective negative-feedback loop circuits. Time-lapse simulations of the adaptive response model uncover how transcriptional and translational changes, mediated by stress sensors NF-κB and mTOR, counteract accumulating damage and dysfunction by modulating mitochondrial respiration, metabolic fluxes, biosynthesis, and autophagy, crucial for cellular survival. The model allows consideration of lifespan optimization scenarios with respect to fitness criteria using a sensitivity analysis. Our work establishes a novel extendable and scalable computational approach capable to connect tractable molecular mechanisms with cellular network dynamics underlying the emerging aging phenotype

Lay perceptions of health, housing and community on the Kent Coast, England

Lay perceptions of health inequalities are becoming increasingly important in developing local housing strategies and many coastal areas have attracted recent attention because of high levels of deprivation. This paper draws from the findings of 14 socioeconomically and geographically representative focus groups as part of the wider French British Interreg IIIA project examining health inequalities and health behaviours in South East England and Northern France. Kent coastal areas were identified as being of particular and unique interest, leading to a wider literature review of socio-economic and health inequalities more generally in coastal towns and the effect of geography on health. Participants in the focus groups particularly suggested that the loss of traditional industries – notably the holiday trade (tourism), but also other local employment – had led to new low-income, deprived communities, including immigrant communities, whose needs often went unmet. Participants identified the changing nature of coastal or seaside housing from guest house to residential living accommodation and the relationship to the benefit system as being of particular concern, affecting both physical and mental health and the wider environment. However, participants also described successful local community-led regeneration solutions which could run alongside new local authority responsibilities to tackle health inequalities. The focus group findings suggest that lay perceptions are in many ways close to recent governmental research findings which identify the coastal regions as unique environments, some with similar levels of deprivation to inner urban and rural areas and lacking sufficient public investment. The results of this study suggest that the public have additional concerns around housing allocation policies creating marginal coastal communities and how these needs might be addressed. New strategies need to involve the communities affected. Although this can prove challenging, there is a new range of legislative provisions to tackle complex and multifaceted housing, social, economic and environmental conditions faced by those suffering some of the most acute health inequalities

Potential benefits of Glycyrrhiza glabra (Liquorice) herb, its chemical make-up and significance in safeguarding poultry health: Current scientific knowledge

Positive results have been seen when bioactive components from herbal plants are added to poultry diets. Efficacy in feeding, digestion of nutrients, antioxidant health, immunological indices, and other factors can all be improved with the help of these additives, which in turn increases growth rates and improves poultry welfare. Several researchers have used sophisticated herbal formulae that included Glycyrrhiza glabra (Liquorice) as an ingredient. Epidemic illnesses, mainly in the respiratory, digestive, and immunological systems, pose the greatest threat to the poultry business. Flavonoids and glycyrrhizin are two of the bioactive compounds in Liquorice. The roots of this plant contain glycyrrhizin at concentrations of 1-9%, which has numerous pharmacological benefits, including anti-infectious, antioxidant, antiviral, and anti-inflammatory properties. Liquorice extracts are helpful in the treatment of multiple common illnesses. These include problems with the liver, the lungs, and the immunological system. Adding Liquorice to chicken diets improves their productivity in several ways, including fostering organ growth and stimulating digestion and appetite. Liquorice has many beneficial effects on birds, including helping them grow larger bodies, cleansing their systems, and protecting them from free radicals, bacteria, and inflammation. In this article, we'll look at the chemical make-up of liquorice herb, its role in protecting poultry health, and its recent applications and benefits

Physiological processes of inflammation and edema initiated by sustained mechanical loading in subcutaneous tissues : a scoping review

Deep tissue injuries are pressure ulcers which initiate in the subcutaneous tissues and extend through a bottom-up pathway. Once deep tissue injuries are visual at skin level, serious irreversible tissue damage has already occurred. In pressure ulcer development, inflammation and edema are coupled physiological processes associated with tissue damage arising due to sustained mechanical loading. This study aimed to provide an in-depth overview of the physiological processes of inflammation and edema initiated by sustained mechanical loading in subcutaneous tissues, in the context of pressure ulceration. A scoping review was performed according to the framework by Arksey and O'Malley. The databases MEDLINE, EMBASE, Web of Science, and Scopus, and the reference lists of included studies were searched for in vivo (animal, human), and in vitro studies matching the study objectives (from inception to 28 May 2018). No restrictions for inclusion were applied for study design, setting, participants, and year of publication. A total of 12 studies were included, varying in study design, sample characteristics, amount and duration of mechanical loads that were applied, follow-up time, and assessment methods. Neutrophil infiltration and edema occur in the subcutaneous tissues nearly immediately after the application of load on soft tissues. The amount of neutrophils and edema increase in the first days after the mechanical insult and decrease once healing has been initiated and no supplementary mechanical load was applied. One study indicated that edema may extend up to the level of the dermo-epidermal junction. Further research should focus on how deep tissue inflammation and edema are reflected into unique tissue changes at skin level, and how abnormal inflammatory responses manifest (e.g. when the nervous system is not functioning normally)

Space-Occupying Brain Lesions, Trauma-Related Tau Astrogliopathy, and ARTAG: A Report of Two Cases and a Literature Review

Astrocytes with intracellular accumulations of misfolded phosphorylated tau protein have been observed in advanced-stage chronic traumatic encephalopathy (CTE) and in other neurodegenerative conditions. There is a growing awareness that astrocytic tau inclusions are also relatively common in the brains of persons over 70 years of age-affecting approximately one-third of autopsied individuals. The pathologic hallmarks of aging-related tau astrogliopathy (ARTAG) include phosphorylated tau protein within thorn-shaped astrocytes (TSA) in subpial, subependymal, perivascular, and white matter regions, whereas granular-fuzzy astrocytes are often seen in gray matter. CTE and ARTAG share molecular and histopathologic characteristics, suggesting that trauma-related mechanism(s) may predispose to the development of tau astrogliopathy. There are presently few experimental systems to study the pathobiology of astrocytic-tau aggregation, but human studies have made recent progress. For example, leucotomy (also referred to as lobotomy) is associated with a localized ARTAG-like neuropathology decades after the surgical brain injury, suggesting that chronic brain injury of any type may predispose to later life ARTAG. To examine this idea in a different context, we report clinical and pathologic features of two middle-aged men who came to autopsy with large (\u3e 6 cm in greatest dimension) arachnoid cysts that had physically displaced and injured the subjects\u27 left temporal lobes through chronic mechanical stress. Despite the similarity of the size and location of the arachnoid cysts, these individuals had dissimilar neurologic outcomes and neuropathologic findings. We review the evidence for ARTAG in response to brain injury, and discuss how the location and molecular properties of astroglial tau inclusions might alter the physiology of resident astrocytes. These cases and literature review point toward possible mechanism(s) of tau aggregation in astrocytes in response to chronic brain trauma

Dopamine neurotoxicity, oxidative stress and schizophrenia : in vitro and in vivo studies of peroxisomal reactions to increased dopamine

Signs of neurodegeneration are commonly found in schizophrenic patients, albeit still unclear, why they occur and whether they are a cause or rather an effect of schizophrenia. Although there are numerous studies supporting either theory, the working hypothesis of this thesis is that an overactivity of mesolimbic dopaminergic pathways leads to dopamine neurotoxicity in terms of an increased production of reactive oxygen species (ROS), in time leading to oxidative stress and thereby to so-called atypical neurodegeneration. This in turn negatively influences i.a. frontal glutamate neurotransmission, thereby linking the proposed schizophrenia-models of hyperdopaminergia and hypoglutamatergia. A key player in the body’s antioxidant capacity is the peroxisome. This cell organelle is involved in both enzymatic (e.g. through the H2O2-degrading enzyme catalase) as well as non-enzymatic antioxidant metabolism. Its role in schizophrenia has, however, only been poorly examined, even though peroxisomes additionally are the only known source to-date of major enzymes for the degradation of cofactors of NMDA-receptors (including NMDA itself). Changes in peroxisomal metabolism and abundance therefore influence both the brain’s capacity to degrade ROS as well as the functionality of its NMDA receptors and vice versa. This thesis therefore examines the reactions of peroxisomes to increased dopamine. Since peroxisomes are involved in a number of other metabolic functions apart from antioxidant defense, their enzyme content is highly heterogeneous. Catalase and ABCD3 are generally used as markers for peroxisomes. Their abundance is, however, highly dependent on metabolic demands and therefore varies extremely between as well as within different organs, tissues and cells. Especially in the brain, both catalase and ABCD3 are barely detectable, thereby leading to a marked underestimation of true peroxisomal abundance and distribution. In the first part of this thesis it was therefore attempted to establish a new peroxisomal marker, peroxin 14 (Pex14p), which is part of a docking complex on the peroxisomal membrane relevant for import of all matrix proteins and therefore independent of individual peroxisomal metabolism. Using various morphological methods in a large variety of organs, tissues and cell types from a number of different species it could be shown that Pex14p is indeed present in the membrane of every healthy peroxisome and is expressed in similarly high levels in tissue sections and cell cultures of different organs and species. As Pex14p is also highly suited as a peroxisomal marker in all neuronal tissue, post mortem brain sections of schizophrenic patients and controls were analyzed regarding the abundance and distribution of peroxisomes as well as catalase. The results were, however, inconclusive, wherefore the reactions of peroxisomes to increased dopamine were analyzed under more controllable conditions within the second part of this thesis. The effects of dopamine in vitro were examined using primary murine neuronal and astrocyte cell cultures and the in vivo-effects in a pharmacological mouse model (through subchronic systemic administration of the selective, non-competitive NMDAR-antagonist MK-801). Analyses of gene expression patterns from the brains of the animals show i.a. an activation of antioxidant pathways in MK-801-treated animals compared to vehicle-treated controls as well as an increase in mRNA copies of enzymes involved in NMDAR-cofactor degradation. Morphological experiments show that dopamine changes peroxisomal reactions and neuronal morphology specifically and only in intact neuron-astrocyte interactions, mimicking the atypical neurodegeneration found in schizophrenic patients. Additionally, increased levels of selected antioxidant enzymes were found to be increased in the brains of MK-801-treated animals. It can therefore be concluded that dopamine does indeed lead to increased ROS production in the brain, which is, however, initially still countered by an increase in antioxidant defense mechanisms. This strengthens the initial hypothesis that oxidative stress (i.e. the state of disequilibrium between ROS production and antioxidant defense) is an effect rather than a cause of schizophrenia. Finally, the dopamine-related increase in the expression of genes encoding for enzymes degrading NMDAR-cofactors, thereby leading to a decrease of NMDAR-mediated neurotransmission, shows that hyperdopaminergia and hypoglutamatergia in schizophrenia are not separate entities, but rather influence, uphold and even exacerbate each other. This led to the proposition of a new integrative model of the etiopathogenesis of schizophrenia, linking both hyperdopaminergia and hypoglutamatergia together.Bezüglich der bei Schizophrenen gefundenen Neurodegeneration ist die Frage nach Ursache und Wirkung unklar. Viele Befunde erlauben jedoch die Hypothese, dass, aufgrund einer Überaktivität des mesolimbischen Dopaminsystems, innerhalb und außerhalb der Neurone eine neurotoxische Wirkung des Dopamins und seiner Metaboliten im Sinne der Produktion reaktiver Sauerstoffspezies (ROS) auftritt. Neben den Mitochondrien und dem Zytoplasma spielt das Peroxisom eine wesentliche Rolle in der enzymatischen (z.B. durch Katalase) und nicht-enzymatischen antioxidativen Abwehr. Die Konzentration des klassischen peroxisomalen Markerenzyms Katalase ist jedoch in Neuronen ausgesprochen niedrig, weshalb im ersten Schritt der Arbeit ein neues Markerprotein für Peroxisomen (Peroxin 14, Pex14p) an einer Vielzahl verschiedener Gewebe und Zellen mittels Proteinlabelingmethoden für Elektronen-, Licht- und Fluoreszenzmiskroskopie etabliert wurde. Über diese neue Methode war es nun möglich, Peroxisomen auch im Nervengewebe unabhängig ihres Katalasegehaltes zu untersuchen. Wir haben daher die Anzahl an Peroxisomen und Katalase an postmortem Hippokampusschnitten von Schizophrenen und Kontrollen verglichen. Aufgrund methodologischer Einschränkungen waren die Befunde jedoch uneindeutig. Im nächsten Schritt wurden Mischkulturen muriner Neurone und Astrozyten mit unterschiedlichen Dopaminkonzentrationen inkubiert, wonach sich eine Erhöhung der Katalasemenge vor allem in Astrozyten, begleitet von einer Umverteilung der Peroxisomen aus den Dendriten in die Somata ohne signifikante Zelltoderhöhung zeigte. Wir wiederholten diese Experimente daher mit reinen Astrozytenkulturen und fanden selbst bei Erhöhung der Dopaminkonzentration und Inkubationsdauer keine Unterschiede zu Vehikel-behandelten Kulturen. Dies spricht für die antitoxische Wirkung der Astrozyten und die Spezifität der Reaktionen aus den ersten Zellkulturen für intakte neuroastrozytäre Verbände. In darauf aufbauenden Tierversuchen untersuchten wir die Erhöhung des mesolimbischen Dopamins in männlichen Wildtypmäusen durch Gabe des NMDAR-Antagonisten MK-801. Im Anschluss an Behandlungsdauern von 1h-72h wurden die Gehirne entnommen und für morphologische Analysen oder Extraktion der RNAs für Expressionsanalysen verwandt. Unsere Befunde stärken die Annahme, dass Dopamin neurodegenerative Veränderungen hervorruft und diese erst im späteren Krankheitsverlauf auftreten und daher vermutlich nicht an der Äthiopathogenese der Schizophrenie beteiligt, sondern eher als Folgeerscheinung der Dopamin-Neurotoxizität anzusehen sind

Modeling of human aging using a systems approach

The healthy aging process involves a range of biological pathways which were investigated based on data from adult human fibroblasts of various ages. Two hybridcomputational models integrating organelle phenotypes with molecular mechanisms were developed using a fuzzy logic, rule‐based approach. One was a vicious cycle model which represents uncontrolled damage accumulation in a positive feedback loop, leading to a rapid cellular degradation. The second model was an adaptive response model which showed that the stress sensors NF‐kB and mTOR provide negative feedback loops causing a linear decline with age, observed in many cellular and physiological parameters.Simulations of mortality data led to discovery that a serial linear model of viability decline with a variable stochastic component would result in mortality rates to match recent data from industrialized countries. Further exploration using general computational models of biochemical networks showed the impact of the rate of linear decline, initial stochastic changes in reaction rates, and network topology on resilience and stability. The conclusion is that linear decline with age is observed and modeled at the cellular through organ system levels however mortality rates are compounded by several factors at the somatic level, leading to the serial linear decline model which combines linear decline with power law frailty models.Ph.D., Biomedical Engineering -- Drexel University, 201