Model discrimination in time-course kinetics : the glyoxalase pathway in S. cerevisiae

Tese de doutoramento, Bioquímica (Bioquímica Teórica), Universidade de Lisboa, Faculdade de Ciências, 2010.The present work addresses the problem of model discrimination in enzyme kinetics. Frequently, more than one kinetic model is considered during the characterization of an enzymatic reaction or a metabolic pathway. The statistical selection of a model may be difficult if the candidate models fit the experimental data with very similar fitting scores. Since each model corresponds to a different possible mechanism of the studied process, model selection also reflects the choice of a particular mechanism. In addition, predictions given by models with equal fitting scores may be different. The glyoxalase system is a metabolic pathway that has been studied using two alternative kinetic models. These models could not be discriminated despite extensive kinetic experiments and an alternative branched mechanism combining the two models has been proposed. This pathway is therefore ideal for model discrimination research in Biochemistry. The glyoxalase pathway comprises the enzymes glyoxalase I and glyoxalase II. Glyoxalase I catalyzes the isomerization of the hemithioacetal that forms from the condensation of methylglyoxal (a by-­product of glycolysis) and glutathione to S-­D-­lactoylglutathione. Glyoxalase II catalyzes the hydrolysis of S-­D-­glutathione to D-­ lactate and glutathione. The methylglyoxal-­glutathione hemithioacetal forms spontaneously without the presence of enzymes. Therefore the glyoxalase I reaction can be described either as irreversible single-­substrate or as irreversible two-­substrate, considering that the hemithioacetal forms before binding the enzyme or that it forms in the active centre of the enzyme after sequential binding of glutathione and methylglyoxal, respectively. The glyoxalase system is the most important catabolic pathway for methylglyoxal. Methylglyoxal is a toxic agent due to its ability to react with proteins and nucleic acid amine groups that leads to formation of advanced glycation end-­products. Therefore the glyoxalase pathway was suggested to be a potential dug target for its cellular defensive role against methylglyoxal. An introduction to the subjects developed through this dissertation is given in chapter 1, covering the state of art of research on the glyoxalase pathway and methylglyoxal metabolism and on relevant mathematical and computational methods for model analysis and discrimination. In chapter 2 the glyoxalase system is investigated by analyzing the algebraic solutions of the rate equations describing the pathway at steady state. The two mentioned glyoxalase I kinetic models were used in this approach. It is observed that for the existence of a steady state a minimum amount of glutathione must be available;; in addition, glyoxalase I and II activities must exceed thresholds higher than the flux of the pathway. It is shown that methylglyoxal steady-­state concentration is not sensitive to variations of glyoxalase II activity but varies significantly with total glutathione concentration and methylglyoxal formation rate. Sensitivity to glyoxalase I activity depends on the kinetic model describing the enzyme: highly sensitivity if the two-­ substrate model is used but not so for the one-­substrate model. The pathway seems to operate very far from the conditions of disruption of the physiological steady state to assure a very low methylglyoxal concentration and a fast regeneration and high concentration of free glutathione. Time-­course kinetic studies with purified yeast enzyme and yeast permeabilized cells are described in chapter 3. Akaike’s information criterion and residual analysis are used to discuss the selection of the most appropriate kinetic model for glyoxalase I. Parameter least-­square estimates for this study are obtained with a combination of the stochastic Differential Evolution with the deterministic downhill-­simplex optimization algorithms. Although the two-­substrate model performs slightly better for the purified enzyme data, the Akaike score differences for both data sets and the residual analysis for the permeabilized cell data are not conclusive. A method developed to design optimized experimental conditions for model discrimination is explained in chapter 4. The method employs a multiobjective optimization algorithm (the Generalized Differential Evolution, generation 3) to search for the experimental conditions that maximize the divergence between the reaction time courses predicted by the models. The Kullback-­Leibler distance is the measure of divergence employed. The combination of the chosen algorithm and divergence criterion is successful in finding solutions that result in very different predictions from the two models for glyoxalase I in the presence of glyoxalase II, proving to be useful for planning model discrimination experiments. The importance of keeping a high free glutathione concentration seems to establish the properties of the glyoxalase pathway identified in chapter 2. Glutathione is also a key antioxidant and its oxidized form is reduced through the glutathione reductase system at the expense of NADPH. Indeed, the pyridine nucleotides NADPH and NADH have crucial metabolic roles. NADH, formed mainly in catabolic reactions, is the substrate of the respiratory chain and therefore it ultimately supplies the synthesis of ATP. NADPH is the main reducing agent in biosynthetic pathways. In addition, the pyridine nucleotides are among the metabolites that participate in a larger number of reactions in the cell. Therefore it is important to understand the effects of concentration changes of these metabolites. In chapter 5 perturbations to pyridine nucleotide concentrations are studied in living yeast cells cultured in bioreactors. The results for five recombinant S. cerevisiae strains overexpressing a cytosolic NADH oxidase, a mitochondrial NADH oxidase, a cytosolic NADH kinase, a mitochondrial NADH kinase and a cytosolic soluble pyridine nucleotide transhydrogenase are discussed. Extracellular and intracellular metabolite measurements and a stoichiometric model are used to assess the consequences of such perturbations, unveiling how metabolism in intact cells adapts to different redox conditions. Strains with enhanced NADH oxidation in the cytosol show a lower glycerol production. On the other hand enhanced NADH consumption in the mitochondrion lowers ethanol production and enhances ATP synthesis efficiency. The results presented here show that different kinetic models may fit experimental data equally well, making the selection of one model extremely. An original contribution is established to aid planning experiments for model discrimination. In addition, a broad characterization of the effects of perturbations to pyridine nucleotide metabolism is given, which is valuable to understand the complex response of yeast’s metabolic network, with direct biotechnological application.Fundação para a Ciência e Tecnologia – Ministério da Ciência, Tecnologia e Ensino Superior, Portugal (SFRH/BD/21947/2005

Bioinformatics analysis of the early inflammatory response in a rat thermal injury model

BACKGROUND: Thermal injury is among the most severe forms of trauma and its effects are both local and systemic. Response to thermal injury includes cellular protection mechanisms, inflammation, hypermetabolism, prolonged catabolism, organ dysfunction and immuno-suppression. It has been hypothesized that gene expression patterns in the liver will change with severe burns, thus reflecting the role the liver plays in the response to burn injury. Characterizing the molecular fingerprint (i.e., expression profile) of the inflammatory response resulting from burns may help elucidate the activated mechanisms and suggest new therapeutic intervention. In this paper we propose a novel integrated framework for analyzing time-series transcriptional data, with emphasis on the burn-induced response within the context of the rat animal model. Our analysis robustly identifies critical expression motifs, indicative of the dynamic evolution of the inflammatory response and we further propose a putative reconstruction of the associated transcription factor activities. RESULTS: Implementation of our algorithm on data obtained from an animal (rat) burn injury study identified 281 genes corresponding to 4 unique profiles. Enrichment evaluation upon both gene ontologies and transcription factors, verifies the inflammation-specific character of the selections and the rationalization of the burn-induced inflammatory response. Conducting the transcription network reconstruction and analysis, we have identified transcription factors, including AHR, Octamer Binding Proteins, Kruppel-like Factors, and cell cycle regulators as being highly important to an organism's response to burn response. These transcription factors are notable due to their roles in pathways that play a part in the gross physiological response to burn such as changes in the immune response and inflammation. CONCLUSION: Our results indicate that our novel selection/classification algorithm has been successful in selecting out genes with play an important role in thermal injury. Additionally, we have demonstrated the value of an integrative approach in identifying possible points of intervention, namely the activation of certain transcription factors that govern the organism's response

Contributions to modelling and control for improved hypoglycaemia and variability mitigation by dual-hormone artificial pancreas systems

[ES] Las personas con diabetes tipo 1 carecen de la capacidad de secretar insulina y, por lo tanto, necesitan regular su glucosa en sangre con la administración de insulina exógena. El páncreas artificial se presenta como la solución tecnológica ideal para alcanzar los objetivos terapéuticos de la normoglucemia, liberando al paciente de la carga actual de autocontrol y manejo. Sin embargo, el riesgo de hipoglucemia y la variabilidad glucémica siguen siendo factores limitantes en los algoritmos de control actuales integrados en el páncreas artificial. El propósito de la presente tesis es profundizar en el conocimiento de la hipoglucemia y avanzar los algoritmos de control del páncreas artificial para minimizar la incidencia de hipoglucemia y reducir la variabilidad glucémica. Después de proporcionar una visión general del estado del arte del control de la glucosa y el páncreas artificial, esta tesis aborda temas relacionados con el modelado y el control, con las siguientes contribuciones: Se presenta una extensión del modelo de Bergman Minimal que tiene en cuenta la respuesta contrarreguladora a la hipoglucemia. Este modelo explica la relación entre los diversos cambios fisiológicos producidos durante la hipoglucemia, con la adrenalina y los ácidos grasos libres como actores principales. Como resultado, se obtiene una mejor comprensión de la hipoglucemia, lo que permite explicar una auto-potenciación paradójica de la hipoglucemia como se modela a través de enfoques funcionales en el ampliamente utilizado simulador de diabetes tipo 1 UVA-Padova, que se utilizará en esta tesis para la validación in silico de los controladores desarrollados. Se realiza una evaluación de las métricas de variabilidad de la glucosa y los índices de calidad de control. La evaluación de la variabilidad glucémica en el desempeño de los controladores es necesaria; pero todavía no hay un conjunto de métricas de variabilidad glucémica que sea considerado como el "gold estándar". Por tanto, se lleva a cabo un análisis de las métricas de variabilidad disponibles en la literatura para definir un conjunto de indicadores recomendables. Debido a las limitaciones de los sistemas de páncreas artificiales unihormonales para mitigar la hipoglucemia en escenarios difíciles como el ejercicio, esta tesis se centra en el desarrollo de nuevos algoritmos de control bihormonales, con infusión simultanea de insulina y glucagón. Se propone un controlador coordinado bihormonal con estructuras de control paralelas como un algoritmo de control factible para la mitigación de la hipoglucemia y la reducción de la variabilidad glucémica, demostrando un rendimiento superior al de las estructuras de control utilizadas actualmente con lazos de control independientes de insulina y glucagón. Los controladores están diseñados y evaluados in silico en escenarios desafiantes y su rendimiento se evalúa principalmente con el conjunto de métricas definidas previamente como las recomendables.[CA] Les persones amb diabetis tipus 1 no tenen la capacitat de secretar insulina secreta i per tant, necessiten regular la seva glucosa en sang amb l'administració d'insulina exògena. El Pàncrees Artificial es presenta com la solució tecnològica ideal per assolir els objectius terapèutics de la normoglucèmia, alliberant al pacient de la càrrega actual d'autocontrol. No obstant, el risc d'hipoglucèmia i l'alta variabilitat glucèmica continuen sent un factor limitant en els algoritmes de control actuals integrats en el Pàncrees Artificials. El propòsit de la present tesi és aprofundir en el coneixement de la hipoglucèmia i millorar els algoritmes de control per corregir amb antelació la dosi excessiva d'insulina, minimitzant la incidència d'hipoglucèmia i reduint la variabilitat glucèmica. Després de donar una visió general de l'estat de l'art del control de la glucosa i el pàncrees artificial, aquesta tesi aborda aspectes de modelització i control, amb les següents contribucions: Es presenta una extensió del model Minimal de Bergman amb la contrarregulació. Aquest model explica la relació entre els diversos canvis siològics produïts durant la hipoglucèmia. Així, permet comprendre millor la hipoglucèmia i comparar els resultats amb els proporcionats per l'enfocament funcional del simulador de diabetis tipus 1 més utilitzat a la comunitat científica. Es realitza una avaluació de les mètriques de variabilitat glucèmica i dels índexs de qualitat de control. Es necessària l'avaluació de la variabilitat glucèmica en el rendiment dels controladors; però encara no hi ha un conjunt de mètriques considerades com les "gold standard". Per tant, es realitza una anàlisi de les mètriques de variabilitat disponibles a la literatura per definir un conjunt d'indicadors recomanables. Es proposa un controlador bi-hormonal coordinat amb estructures de control paral.leles com un algoritme de control viable per a la mitigació d'hipoglucèmia i la reducció de la variabilitat glucèmica. Els controladors estan dissenyats i avaluats in-silico en escenaris desafiadors i el seu rendiment es valora principalment amb el conjunt de mètriques definides prèviament com les mètriques recomanables.[EN] People with Type 1 Diabetes lack the ability to secrete insulin and therefore need to regulate their blood glucose with exogenous insulin delivery. The Artificial Pancreas is presented as the ideal technological solution to reach the therapeutic goals of normoglycaemia, freeing the patient from the current burden of self-control and management. Nevertheless, the risk of hypoglycaemia and the high glycaemic variability are still a limiting factors in the current control algorithms integrated in the Artificial Pancreas. The purpose of the present thesis is to delve into knowledge of hypoglycaemia and to advance in the artificial pancreas control algorithms in order to minimise hypoglycaemia incidence and reduce glycaemic variability. After providing an overview of the state of the art in the eld of glucose control and articial pancreas, this thesis addresses issues on modelling and control, with the following contributions: An extension of the Bergman Minimal model accounting for counterregulatory response to hypoglycaemia is presented. This model explains the relationship between the several physiological changes produced during hypoglycaemia, with adrenaline and free fatty acids as main players. As a result, a better understanding of hypoglycaemia is gained, allowing to explain a paradoxical auto-potentiation of hypoglycaemia as modeled through functional approaches in the widespread used UVA-Padova Type 1 Diabetes simulator, which will be used in this thesis for in silico validation of the developed controllers. An assessment of glucose variability metrics and control quality indices is carried out. The evaluation of the glycaemic variability on the controllers performance is necessary; but there is not a gold standard variability metrics yet. Therefore, an analysis of the variability metrics available in literature is conducted in order to define a recommendable set of indicators. Due to the limitations of single-hormone artificial pancreas systems in mitigating hypoglycaemia in challenging scenarios such as exercise, this thesis focuses on the developement of new dual-hormone control algorithms, with concomitant infusion of insulin and glucagon. A coordinated dual-hormone controller with parallel control structures is proposed as a feasible control algorithm for hypoglycaemia mitigation and glycaemic variability reduction, demonstrating superior performance as currently used control structures with independent insulin and glucagon control loops. The controllers are designed and evaluated in-silico under challenging scenarios and their performance are assessed mainly with the set of metrics defined previously as the recommendable ones.Moscardó García, V. (2019). Contributions to modelling and control for improved hypoglycaemia and variability mitigation by dual-hormone artificial pancreas systems [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/120456TESI

Heart rate variability in young adults - Reference values and associations with cardiometabolic risk factors and vascular properties. The Cardiovascular Risk in Young Finns Study.

Background: The function of the autonomic nervous system (ANS) can be evaluated with heart rate variability (HRV). Decreased HRV is associated with aging, the male sex, increased heart rate, and overall increased cardiometabolic risk. It has been hypothesized that early atherosclerotic vascular changes and ANS function are related. Aims: The aims were to assess reference values on HRV in young adults, and examine associations with HRV and cardiometabolic risk factors and metabolic syndrome (MetS) and to study relations between HRV and ultrasonographically measured vascular properties. Participants and methods: The present thesis is part of the Cardiovascular Risk in Young Finns Study. The thesis is based on the follow-up study in 2001, when the study individuals were 24-39 years of age. HRV data were available on 1 956 individuals. Results: HRV was inversely associated with age and heart rate (for all p<0.001). Highfrequency HRV (HF) was higher, and low-frequency HRV (LF) lower in women than men (p<0.0001 for both). MetS was associated with 11% decreased HF and 12% increased LF/HF-ratio in women, and 8% decreased HF and 4% increased LF/HF-ratio in men. Carotid artery distensibility was independently associated with HF and total HRV (for both p<0.05). Conclusions: The reference values in young adults were generated. Decreased HRV was associated with age, the male sex and increased heart rate. Women had higher HF and lower LF variability than men. MetS was related to decrease in HRV. The observed associations between carotid elasticity and HRV, supports the hypothesis that reduction in carotid elasticity may lead to decrease in autonomic cardiac control.Sydämen sykevaihtelu nuorilla aikuisilla – viitearvot ja yhteys sydän- ja verisuonitautien riskitekijöihin sekä varhaisiin valtimomuutoksiin Tausta: Autonomisen hermoston toimintaa voidaan arvioida mittaamalla sydämen syketaajuudessa tapahtuvaa jaksoittaista vaihtelua, sydämen sykevaihtelua. Vähentynyt sydämen sykevaihtelu on sydän- ja verisuonitautien itsenäinen riskitekijä. Sykevaihtelun väheneminen liittyy ikääntymiseen, miessukupuoleen ja kiihtyneeseen sydämen syketaajuuteen sekä useisiin valtimotaudin riskitekijöihin. Varhaisten valtimotautimuutosten sekä autonomisen hermoston toiminnan välillä on aiemmin esitetty olevan yhteys, jota voidaan tutkia sykevaihtelun ja ultraäänellä mitattujen varhaisten valtimomuuttujien avulla. Tavoite: Tutkimuksen tavoitteena oli luoda sykevaihtelun viitearvot nuorille aikuisille sekä tutkia sykevaihtelun yhteyttä sydän- ja verisuonitautien riskitekijöihin ja metaboliseen oireyhtymään sekä selvittää onko varhaisilla valtimomuutoksilla yhteyttä sydämen autonomiseen säätelyyn. Menetelmät: Väitöskirjatutkimus on osa Lasten Sepelvaltimotaudin Riskitekijät – tutkimusta ja perustuu vuonna 2001 toteutettuun seurantatutkimukseen, jolloin tutkittavat olivat iältään 24–39 vuotta. Tutkimukseen oli käytettävissä 1 956 tutkimushenkilön sykevaihtelumittaukset. Tulokset: Kaikki sykevaihtelun muuttujat olivat yhteydessä tutkittavien ikään ja syketaajuuteen (molemmilla p<0.001). Naisilla korkeataajuuksinen sykevaihtelu oli miehiä runsaampaa (p<0.0001) ja matalataajuuksinen sykevaihtelu vähäisempää (p<0.0001). Metaboliseen oireyhtymään liittyi vähentynyt matalataajuuksinen sykevaihtelu (-11% naisilla ja -8% miehillä). Kaulavaltimon elastisuus oli itsenäisesti yhteydessä sydämen sykevaihteluun (p<0.05). Johtopäätökset: Tutkimuksessa luotiin sykevaihtelun viitearvot terveille aikuisille. Sykevaihteluun vaikuttivat voimakkaimmin ikä, sukupuoli sekä syketaajuus. Metaboliseen oireyhtymään liittyi merkittävästi vähentynyt sykevaihtelu. Valtimoiden seinämän jäykistyminen saattaa olla yksi mekanismi sydämen autonomisen säätelyn muutosten taustalla.Siirretty Doriast

Continuous Biochemical Processing: Investigating Novel Strategies to Produce Sustainable Fuels and Pharmaceuticals

Biochemical processing methods have been targeted as one of the potential renewable strategies for producing commodities currently dominated by the petrochemical industry. To design biochemical systems with the ability to compete with petrochemical facilities, inroads are needed to transition from traditional batch methods to continuous methods. Recent advancements in the areas of process systems and biochemical engineering have provided the tools necessary to study and design these continuous biochemical systems to maximize productivity and substrate utilization while reducing capital and operating costs. The first goal of this thesis is to propose a novel strategy for the continuous biochemical production of pharmaceuticals. The structural complexity of most pharmaceutical compounds makes chemical synthesis a difficult option, facilitating the need for their biological production. To this end, a continuous, multi-feed bioreactor system composed of multiple independently controlled feeds for substrate(s) and media is proposed to freely manipulate the bioreactor dilution rate and substrate concentrations. The optimal feed flow rates are determined through the solution to an optimal control problem where the kinetic models describing the time-variant system states are used as constraints. This new bioreactor paradigm is exemplified through the batch and continuous cultivation of β-carotene, a representative product of the mevalonate pathway, using Saccharomyces cerevisiae strain mutant SM14. The second goal of this thesis is to design continuous, biochemical processes capable of economically producing alternative liquid fuels. The large-scale, continuous production of ethanol via consolidated bioprocessing (CBP) is examined. Optimal process topologies for the CBP technology selected from a superstructure considering multiple biomass feeds, chosen from those available across the United States, and multiple prospective pretreatment technologies. Similarly, the production of butanol via acetone-butanol-ethanol (ABE) fermentation is explored using process intensification to improve process productivity and profitability. To overcome the inhibitory nature of the butanol product, the multi-feed bioreactor paradigm developed for pharmaceutical production is utilized with in situ gas stripping to simultaneously provide dilution effects and selectively remove the volatile ABE components. Optimal control and process synthesis techniques are utilized to determine the benefits of gas stripping and design a butanol production process guaranteed to be profitable

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 349)

This bibliography lists 149 reports, articles and other documents introduced into the NASA Scientific and Technical Information System during April, 1991. Subject coverage includes: aerospace medicine and psychology, life support systems and controlled environments, safety equipment, exobiology and extraterrestrial life, and flight crew behavior and performance

Network design and analysis for multi-enzyme biocatalysis

In vitro synthesis is a biotechnological alternative to classic chemical catalysts. However, the manual design of multi-step biosynthesis routes is very challenging, especially when enzymes from different organisms are involved. There is therefore a demand for in silico tools to guide the design of such synthesis routes using computational methods for the path-finding, as well as the reconstruction of suitable genome-scale metabolic networks that are able to harness the growing amount of biological data available. This work presents an algorithm for finding pathways from arbitrary metabolites to a target product of interest. The algorithm is based on a mixed-integer linear program (MILP) and combines graph topology and reaction stoichiometry. The pathway candidates are ranked using different ranking criteria to help finding the best suited synthesis pathway candidates. Additionally, a comprehensive workflow for the reconstruction of metabolic networks based on data of the Kyoto Encyclopedia of Genes and Genomes (KEGG) combined with thermodynamic data for the determination of reaction directions is presented. The workflow comprises a filtering scheme to remove unsuitable data. With this workflow, a panorganism network reconstruction as well as single organism network models are established. These models are analyzed with graph-theoretical methods. It is also discussed how the results can be used for the planning of biosynthetic production pathways.In vitro Synthese ist eine biotechnologische Alternative zu klassischen chemischen Katalysen. Der manuelle Entwurf von mehrstufigen Biosynthesewegen ist jedoch sehr anspruchsvoll, vor allem wenn Enzyme verschiedener Organismen beteiligt sind. Daher besteht ein Bedarf an Methoden, die helfen solche Synthesewege in silico zu entwerfen und die in der Lage sind große Mengen biologischer Daten zu bewältigen - insbesondere in Hinblick auf die Rekonstruktion genomskaliger metabolischer Netzwerkmodelle und die Pfadsuche in solchen Netzwerken. In dieser Arbeit wird ein Algorithmus zur Pfadsuche zu einem Zielprodukt ausgehend von beliebigen Substraten präsentiert. Der Algorithmus basiert auf einem gemischt-ganzzahligen linearen Programm, das Graphtopologie mit Reaktionsstöchiometrien kombiniert. Die Pfadkandidaten werden anhand verschiedener Kriterien geordnet, um die am besten geeigneten Kandidaten für die Synthese zu finden. Außerdem wird ein umfassender Workflow für die Rekonstruktion metabolischer Netzwerke basierend auf der Datenbank KEGG sowie thermodynamischen Daten vorgestellt. Dieser umfasst einen Filter, der anhand verschiedener Kriterien geeignete Reaktionen auswählt. Der Workflow wird zum Erstellen einer organismusübergreifenden Netzwerkrekonstruktion, sowie Netzwerken einzelner Organismen genutzt. Diese Modelle werden mit graphentheoretischen Methoden analysiert. Es wird diskutiert, wie die Ergebnisse für die Planung von biosynthetischen Produktionswegen genutzt werden können.BMBF; Initiative “Biotechnologie 2020+: Basistechnologien für eine nächste Generation biotechnologischer Verfahren”; Projekt MECA

Uncovering Molecular Biomarkers That Correlate Cognitive Decline with the Changes of Hippocampus' Gene Expression Profiles in Alzheimer's Disease

Background: Alzheimer’s disease (AD) is characterized by a neurodegenerative progression that alters cognition. On a phenotypical level, cognition is evaluated by means of the MiniMental State Examination (MMSE) and the post-morten examination of Neurofibrillary Tangle count (NFT) helps to confirm an AD diagnostic. The MMSE evaluates different aspects of cognition including orientation, short-term memory (retention and recall), attention and language. As there is a normal cognitive decline with aging, and death is the final state on which NFT can be counted, the identification of brain gene expression biomarkers from these phenotypical measures has been elusive. Methodology/Principal Findings: We have reanalysed a microarray dataset contributed in 2004 by Blalock et al. of 31 samples corresponding to hippocampus gene expression from 22 AD subjects of varying degree of severity and 9 controls. Instead of only relying on correlations of gene expression with the associated MMSE and NFT measures, and by using modern bioinformatics methods based on information theory and combinatorial optimization, we uncovered a 1,372-probe gene expression signature that presents a high-consensus with established markers of progression in AD. The signature reveals alterations in calcium, insulin, phosphatidylinositol and wnt-signalling. Among the most correlated gene probes with AD severity we found those linked to synaptic function, neurofilament bundle assembly and neuronal plasticity. Conclusions/Significance: A transcription factors analysis of 1,372-probe signature reveals significant associations with the EGR/KROX family of proteins, MAZ, and E2F1. The gene homologous of EGR1, zif268, Egr-1 or Zenk, together with other members of the EGR family, are consolidating a key role in the neuronal plasticity in the brain. These results indicate a degree of commonality between putative genes involved in AD and prion-induced neurodegenerative processes that warrants further investigation

Aerospace Medicine and Biology: A continuing bibliography with indexes

This bibliography lists 253 reports, articles, and other documents introduced into the NASA scientific and technical information system in October 1975