The role of pregnenolone sulfate in modulating neuronal excitability

Thesis (M.A.)--Boston UniversityThe central nervous system operates through a tightly balanced relationship of excitatory and inhibitory synaptic transmission. Neurosteroids, synthesized de novo from cholesterol in the human brain as well as converted from precursors circulating in the blood, are proven modulators of this synaptic activity. Pregnenolone sulfate, one of the most abundant endogenous neurosteroids, is a negative modulator of the GABA receptor and positive modulator of NMDA and AMPA receptors, increasing the frequency of excitatory transmission in the brain. Here, we show that low concentrations (50pM) of pregnenolone sulfate increase receptor trafficking in cultured rat hippocampal and cortical cells. Immunocytochemistry data shows that a ten-minute treatment with 50pM PS increases NR2B subunit protein. Preliminary surface biotinylation results highlight a potential increase in NR1 subunit protein. Since NMDA receptors play a pivotal role in learning and memory and have been implicated in neuropsychiatric disorder, an endogenous positive modulator of NMDA receptors is likely to play a major pharmaceutical role in neurodegenerative and memory disorders

Integrating Large Scale Data Sets to Develop Predictive Hypotheses of Low-Dose Radiation-Induced Health Effects

Over one hundred years of radiation biology research has revealed much about the DNA damages induced by the deposition of energy from exposure to ionizing radiation and the subsequent cellular responses. However, there are still significant gaps in our understanding of how these might lead to detrimental health effects, particularly at low doses (100 mGy (milligray)). Recent advances in high throughput omics technologies enable interrogation of induced radiation effects at the genomic, proteomic and metabolomic levels. These include changes in gene expression, protein modifications, e.g., phosphorylation, acetylation, and methylation, and metabolic changes. We will discuss the integration of data obtained from multiple omics platforms to understand radiation dose, and dose rate effects in a complex human tissue model as a function of time. We will use as an example our results on the low dose responses in a 3D human skin model

27. Time factor in postoperative radiotherapy for squamous cell head and neck cancer; a multivariate locoregional control analysis in 942 patients

PurposeTo analyze the influence of overall radiation treatment time and duration of the interval surgery-radiotherapy on local tumor control (LTC) in postoperative radiotherapy (PRT) for squamous cell head and neck cancer (SCHNC).Material/methodsA multivariate Cox proportional hazard regression analysis included 942 patients with locally advanced SCHNC. Mean total radiation dose, dose per fraction, treatment time, and the interval surgery-PRT were 62,5 Gy, 2,1 Gy, 46 days, and 62 days respectively. No interruptions during PRT (except for weekend brakes) appeared in 29% of patients, while 28% had more than 5 days of gap. The data were grouped into seven categories depending on the position of gap (weeks 1–7).ResultsIncrease in treatment gaps, the presence of tumor recurrence after surgery, N stage, and extra-laryngeal site of cancer were significantly related to decrease in LTC. The duration of time interval surgery-PRT had only marginal significance for LTC. Other variables did not appear significant. Consideration of seven time intervals for treatment gaps in the multivariate model has shown a significant progressive increase in the hazard of recurrence for gaps in the respective weeks 1 to 7.ConclusionsThis analysis shows a detrimental effect of interruptions during PRT, and only marginal decrease in LTC from the extension of the interval surgery-PRT. Therefore it seems unjustified to rush with PRT at the expense of possible increase in radiation treatment gaps. However, excessive delays in initiating PRT should be avoided, since they may lead to a recurrence prior to irradiation

A formal verification framework and associated tools for enterprise modeling : application to UEML

The aim of this paper is to propose and apply a verification and validation approach to Enterprise Modeling that enables the user to improve the relevance and correctness, the suitability and coherence of a model by using properties specification and formal proof of properties

Conformational spread as a mechanism for cooperativity in the bacterial flagellar switch

The bacterial flagellar switch that controls the direction of flagellar rotation during chemotaxis has a highly cooperative response. This has previously been understood in terms of the classic two-state, concerted model of allosteric regulation. Here, we used high-resolution optical microscopy to observe switching of single motors and uncover the stochastic multistate nature of the switch. Our observations are in detailed quantitative agreement with a recent general model of allosteric cooperativity that exhibits conformational spread—the stochastic growth and shrinkage of domains of adjacent subunits sharing a particular conformational state. We expect that conformational spread will be important in explaining cooperativity in other large signaling complexes

Kinetic Model of Development and Aging of Artificial Skin Based on Analysis of Microscopy Data

Artificial human skin is available commercially or can be grown in the laboratory from established cell lines. Standard microscopy techniques show that artificial human skin has a fully developed basement membrane that separates an epidermis with the corneal, granular, spinosal, and basal layers from a dermis consisting of fibroblasts in an extracellular matrix. In this chapter, we show how modeling can integrate microscopy data to obtain a better understanding of the development and aging of artificial human skin. We use the time-dependent structural information predicted by our model to show how irradiation with an electron beam at different times in the life of artificial human skin affects the amount of energy deposited in different layers of the tissue. Experimental studies of this type will enable a better understanding of how different cell types in human skin contribute to overall tissue response to ionizing radiation

Learning about knowledge: A complex network approach

This article describes an approach to modeling knowledge acquisition in terms of walks along complex networks. Each subset of knowledge is represented as a node, and relations between such knowledge are expressed as edges. Two types of edges are considered, corresponding to free and conditional transitions. The latter case implies that a node can only be reached after visiting previously a set of nodes (the required conditions). The process of knowledge acquisition can then be simulated by considering the number of nodes visited as a single agent moves along the network, starting from its lowest layer. It is shown that hierarchical networks, i.e. networks composed of successive interconnected layers, arise naturally as a consequence of compositions of the prerequisite relationships between the nodes. In order to avoid deadlocks, i.e. unreachable nodes, the subnetwork in each layer is assumed to be a connected component. Several configurations of such hierarchical knowledge networks are simulated and the performance of the moving agent quantified in terms of the percentage of visited nodes after each movement. The Barab\'asi-Albert and random models are considered for the layer and interconnecting subnetworks. Although all subnetworks in each realization have the same number of nodes, several interconnectivities, defined by the average node degree of the interconnection networks, have been considered. Two visiting strategies are investigated: random choice among the existing edges and preferential choice to so far untracked edges. A series of interesting results are obtained, including the identification of a series of plateaux of knowledge stagnation in the case of the preferential movements strategy in presence of conditional edges.Comment: 18 pages, 19 figure

Requirements modelling and formal analysis using graph operations

The increasing complexity of enterprise systems requires a more advanced analysis of the representation of services expected than is currently possible. Consequently, the specification stage, which could be facilitated by formal verification, becomes very important to the system life-cycle. This paper presents a formal modelling approach, which may be used in order to better represent the reality of the system and to verify the awaited or existing system’s properties, taking into account the environmental characteristics. For that, we firstly propose a formalization process based upon properties specification, and secondly we use Conceptual Graphs operations to develop reasoning mechanisms of verifying requirements statements. The graphic visualization of these reasoning enables us to correctly capture the system specifications by making it easier to determine if desired properties hold. It is applied to the field of Enterprise modelling

Steps in the bacterial flagellar motor

The bacterial flagellar motor is a highly efficient rotary machine used by many bacteria to propel themselves. It has recently been shown that at low speeds its rotation proceeds in steps [Sowa et al. (2005) Nature 437, 916--919]. Here we propose a simple physical model that accounts for this stepping behavior as a random walk in a tilted corrugated potential that combines torque and contact forces. We argue that the absolute angular position of the rotor is crucial for understanding step properties, and show this hypothesis to be consistent with the available data, in particular the observation that backward steps are smaller on average than forward steps. Our model also predicts a sublinear torque-speed relationship at low torque, and a peak in rotor diffusion as a function of torque

Radioimmunotherapy for lymphoma - analysis of clinical trials and treatment algorithms

Ibritumomab, an 90Yttrium (90Y) labelled radioimmunoconjugate, is registered in Europe to treat follicular lymphomas. Its mode of action combines the selectivity of monoclonal antibodies with the efficiency of radiotherapy, making it a unique and useful therapeutic agent. This paper is for haemato-oncologists with a decent practice in lymphoma therapy, who have not yet used ibritumomab themselves. It summarizes clinical trials with radioimmunotherapy, indicating clinical situations where it may be specifically useful