Structural bioinformatics study of cyclin-dependent kinases complexed with inhibitors

The present work describes molecular models for the binary complexes CDK9, CDK5 and CDK1 complexed with Flavopiridol and Roscovitine. These structural models indicate that the inhibitors strongly bind to the ATP-binding pocket of CDKs and the structural comparison with the complexes CDK2:Flavopiridol and CDK2:Roscovitine correlates the structural differences with differences in inhibition of these CDKs by the inhibitors. These structures open the possibility of testing new inhibitor families, in addition to new substituents for the already known lead structures such as flavones and adenine derivatives.

Environmental inFluences on the Adoption of Open Innovation: Analysis of Structural, Institutional and Cultural Impacts

The concept of open innovation has recently gained widespread attention, and is particularly relevant now as many firms endeavouring to implement open innovation, face different sets of challenges associated with managing it. Prior research on open innovation has focused on the internal processes dealing with open innovation implementation and the organizational changes, already taking place or yet required in companies order to succeed in the global open innovation market. Despite the intensive research on open innovation, the question of what influences its adoption by companies in different contexts has not received much attention in studies. To fill this gap, this thesis contribute to the discussion on open innovation influencing factors by bringing in the perspective of environmental impacts, i.e. gathering data on possible sources of external influences, classifying them and testing their systemic impact through conceptual system dynamics simulation model. The insights from data collection and conceptualization in modelling are used to answer the question of how the external environment affects the adoption of open innovation. The thesis research is presented through five research papers reflecting the method triangulation based study (conducted at initial stage as case study, later as quantitative analysis and finally as system dynamics simulation). This multitude of methods was used to collect the possible external influence factors and to assess their impact (on positive/negative scale rather than numerical). The results obtained throughout the thesis research bring valuable insights into understanding of open innovation influencing factors inside a firm’s operating environment, point out the balance required in the system for successful open innovation performance and discover the existence of tipping point of open innovation success when driven by market dynamics and structures. The practical implications on how firms and policy-makers can leverage environment for their potential benefits are offered in the conclusions.

Conventional and novel cardiovascular risk factors in young Finns and their associations with structural and functional vascular changes of subclinical atherosclerosis. The Cardiovascular Risk in Young Finns Study

Background: Atherosclerosis begins in early life progressing from asymptomatic to symptomatic as we age. Although substantial progress has been made in identifying the determinants of atherosclerosis in middle to older age adults at increased cardiovascular risk, there is lack of data examining determinants and prediction of atherosclerosis in young adults. Aims: The current study was designed to investigate levels of cardiovascular risk factors in young adults, subclinical measures of atherosclerosis, and prediction of subclinical arterial changes with conventional risk factor measures and novel metabolic profiling of serum samples. Subjects and Methods: This thesis utilised data from the follow-ups performed in 2001 and 2007 in the Cardiovascular Risk in Young Finns study, a Finnish population-based prospective cohort study that examined 2,204 subjects who were aged 30-45 years in 2007. Subclinical atherosclerosis was studied using noninvasive ultrasound measurements of carotid intima-media thickness (IMT), carotid arterial distensibility (CDist) and brachial flow-mediated dilation (FMD). Measurements included conventional risk factors and metabolic profiling using highthroughput nuclear magnetic resonance (NMR) methods that provided data on 42 lipid markers and 16 circulating metabolites. Results: Trends in lipids were favourable between 2001 and 2007, whereas waist circumference, fasting glucose, and blood pressure levels increased. To study the stability of noninvasive ultrasound markers, 6-year tracking (the likelihood to maintain the original fractile over time) in 6 years was examined. IMT tracked more strongly than CDist and FMD. Cardiovascular risk scores (Framingham, SCORE, Finrisk, Reynolds and PROCAM) predicted subclinical atherosclerosis equally. Lipoprotein subclass testing did not improve the prediction of subclinical atherosclerosis over and above conventional risk factors. However, circulating metabolites improved risk stratification. Tyrosine and docosahexaenoic acid were found to be novel biomarkers of high IMT. Conclusions: Prediction of cardiovascular risk in young Finnish adults can be performed with any of the existing risk scores. The addition of metabonomics to risk stratification improves prediction of subclinical changes and enables more accurate targeting of prevention at an early stage.

Alternative methodology for calculating the modulus of elasticity of wooden beams of structural dimensions

This study aims to present an alternative calculation methodology based on the Least Squares Method for determining the modulus of elasticity in bending wooden beams of structural dimensions. The equations developed require knowledge of three or five points measured in displacements along the piece, allowing greater reliability on the response variable, using the statistical bending test at three points and non-destructively, resulting from imposition of measures from small displacements L/300 and L/200, the largest being stipulated by the Brazilian norm NBR 7190:1997. The woods tested were Angico, Cumaru, Garapa and Jatoba. Besides obtaining the modulus of elasticity through the alternative methodology proposed, these were also obtained employing the Brazilian norm NBR 7190:1997, adapted to the condition of non-destructive testing (small displacements) and for pieces of structural dimensions. The results of the modulus of elasticity of the four species of wood according to both calculation approaches used proved to be equivalent, implying the good approximation provided by the methodology of calculation adapted from the Brazilian norm.

Modal testing and numerical modeling of the dynamic properties of layered sheet-steel structure

Recently, due to the increasing total construction and transportation cost and difficulties associated with handling massive structural components or assemblies, there has been increasing financial pressure to reduce structural weight. Furthermore, advances in material technology coupled with continuing advances in design tools and techniques have encouraged engineers to vary and combine materials, offering new opportunities to reduce the weight of mechanical structures. These new lower mass systems, however, are more susceptible to inherent imbalances, a weakness that can result in higher shock and harmonic resonances which leads to poor structural dynamic performances. The objective of this thesis is the modeling of layered sheet steel elements, to accurately predict dynamic performance. During the development of the layered sheet steel model, the numerical modeling approach, the Finite Element Analysis and the Experimental Modal Analysis are applied in building a modal model of the layered sheet steel elements. Furthermore, in view of getting a better understanding of the dynamic behavior of layered sheet steel, several binding methods have been studied to understand and demonstrate how a binding method affects the dynamic behavior of layered sheet steel elements when compared to single homogeneous steel plate. Based on the developed layered sheet steel model, the dynamic behavior of a lightweight wheel structure to be used as the structure for the stator of an outer rotor Direct-Drive Permanent Magnet Synchronous Generator designed for high-power wind turbines is studied.

Testing FCM technique for the wind energy scenarios in Finland

In the latter days, human activities constantly increase greenhouse gases emissions in the atmosphere, which has a direct impact on a global climate warming. Finland as European Union member, developed national structural plan to promote renewable energy generation, pursuing the aspects of Directive 2009/28/EC and put it on the sharepoint. Finland is on a way of enhancing national security of energy supply, increasing diversity of the energy mix. There are plenty significant objectives to develop onshore and offshore wind energy generation in country for a next few decades, as well as another renewable energy sources. To predict the future changes, there are a lot of scenario methods developed and adapted to energy industry. The Master’s thesis explored “Fuzzy cognitive maps” approach in scenarios developing, which captures expert’s knowledge in a graphical manner and using these captures for a raw scenarios testing and refinement. There were prospects of Finnish wind energy development for the year of 2030 considered, with aid of FCM technique. Five positive raw scenarios were developed and three of them tested against integrated expert’s map of knowledge, using graphical simulation. The study provides robust scenarios out of the preliminary defined, as outcome, assuming the impact of results, taken after simulation. The thesis was conducted in such way, that there will be possibilities to use existing knowledge captures from expert panel, to test and deploy different sets of scenarios regarding to Finnish wind energy development.

VAP-1 as drug target in inflammation : structural features determining ligand interactions

Vascular adhesion protein-1 (VAP-1), which belongs to the copper amine oxidases (CAOs), is a validated drug target in inflammatory diseases. Inhibition of VAP-1 blocks the leukocyte trafficking to sites of inflammation and alleviates inflammatory reactions. In this study, a novel set of potent pyridazinone inhibitors is presented together with their X-ray structure complexes with VAP-1. The crystal structure of serum VAP-1 (sVAP-1) revealed an imidazole binding site in the active site channel and, analogously, the pyridazinone inhibitors were designed to bind into the channel. This is the first time human VAP-1 has been crystallized with a reversible inhibitor and the structures reveal detailed information of the binding mode on the atomic level. Similarly to some earlier studied inhibitors of human VAP-1, the designed pyridazinone inhibitors bind rodent VAP-1 with a lower affinity than human VAP-1. Therefore, we made homology models of rodent VAP-1 and compared human and rodent enzymes to determine differences that might affect the inhibitor binding. The comparison of the crystal structures of the human VAP-1 and the mouse VAP-1 homology model revealed key differences important for the species specific binding properties. In general, the channel in mouse VAP-1 is more narrow and polar than the channel in human VAP-1, which is wider and more hydrophobic. The differences are located in the channel leading to the active site, as well as, in the entrance to the active site channel. The information obtained from these studies is of great importance for the development and design of drugs blocking the activity of human VAP-1, as rodents are often used for in vivo testing of candidate drugs. In order to gain more insight into the selective binding properties of the different CAOs in one species a comprehensive evolutionary study of mammalian CAOs was performed. We found that CAOs can be classified into sub-families according to the residues X1 and X2 of the Thr/Ser-X1-X2-Asn-Tyr-Asp active site motif. In the phylogenetic tree, CAOs group into diamine oxidase, retina specific amine oxidase and VAP-1/serum amine oxidase clades based on the residue in the position X2. We also found that VAP-1 and SAO can be further differentiated based on the residue in the position X1. This is the first large-scale comparison of CAO sequences, which explains some of the reasons for the unique substrate specificities within the CAO family.

Computation and Analysis of Multiple Structural-Change Models

In a recent paper, Bai and Perron (1998) considered theoretical issues related to the limiting distribution of estimators and test statistics in the linear model with multiple structural changes. In this companion paper, we consider practical issues for the empirical applications of the procedures. We first address the problem of estimation of the break dates and present an efficient algorithm to obtain global minimizers of the sum of squared residuals. This algorithm is based on the principle of dynamic programming and requires at most least-squares operations of order O(T 2) for any number of breaks. Our method can be applied to both pure and partial structural-change models. Secondly, we consider the problem of forming confidence intervals for the break dates under various hypotheses about the structure of the data and the errors across segments. Third, we address the issue of testing for structural changes under very general conditions on the data and the errors. Fourth, we address the issue of estimating the number of breaks. We present simulation results pertaining to the behavior of the estimators and tests in finite samples. Finally, a few empirical applications are presented to illustrate the usefulness of the procedures. All methods discussed are implemented in a GAUSS program available upon request for non-profit academic use.

Projection-Based Statistical Inference in Linear Structural Models with Possibly Weak Instruments

It is well known that standard asymptotic theory is not valid or is extremely unreliable in models with identification problems or weak instruments [Dufour (1997, Econometrica), Staiger and Stock (1997, Econometrica), Wang and Zivot (1998, Econometrica), Stock and Wright (2000, Econometrica), Dufour and Jasiak (2001, International Economic Review)]. One possible way out consists here in using a variant of the Anderson-Rubin (1949, Ann. Math. Stat.) procedure. The latter, however, allows one to build exact tests and confidence sets only for the full vector of the coefficients of the endogenous explanatory variables in a structural equation, which in general does not allow for individual coefficients. This problem may in principle be overcome by using projection techniques [Dufour (1997, Econometrica), Dufour and Jasiak (2001, International Economic Review)]. AR-types are emphasized because they are robust to both weak instruments and instrument exclusion. However, these techniques can be implemented only by using costly numerical techniques. In this paper, we provide a complete analytic solution to the problem of building projection-based confidence sets from Anderson-Rubin-type confidence sets. The latter involves the geometric properties of “quadrics” and can be viewed as an extension of usual confidence intervals and ellipsoids. Only least squares techniques are required for building the confidence intervals. We also study by simulation how “conservative” projection-based confidence sets are. Finally, we illustrate the methods proposed by applying them to three different examples: the relationship between trade and growth in a cross-section of countries, returns to education, and a study of production functions in the U.S. economy.

The role of porcine reproductive and respiratory syndrome (PRRS) virus structural and non-structural proteins in virus pathogenesis.

Porcine reproductive and respiratory syndrome (PRRS) is an economically devastating viral disease affecting the swine industry worldwide. The etiological agent, PRRS virus (PRRSV), possesses a RNA viral genome with nine open reading frames (ORFs). The ORF1a and ORF1b replicase-associated genes encode the polyproteins pp1a and pp1ab, respectively. The pp1a is processed in nine non-structural proteins (nsps): nsp1a, nsp1b, and nsp2 to nsp8. Proteolytic cleavage of pp1ab generates products nsp9 to nsp12. The proteolytic pp1a cleavage products process and cleave pp1a and pp1ab into nsp products. The nsp9 to nsp12 are involved in virus genome transcription and replication. The 30 end of the viral genome encodes four minor and three major structural proteins. The GP2a, GP3 and GP4 (encoded by ORF2a, 3 and 4), are glycosylated membrane associated minor structural proteins. The fourth minor structural protein, the E protein (encoded by ORF2b), is an unglycosylated membrane associated protein. The viral envelope contains two major structural proteins: a glycosylated major envelope protein GP5 (encoded by ORF5) and an unglycosylated membrane M protein (encoded by ORF6). The third major structural protein is the nucleocapsid N protein (encoded by ORF7). All PRRSV non-structural and structural proteins are essential for virus replication, and PRRSV infectivity is relatively intolerant to subtle changes within the structural proteins. PRRSV virulence is multigenic and resides in both the non-structural and structural viral proteins. This review discusses the molecular characteristics, biological and immunological functions of the PRRSV structural and nsps and their involvement in the virus pathogenesis.

Numerical Investigations on Soil Structure Interaction of Multistorey Frames

Frames are the most widely used structural system for multistorey buildings. A building frame is a three dimensional discrete structure consisting of a number of high rise bays in two directions at right angles to each other in the vertical plane. Multistorey frames are a three dimensional lattice structure which are statically indeterminate. Frames sustain gravity loads and resist lateral forces acting on it. India lies at the north westem end of the Indo-Australian tectonic plate and is identified as an active tectonic area. Under horizontal shaking of the ground, horizontal inertial forces are generated at the floor levels of a multistorey frame. These lateral inertia forces are transferred by the floor slab to the beams, subsequently to the columns and finally to the soil through the foundation system. There are many parameters that affect the response of a structure to ground excitations such as, shape, size and geometry of the structure, type of foundation, soil characteristics etc. The Soil Structure Interaction (SS1) effects refer to the influence of the supporting soil medium on the behavior of the structure when it is subjected to different types of loads. Interaction between the structure and its supporting foundation and soil, which is a complete system, has been modeled with finite elements. Numerical investigations have been carried out on a four bay, twelve storeyed regular multistorey frame considering depth of fixity at ground level, at characteristic depth of pile and at full depth. Soil structure interaction effects have been studied by considering two models for soil viz., discrete and continuum. Linear static analysis has been conducted to study the interaction effects under static load. Free vibration analysis and further shock spectrum analysis has been conducted to study the interaction effects under time dependent loads. The study has been extended to four types of soil viz., laterite, sand, alluvium and layered.The structural responses evaluated in the finite element analysis are bending moment, shear force and axial force for columns, and bending moment and shear force for beams. These responses increase with increase in the founding depth; however these responses show minimal increase beyond the characteristic length of pile. When the soil structure interaction effects are incorporated in the analysis, the aforesaid responses of the frame increases upto the characteristic depth and decreases when the frame has been analysed for the full depth. It has been observed that shock spectrum analysis gives wide variation of responses in the frame compared to linear elastic analysis. Both increase and decrease in responses have been observed in the interior storeys. The good congruence shown by the two finite element models viz., discrete and continuum in linear static analysis has been absent in shock spectrum analysis.

Parameter identification of structural dynamic models by inverse statistical analysis

Auf dem Gebiet der Strukturdynamik sind computergestützte Modellvalidierungstechniken inzwischen weit verbreitet. Dabei werden experimentelle Modaldaten, um ein numerisches Modell für weitere Analysen zu korrigieren. Gleichwohl repräsentiert das validierte Modell nur das dynamische Verhalten der getesteten Struktur. In der Realität gibt es wiederum viele Faktoren, die zwangsläufig zu variierenden Ergebnissen von Modaltests führen werden: Sich verändernde Umgebungsbedingungen während eines Tests, leicht unterschiedliche Testaufbauten, ein Test an einer nominell gleichen aber anderen Struktur (z.B. aus der Serienfertigung), etc. Damit eine stochastische Simulation durchgeführt werden kann, muss eine Reihe von Annahmen für die verwendeten Zufallsvariablengetroffen werden. Folglich bedarf es einer inversen Methode, die es ermöglicht ein stochastisches Modell aus experimentellen Modaldaten zu identifizieren. Die Arbeit beschreibt die Entwicklung eines parameter-basierten Ansatzes, um stochastische Simulationsmodelle auf dem Gebiet der Strukturdynamik zu identifizieren. Die entwickelte Methode beruht auf Sensitivitäten erster Ordnung, mit denen Parametermittelwerte und Kovarianzen des numerischen Modells aus stochastischen experimentellen Modaldaten bestimmt werden können.

Measuring and testing for the systemically important financial institutions

This paper analyzes the measure of systemic importance ∆CoV aR proposed by Adrian and Brunnermeier (2009, 2010) within the context of a similar class of risk measures used in the risk management literature. In addition, we develop a series of testing procedures, based on ∆CoV aR, to identify and rank the systemically important institutions. We stress the importance of statistical testing in interpreting the measure of systemic importance. An empirical application illustrates the testing procedures, using equity data for three European banks.

Variable mixed-mode delamination in composite laminates under fatigue conditions: testing & analysis

La majoria de les fallades en elements estructurals són degudes a càrrega per fatiga. En conseqüència, la fatiga mecànica és un factor clau per al disseny d'elements mecànics. En el cas de materials compòsits laminats, el procés de fallada per fatiga inclou diferents mecanismes de dany que resulten en la degradació del material. Un dels mecanismes de dany més importants és la delaminació entre capes del laminat. En el cas de components aeronàutics, les plaques de composit estan exposades a impactes i les delaminacions apareixen facilment en un laminat després d'un impacte. Molts components fets de compòsit tenen formes corbes, superposició de capes i capes amb diferents orientacions que fan que la delaminació es propagui en un mode mixt que depen de la grandària de la delaminació. És a dir, les delaminacions generalment es propaguen en mode mixt variable. És per això que és important desenvolupar nous mètodes per caracteritzar el creixement subcrític en mode mixt per fatiga de les delaminacions. El principal objectiu d'aquest treball és la caracterització del creixement en mode mixt variable de les delaminacions en compòsits laminats per efecte de càrregues a fatiga. Amb aquest fi, es proposa un nou model per al creixement per fatiga de la delaminació en mode mixt. Contràriament als models ja existents, el model que es proposa es formula d'acord a la variació no-monotònica dels paràmetres de propagació amb el mode mixt observada en diferents resultats experimentals. A més, es du a terme un anàlisi de l'assaig mixed-mode end load split (MMELS), la característica més important del qual és la variació del mode mixt a mesura que la delaminació creix. Per a aquest anàlisi, es tenen em compte dos mètodes teòrics presents en la literatura. No obstant, les expressions resultants per l'assaig MMELS no són equivalents i les diferències entre els dos mètodes poden ser importants, fins a 50 vegades. Per aquest motiu, en aquest treball es porta a terme un anàlisi alternatiu més acurat del MMELS per tal d'establir una comparació. Aquest anàlisi alternatiu es basa en el mètode dels elements finits i virtual crack closure technique (VCCT). D'aquest anàlisi en resulten importants aspectes a considerar per a la bona caracterització de materials utilitzant l'assaig MMELS. Durant l'estudi s'ha dissenyat i construït un utillatge per l'assaig MMELS. Per a la caracterització experimental de la propagació per fatiga de delaminacions en mode mixt variable s'utilitzen diferents provetes de laminats carboni/epoxy essencialment unidireccionals. També es du a terme un anàlisi fractogràfic d'algunes de les superfícies de fractura per delaminació. Els resultats experimentals són comparats amb les prediccions del model proposat per la propagació per fatiga d'esquerdes interlaminars.

Bayesian model averaging and identification of structural breaks in time series

Bayesian Model Averaging (BMA) is used for testing for multiple break points in univariate series using conjugate normal-gamma priors. This approach can test for the number of structural breaks and produce posterior probabilities for a break at each point in time. Results are averaged over specifications including: stationary; stationary around trend and unit root models, each containing different types and number of breaks and different lag lengths. The procedures are used to test for structural breaks on 14 annual macroeconomic series and 11 natural resource price series. The results indicate that there are structural breaks in all of the natural resource series and most of the macroeconomic series. Many of the series had multiple breaks. Our findings regarding the existence of unit roots, having allowed for structural breaks in the data, are largely consistent with previous work.