Tetrahydrobenzo[h][1,6]naphthyridine-6-chlorotacrine hybrids as a new family of anti-Alzheimer agents targeting beta-amyloid, tau, and cholinesterase pathologies

Optimization of an essentially inactive 3,4-dihydro-2H-pyrano[3,2-c]quinoline carboxylic ester derivative as acetylcholinesterase (AChE) peripheral anionic site (PAS)-binding motif by double O → NH bioisosteric replacement, combined with molecular hybridization with the AChE catalytic anionic site (CAS) inhibitor 6-chlorotacrine and molecular dynamics-driven optimization of the length of the linker has resulted in the development of the trimethylene-linked 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine6-chlorotacrine hybrid 5a as a picomolar inhibitor of human AChE (hAChE). The tetra-, penta-, and octamethylene-linked homologues 5bd have been also synthesized for comparison purposes, and found to retain the nanomolar hAChE inhibitory potency of the parent 6-chlorotacrine. Further biological profiling of hybrids 5ad has shown that they are also potent inhibitors of human butyrylcholinesterase and moderately potent Aβ42 and tau anti-aggregating agents, with IC50 values in the submicromolar and low micromolar range, respectively. Also, in vitro studies using an artificial membrane model have predicted a good brain permeability for hybrids 5ad, and hence, their ability to reach their targets in the central nervous system. The multitarget profile of the novel hybrids makes them promising leads for developing anti-Alzheimer drug candidates with more balanced biological activities.

Control and femtosecond time-resolved imaging of torsion in a chiral molecule

We study how the combination of long and short laser pulses can be used to induce torsion in an axially chiral biphenyl derivative (3,5-difluoro-3 ,5 -dibromo-4 -cyanobiphenyl). A long, with respect to the molecular rotational periods, elliptically polarized laser pulse produces 3D alignment of the molecules, and a linearly polarized short pulse initiates torsion about the stereogenic axis. The torsional motion is monitored in real-time by measuring the dihedral angle using femtosecond time-resolved Coulomb explosion imaging. Within the first 4 picoseconds (ps), torsion occurs with a period of 1.25 ps and an amplitude of 3◦ in excellent agreement with theoretical calculations. At larger times, the quantum states of the molecules describing the torsional motion dephase and an almost isotropic distribution of the dihedral angle is measured.We demonstrate an original application of covariance analysis of two-dimensional ion images to reveal strong correlations between specific ejected ionic fragments from Coulomb explosion. This technique strengthens our interpretation of the experimental data

Um paradigma da química medicinal: a flexibilidade dos ligantes e receptores

In general, molecular modeling techniques applied in medicinal chemistry have been static and drug based. However the active site geometry and the intrinsic flexibility of both receptor and ligand are fundamental properties for molecular recognition and drug action. As a consequence, the use of dynamic models to describe the ligand-receptor complex is becoming a more common procedure. In this work we discuss the relevance of considering the receptor structure in medicinal chemistry studies as well as the flexibility of the ligand-receptor complex.

Investigating the spontaneous formation of SDS micelle in aqueous solution using a coarse-grained force field

A 1µs Molecular Dynamic simulation was performed with a realistic model system of Sodium Dodecyl Sulfate (SDS) micelles in aqueous solution, comprising of 360 DS-, 360 Na+ and 90000 water particles. After 300 ns three different micellar shapes and sizes 41, 68 and 95 monomers, were observed. The process led to stabilization in the total number of SDS clusters and an increase in the micellar radius to 2.23 nm, in agreement with experimental results. An important conclusion, is be aware that simulations employed in one aggregate, should be considered as a constraint. Size and shape distribution must be analyzed.

Software para simulação de mecanismo de supressão da luminescência: modelo cinético de Stern-Volmer

A software that includes both Stochastic and Molecular Dynamics procedures has been developed with the aim of visualizing the Stern-Volmer kinetic mechanism of dynamic luminescence quenching. The software allows the student to easily simulate and graphically visualize the molecular collisions, the molecular speed distributions, the luminescence decay curves, and the Stern-Volmer graphs. The software named "SternVolmer" is written for the FreeBASIC compiler and can be applied to dynamic systems where luminescent molecules, during their excited state lifetimes, are able to collide with quenching molecules (collisional quenching). The good agreement found between the simulations and the expected results shows that this software can be used as an effective teaching aid for the study of luminescence and kinetic decay of excited states.

MÉTODO ALTERNATIVO PARA A SÍNTESE E MECANISMO DE 2-(1,3-DITIANO-2-ILIDENO)-ACETONITRILA

We report an alternative method for the synthesis of 2-(1,3-dithian-2-ylidene)-acetonitrile using 3-(4-chlorophenyl)-3-oxopropanenitrile and carbon disulfide as starting materials. The methanolysis of the intermediate 3-(4-chlorophenyl)-2-(1,3-dithian-2-ylidene)-3-oxopropanenitrile occurs via three possible intermediates, leading to the formation of the product at a 75% overall yield. Molecular modeling simulation of the reaction pathway using B3LYP 6-311G++(2df,2p) justified the proposed reaction mechanism.

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.

Flexible multibody approach in bone strain estimation during physical activity:

Bone strain plays a major role as the activation signal for the bone (re)modeling process, which is vital for keeping bones healthy. Maintaining high bone mineral density reduces the chances of fracture in the event of an accident. Numerous studies have shown that bones can be strengthened with physical exercise. Several hypotheses have asserted that a stronger osteogenic (bone producing) effect results from dynamic exercise than from static exercise. These previous studies are based on short-term empirical research, which provide the motivation for justifying the experimental results with a solid mathematical background. The computer simulation techniques utilized in this work allow for non-invasive bone strain estimation during physical activity at any bone site within the human skeleton. All models presented in the study are threedimensional and actuated by muscle models to replicate the real conditions accurately. The objective of this work is to determine and present loading-induced bone strain values resulting from physical activity. It includes a comparison of strain resulting from four different gym exercises (knee flexion, knee extension, leg press, and squat) and walking, with the results reported for walking and jogging obtained from in-vivo measurements described in the literature. The objective is realized primarily by carrying out flexible multibody dynamics computer simulations. The dissertation combines the knowledge of finite element analysis and multibody simulations with experimental data and information available from medical field literature. Measured subject-specific motion data was coupled with forward dynamics simulation to provide natural skeletal movement. Bone geometries were defined using a reverse engineering approach based on medical imaging techniques. Both computed tomography and magnetic resonance imaging were utilized to explore modeling differences. The predicted tibia bone strains during walking show good agreement with invivo studies found in the literature. Strain measurements were not available for gym exercises; therefore, the strain results could not be validated. However, the values seem reasonable when compared to available walking and running invivo strain measurements. The results can be used for exercise equipment design aimed at strengthening the bones as well as the muscles during workout. Clinical applications in post fracture recovery exercising programs could also be the target. In addition, the methodology introduced in this study, can be applied to investigate the effect of weightlessness on astronauts, who often suffer bone loss after long time spent in the outer space.

Computational chemistry studies of wood-derived lignans

This thesis is based on computational chemistry studies on lignans, focusing on the naturally occurring lignan hydroxymatairesinol (HMR) (Papers I II) and on TADDOL-like conidendrin-based chiral 1,4-diol ligands (LIGNOLs) (Papers III V). A complete quantum chemical conformational analysis on HMR was previously conducted by Dr. Antti Taskinen. In the works reported in this thesis, HMR was further studied by classical molecular dynamics (MD) simulations in aqueous solution including torsional angle analysis, quantum chemical solvation e ect study by the COnductorlike Screening MOdel (COSMO), and hydrogen bond analysis (Paper I), as well as from a catalytic point of view including protonation and deprotonation studies at di erent levels of theory (Paper II). The computational LIGNOL studies in this thesis constitute a multi-level deterministic structural optimization of the following molecules: 1,1-diphenyl (2Ph), two diastereomers of 1,1,4-triphenyl (3PhR, 3PhS), 1,1,4,4-tetraphenyl (4Ph) and 1,1,4,4-tetramethyl (4Met) 1,4-diol (Paper IV) and a conformational solvation study applying MD and COSMO (Paper V). Furthermore, a computational study on hemiketals in connection with problems in the experimental work by Docent Patrik Eklund's group synthesizing the LIGNOLs based on natural products starting from HMR, is shortly described (Paper III).

Kaivoslastauskoneen hybridisointianalyysi virtuaali- ja in-loop -simuloinnin avulla

Työssä tutkitaan raskaiden työkoneiden hybridisointimitoitusta simuloimalla. Työssä esitetään simulation-in-the-loop-simulointiin perustuva järjestelmä, jolla esimerkkitapauksena oleva kaivoslastauskone työympäristöineen voidaan mallintaa mekaaniselta osaltaan monikappaledynamiikkaan perustuvalla ohjelmistolla ja hybridijärjestelmän osalta Simulinkissa. Yhdistetty simulointi mahdollistaa hybridityökoneen virtuaalimallin ohjaamisen käyttäjän toimesta reaaliajassa. Simuloinnista saadaan tuloksena mm. työsykli, jota voidaan käyttää hybridisointimitoitukseen. Hybridisointi toteutetaan kahdella erilaisella kokoonpanolla, joista analysoidaan suorituskykyä sekä polttoaineen kulutusta. Tuloksia verrataan pelkästään dieselmoottoria voimanlähteenä käyttävään lastauskoneeseen. Työssä tehty tutkimus osoittaa, että (sarja-) hybridisoinnilla voidaan saavuttaa merkittäviä etuja raskaiden työkoneiden polttoainetehokkuudessa. Dieselmoottoria voidaan ajaa sellaisessa staattisessa toimintapisteessä, jonka hyötysuhde on korkea riippumatta työkoneen kuormituksesta. Saavutettu hyöty on toteutetussa tutkimuksessa parhaimmillaan jopa 56 % vähennys polttoaineenkulutuksessa. Lisäksi tarvittava dieselin nimellisteho pienenee huomattavasti. Tutkimuksen osana esitellään myös Hardware-in-the-Loop -laitteisto, jonka avulla voidaan liittää oikea sähkömoottori ja taajuudenmuuttaja osaksi virtuaalisesti simuloitua työkonetta.

Vibrations in Rotating Machinery Arising from Minor Imperfections in Component Geometries

Vibrations in machines can cause noise, decrease the performance, or even damage the machine. Vibrations appear if there is a source of vibration that excites the system. In the worst case scenario, the excitation frequency coincides with the natural frequency of the machine causing resonance. Rotating machines are a machine type, where the excitation arises from the machine itself. The excitation originates from the mass imbalance in the rotating shaft, which always exists in machines that are manufactured using conventional methods. The excitation has a frequency that is dependent on the rotational speed of the machine. The rotating machines in industrial use are usually designed to rotate at a constant rotational speed, the case where the resonances can be easily avoided. However, the machines that have a varying operational speed are more problematic due to a wider range of frequencies that have to be avoided. Vibrations, which frequencies equal to rotational speed frequency of the machine are widely studied and considered in the typical machine design process. This study concentrates on vibrations, which arise from the excitations having frequencies that are multiples of the rotational speed frequency. These vibrations take place when there are two or more excitation components in a revolution of a rotating shaft. The dissertation introduces four studies where three kinds of machines are experiencing vibrations caused by different excitations. The first studied case is a directly driven permanent magnet generator used in a wind power plant. The electromagnetic properties of the generator cause harmonic excitations in the system. The dynamic responses of the generator are studied using the multibody dynamics formulation. In another study, the finite element method is used to study the vibrations of a magnetic gear due to excitations, which frequencies equal to the rotational speed frequency. The objective is to study the effects of manufacturing and assembling inaccuracies. Particularly, the eccentricity of the rotating part with respect to non-rotating part is studied since the eccentric operation causes a force component in the direction of the shortest air gap. The third machine type is a tube roll of a paper machine, which is studied while the tube roll is supported using two different structures. These cases are studied using different formulations. In the first case, the tube roll is supported by spherical roller bearings, which have some wavinesses on the rolling surfaces. Wavinesses cause excitations to the tube roll, which starts to resonate at the frequency that is a half of the first natural frequency. The frequency is in the range where the machine normally operates. The tube roll is modeled using the finite element method and the bearings are modeled as nonlinear forces between the tube roll and the pedestals. In the second case studied, the tube roll is supported by freely rotating discs, which wavinesses are also measured. The above described phenomenon is captured as well in this case, but the simulation methodology is based on the flexible multibody dynamics formulation. The simulation models that are used in both of the last two cases studied are verified by measuring the actual devices and comparing the simulated and measured results. The results show good agreement.

Nonconventional amide bond formation catalysis: programming enzyme specificity with substrate mimetics

This article reports on the design and characteristics of substrate mimetics in protease-catalyzed reactions. Firstly, the basis of protease-catalyzed peptide synthesis and the general advantages of substrate mimetics over common acyl donor components are described. The binding behavior of these artificial substrates and the mechanism of catalysis are further discussed on the basis of hydrolysis, acyl transfer, protein-ligand docking, and molecular dynamics studies on the trypsin model. The general validity of the substrate mimetic concept is illustrated by the expansion of this strategy to trypsin-like, glutamic acid-specific, and hydrophobic amino acid-specific proteases. Finally, opportunities for the combination of the substrate mimetic strategy with the chemical solid-phase peptide synthesis and the use of substrate mimetics for non-peptide organic amide synthesis are presented.

Electron paramagnetic resonance study of lipid and protein membrane components of erythrocytes oxidized with hydrogen peroxide

Electron paramagnetic resonance (EPR) spectroscopy of spin labels was used to monitor membrane dynamic changes in erythrocytes subjected to oxidative stress with hydrogen peroxide (H2O2). The lipid spin label, 5-doxyl stearic acid, responded to dramatic reductions in membrane fluidity, which was correlated with increases in the protein content of the membrane. Membrane rigidity, associated with the binding of hemoglobin (Hb) to the erythrocyte membrane, was also indicated by a spin-labeled maleimide, 5-MSL, covalently bound to the sulfhydryl groups of membrane proteins. At 2% hematocrit, these alterations in membrane occurred at very low concentrations of H2O2 (50 µM) after only 5 min of incubation at 37°C in azide phosphate buffer, pH 7.4. Lipid peroxidation, suggested by oxidative hemolysis and malondialdehyde formation, started at 300 µM H2O2 (for incubation of 3 h), which is a concentration about six times higher than those detected with the probes. Ascorbic acid and α-tocopherol protected the membrane against lipoperoxidation, but did not prevent the binding of proteins to the erythrocyte membrane. Moreover, the antioxidant (+)-catechin, which also failed to prevent the cross-linking of cytoskeletal proteins with Hb, was very effective in protecting erythrocyte ghosts from lipid peroxidation induced by the Fenton reaction. This study also showed that EPR spectroscopy can be useful to assess the molecular dynamics of red blood cell membranes in both the lipid and protein domains and examine oxidation processes in a system that is so vulnerable to oxidation.

Improving Cost-Efficiency and Reducing Environmental Impacts of Intermodal Transportation with Dry Port Concept – Major Rail Transport Corridor in Baltic Sea Region

Transportation plays a major role in the gross domestic product of various nations. There are, however, many obstacles hindering the transportation sector. Cost-efficiency along with proper delivery times, high frequency and reliability are not a straightforward task. Furthermore, environmental friendliness has increased the importance of the whole transportation sector. This development will change roles inside the transportation sector. Even now, but especially in the future, decisions regarding the transportation sector will be partly based on emission levels and other externalities originating from transportation in addition to pure transportation costs. There are different factors, which could have an impact on the transportation sector. IMO’s sulphur regulation is estimated to increase the costs of short sea shipping in the Baltic Sea. Price development of energy could change the roles of different transport modes. Higher awareness of the environmental impacts originating from transportation could also have an impact on the price level of more polluting transport modes. According to earlier research, increased inland transportation, modal shift and slowsteaming can be possible results of these changes in the transportation sector. Possible changes in the transportation sector and ways to settle potential obstacles are studied in this dissertation. Furthermore, means to improve cost-efficiency and to decrease environmental impacts originating from transportation are researched. Hypothetical Finnish dry port network and Rail Baltica transport corridor are studied in this dissertation. Benefits and disadvantages are studied with different methodologies. These include gravitational models, which were optimized with linear integer programming, discrete-event and system dynamics simulation, an interview study and a case study. Geographical focus is on the Baltic Sea Region, but the results can be adapted to other geographical locations with discretion. Results indicate that the dry port concept has benefits, but optimization regarding the location and the amount of dry ports plays an important role. In addition, the utilization of dry ports for freight transportation should be carefully operated, since only a certain amount of total freight volume can be cost-efficiently transported through dry ports. If dry ports are created and located without proper planning, they could actually increase transportation costs and delivery times of the whole transportation system. With an optimized dry port network, transportation costs can be lowered in Finland with three to five dry ports. Environmental impacts can be lowered with up to nine dry ports. If more dry ports are added to the system, the benefits become very minor, i.e. payback time of investments becomes extremely long. Furthermore, dry port network could support major transport corridors such as Rail Baltica. Based on an analysis of statistics and interview study, there could be enough freight volume available for Rail Baltica, especially, if North-West Russia is part of the Northern end of the corridor. Transit traffic to and from Russia (especially through the Baltic States) plays a large role. It could be possible to increase transit traffic through Finland by connecting the potential Finnish dry port network and the studied transport corridor. Additionally, sulphur emission regulation is assumed to increase the attractiveness of Rail Baltica in the year 2015. Part of the transit traffic could be rerouted along Rail Baltica instead of the Baltic Sea, since the price level of sea transport could increase due to the sulphur regulation. Both, the hypothetical Finnish dry port network and Rail Baltica transport corridor could benefit each other. The dry port network could gain more market share from Russia, but also from Central Europe, which is the other end of Rail Baltica. In addition, further Eastern countries could also be connected to achieve higher potential freight volume by rail.

Virtuaaliprototyypin käyttö roottorin dynamiikan analysoinnissa

Työn tavoitteena oli selvittää kaupallisen dynamiikansimulointiohjelmiston so-veltuvuus roottoridynamiikan analysointiin. Työssä keskityttiin erityisesti rootto-rin dynamiikkaan vaikuttavien epäideaalisuuksien mallintamiseen. Simulointitu-losten tarkkuutta selvitettiin mittauksilla. Lisäksi vertailtiin yleiskäyttöisen dyna-miikan simulointiohjelmiston ja roottoridynamiikan erikoisohjelmiston teoriaa. Tutkittava roottori oli paperikoneen putkitela. Telan joustavuus kuvattiin ele-menttimenetelmällä ratkaistujen moodien avulla. Elementtimallissa huomioitiin telan vaipan seinämänpaksuusvaihtelu, joka vaikuttaa telan massa- ja jäykkyysja-kaumaan. Dynamiikkaohjelmistossa mallinnettiin telan tuennasta tulevat herätteet. Dynamiikkaohjelmistona käytettiin ADAMS:ia ja FEM-ohjelmana ANSYS:stä. Tuloksista havaittiin käytetyn menetelmän soveltuvan roottoridynamiikan ana-lysointiin ja roottorin epäideaalisuuksien mallintamiseen. Simulointimallilla saa-tiin esille murtolukukriittiset pyörimisnopeudet ja telan kriittinen pyörimisnopeus vastasi hyvin mittaustuloksia.