1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

1,2,3,4-Tetrahydrobenzo[h][1,6]naphthyridines as a new family of potent peripheral-to-midgorge-site inhibitors of acetylcholinesterase: synthesis, pharmacological evaluation and mechanistic studies

A series of 1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridines differently substituted at positions 1, 5, and 9 have been designed from the pyrano[3,2-c]quinoline derivative 1, a weak inhibitor of acetylcholinesterase (AChE) with predicted ability to bind to the AChE peripheral anionic site (PAS), at the entrance of the catalytic gorge. Fourteen novel benzonaphthyridines have been synthesized through synthetic sequences involving as the key step a multicomponent Povarov reaction between an aldehyde, an aniline and an enamine or an enamide as the activated alkene. The novel compounds have been tested against Electrophorus electricus AChE (EeAChE), human recombinant AChE (hAChE), and human serum butyrylcholinesterase (hBChE), and their brain penetration has been assessed using the PAMPA-BBB assay. Also, the mechanism of AChE inhibition of the most potent compounds has been thoroughly studied by kinetic studies, a propidium displacement assay, and molecular modelling. We have found that a seemingly small structural change such as a double O → NH bioisosteric replacement from the hit 1 to 16a results in a dramatic increase of EeAChE and hAChE inhibitory activities (>217- and >154-fold, respectively), and in a notable increase in hBChE inhibitory activity (> 11-fold), as well. An optimized binding at the PAS besides additional interactions with AChE midgorge residues seem to account for the high hAChE inhibitory potency of 16a (IC50 = 65 nM), which emerges as an interesting anti-Alzheimer lead compound with potent dual AChE and BChE inhibitory activities.

Azimuth thrusterin rungon lujuustekninen tarkastelu

Työssä perehdyttiin azimuth potkurilaitteen rakenteelliseen kestävyyteen vaikuttaviin seikkoihin. Työn tavoitteena oli tutkia eri rakenneratkaisuja ja yksityiskohtia sekä niiden vaikutusta koko potkurilaitteen toimintaan. Potkurilaitteiden lujuustekninen tarkastelu sisälsi rakenteen eheyden tarkistuksen mekaanisten kuormitusten alla kuin myös värähtelykäyttäytymisen tutkimisen. Tarkastelun pääsääntöinen kohde oli potkurilaitteen alarunko, eli laivan ulkopuolelle jäävä osa. Diplomityö oli osa kahden uuden potkurilaitteen kehitysprojektia. Projektissa esiin tulleita rakennemuutoksia vertailtiin vanhoihin, jo toteutettuihin rakenneyksityiskohtiin. Lisäksi tutkittiin olemassa olevien rakenneratkaisujen hyödyntämistä uusissa laitteissa. Huomiota kiinnitettiin myös hitsien muotoiluun ja näiden mitoituskäytäntöihin. Rungon ehyyttä koskevat laskelman ovat hyvin pitkälti suoritettu elementtimenetelmää apuna käyttäen. Elementtimenetelmää varten luotiin useita malleja kattaen kokonaisia potkurilaittee runkoja kuin myös sen yksittäisiä osia. Elementtimenetelmän avulla saatuja tuloksia vertailtiin käytettävissä oleviin mittaustuloksiin. Työssä havaittiin potkurilaitteen rungon mitoittavaksi tekijäksi staattisessa tilanteessa muodostuvan voimansiirtolinja ja siinä sijaitsevien hammaspyörien siirtymät. Tämän seurauksena rungon taipumat ovat määräävämpiä geometrian kannalta kuin materiaalien sallitut jännitykset.

Conceitos de química dos ingressantes nos cursos de graduação do Instituto de Química da Universidade de São Paulo

A diagnostic instrument was developed to evaluate the basic chemistry concepts held by freshmen students of the three Chemistry undergraduate courses offered by the University of São Paulo. The instrument minimizes the use of algorithms or memorization by students and values high-order cognitive skills. Analysis of the students' performances reveals systematic use of "displacement reaction" as an algorithm and a mechanical use of Le Chatelier's Principle. Failure in comprehending the chemical equation and chemical language drives students to alternative models for chemical reactions in aqueous solution. For instance, reaction would occur between "ionic pairs" and/or between species situated in separate compartments.

Hidrogenação eletrocatalítica de substratos orgânicos utilizando eletrodos modificados poliméricos contendo partículas de Ni/Pd e Ni/Pt

Novel modified electrodes bearing dispersed Pd and Pt particles have been prepared from poly (allyl ether of the p-benzenesulfonic acid) films with incorporated nickel particles making use of galvanic displacement reactions. The SEM analysis of the new modified electrodes revealed efficient deposition of Pd but weak up-take of Pt. Electrocatalytic hydrogenation of several classes of organic substrates were carried out using the MEs Ni, Ni/Pd and Ni/Pt. The Ni/Pd ME showed to be the best of them for the hydrogenation of double, triple and carbonyl bonds. The complete hydrogenation of the aromatic rings for the well-adsorbed substrates acetophenone and benzophenone is noteworthy.

Nanocompósitos de poliuretana termoplástica e nanotubos de carbono de paredes múltiplas para dissipação eletrostática

Polyurethane/multi-walled carbon nanotube (MWCNT) nanocomposites have been prepared with nanotube concentrations between 0.01 wt% and 1 wt%. MWCNT as-synthesized samples with ~74 nm diameter and ~7 μm length were introduced by solution processing in the polyurethane matrix. Scanning electron microscopy (SEM) images demonstrated good dispersion and adhesion of the CNTs to the polymeric matrix. The C=O stretching band showed evidence of perturbation of the hydrogen interaction between urethanic moieties in the nanocomposites as compared to pure TPU. Differential scanning calorimetry and positron anihilation lifetime spectroscopy measurements allowed the detection of glass transition displacement with carbon nanotube addition. Furthermore, the electrical conductivity of the nanocomposites was significantly increased with the addition of CNT.

Energia de superfície para nanossuperfícies de TiO2 na direção (001)

In this work was made an investigation about bulk and surface models (at maximum 20 layers) of the TiO2 material in the (001) direction. TiO2 commercial sample was feature using XDR technique to determine phase and crystallites average size. Bulk and (001) surface models were simulated for TiO2 material using DFT/B3LYP and its results were used for calculating energy surface, electronic levels, superficial atomic displacement and charge maps. Atoms of the first and second layers of the slab model showed electronic densities very well organized in the form of chains or wires.

Theoretical investigations of the bulk modulus in the tetra-cubic transition of PbTiO3 material

Resulting from ion displacement in a solid under pressure, piezoelectricity is an electrical polarization that can be observed in perovskite-type electronic ceramics, such as PbTiO3, which present cubic and tetragonal symmetries at different pressures. The transition between these crystalline phases is determined theoretically through the bulk modulus from the relationship between material energy and volume. However, the change in the material molecular structure is responsible for the piezoelectric effect. In this study, density functional theory calculations using the Becke 3-Parameter-Lee-Yang-Parr hybrid functional were employed to investigate the structure and properties associated with the transition state of the tetragonal-cubic phase change in PbTiO3 material.

MÉTODO DE SÍNTESE DE AZIDAS AROMÁTICAS USANDO VINAGRE

The present paper describes a simple and low-cost procedure for preparation of aryl azides from anilines using vinegar as an unusual solvent/reagent. We observed the sequence of diazotation followed by diazo displacement with sodium azide can be carried out in aqueous solution of acetic acid

OBTENÇÃO E CARACTERIZAÇÃO DE MATERIAL HÍBRIDO ENTRE SÍLICA E CICLODEXTRINAS

The obtention of silica and cyclodextrin hybrid materials was accomplished by refluxing them in xylol using citric acid as a binding agent. The materials were characterized by infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, scanning electron microscopy, and elemental analysis. Evidence for the docking of cyclodextrins α and γ was substantiated based on the variation in band intensity for groups such as ≡Si-OH. Additional docking evidence includes the displacement of some of the bands that are related to cyclodextrin such as the deformation of the C-H axial bond. The α and γ-CDSi materials were characterized as amorphous compounds. The products obtained in the synthesis showed changes in the decomposition temperatures of their isolated constituents, in which the mass of α and γ-CD docked to the silica surface gave the estimated values of 41% and 47%, respectively. The elemental constituents were shown to be consistent and close to their relative theoretical values. ​Thermogravimetric analysis showed that a reduction in the percentage of the hybrids was proportional to the amount of lost mass. This new material is an improvement over synthesized organosilane materials because the operator and the environment benefit from a less toxic methodology. In addition, the material has several potential applications in complexation systems with cyclodextrin.

Painediffusöörin suunnitteluperusteiden kehittäminen

Pesu on tärkeä osa sellun tuotantoprosessia. Eräs tapa toteuttaa sellun pesu on käyttää painediffusööriä. Painediffusööri toimii syrjäytyspesuperiaatteella, eli poistaa sellu-massasta keittolipeää paineistetun pesuveden avulla. Työssä on kehitetty painediffusöörin suunnittelun lähtökohtia keräämällä tietoa laitteen toiminnasta, rakenteesta, valmistuksesta sekä nykyisistä epäkohdista, joihin esitetään parannusmahdollisuuksia. Tärkeimmät kehitysalueet laitteessa ovat valmistus-toleranssien väljentäminen sekä sihdin pystysuuntaisen liikkeen tuottaminen. Laitteen valmistustoleranssit on analysoitu perusteellisesti, ja niiden väljentämis-mahdollisuuksia on tutkittu. Väljentämiseen ehdotetaan erilaisia keinoja. Sihdin liike tuotetaan tällä hetkellä hydrauliikalla. Hydrauliikkakomponenteille on koottu mitoitusohjeita, joiden jälkeen esitellään keinoja hydrauliikkajärjestelmän kehittämiseen. Lopuksi esitellään muita lineaarisen liikkeen tuottamisvaihtoehtoja, joilla hydrauliikan voisi korvata. Rakenteessa käytetyille valmistusmateriaaleille on etsitty olemassa olevat yleisimpien materiaalistandardien mukaiset nimikkeet materiaalinvalinnan helpottamiseksi jatkossa. Pääasiallisten valmistusmateriaalien lisäksi on kerätty tietoa myös vaihtoehtoisista konstruktiomateriaaleista sekä materiaalinvalinnasta ja tuotesuunnittelusta yleensä.

The intrinsic mechanisms of softwood fiber damage in brown stock fiber line unit operations Lappeenranta 2010

The effects of pulp processing on softwood fiber properties strongly influence the properties of wet and dry paper webs. Pulp strength delivery studies have provided observations that much of the strength potential of long fibered pulp is lost during brown stock fiber line operations where the pulp is merely washed and transferred to the subsequent processing stages. The objective of this work was to study the intrinsic mechanisms which maycause fiber damage in the different unit operations of modern softwood brown stock processing. The work was conducted by studying the effects of industrial machinery on pulp properties with some actions of unit operations simulated in laboratory scale devices under controlled conditions. An optical imaging system was created and used to study the orientation of fibers in the internal flows during pulp fluidization in mixers and the passage of fibers through the screen openings during screening. The qualitative changes in fibers were evaluated with existing and standardized techniques. The results showed that each process stage has its characteristic effects on fiber properties: Pulp washing and mat formation in displacement washers introduced fiber deformations especially if the fibers entering the stage were intact, but it did not decrease the pulp strength properties. However, storage chests and pulp transfer after displacement washers contributed to strength deterioration. Pulp screening proved to be quite gentle, having the potential of slightly evening out fiber deformations from very deformed pulps and vice versa inflicting a marginal increase in the deformation indices if the fibers were previously intact. Pulp mixing in fluidizing industrial mixers did not have detrimental effects on pulp strength and had the potential of slightly evening out the deformations, provided that the intensity of fluidization was high enough to allow fiber orientation with the flow and that the time of mixing was short. The chemical and mechanical actions of oxygen delignification had two distinct effects on pulp properties: chemical treatment clearly reduced pulp strength with and without mechanical treatment, and the mechanical actions of process machinery introduced more conformability to pulp fibers, but did not clearly contribute to a further decrease in pulp strength. The chemical composition of fibers entering the oxygen stage was also found to affect the susceptibility of fibers to damage during oxygen delignification. Fibers with the smallest content of xylan were found to be more prone to irreversibledeformations accompanied with a lower tensile strength of the pulp. Fibers poor in glucomannan exhibited a lower fiber strength while wet after oxygen delignification as compared to the reference pulp. Pulps with the smallest lignin content on the other hand exhibited improved strength properties as compared to the references.

Nosturin kuormauselimen liitynnän suunnittelu

Paperiteollisuuden prosessituotteista paperia varastoidaan erikokoisina rullina esim. pystyrullavarastoihin. Tämän diplomityön tavoitteena oli kehittää Konecranesin prosessinosturille liityntä paperirullia käsittelevän kuormauselimen ja nosturin välille. Tavoitteena oli löytää kiinnitysmenetelmä, joka mahdollistaa nosturien joustavan käytön mahdollisimman pienin muutoksin itse nosturin standardoituun rakenteeseen. Pääasiallisena syventymisen kohteena oli alipaineella paperirullia nostettavan kuormauselimen liityntä. Liitynnän on kyettävä joustamaan ja vaimentamaan paperirullia nostavaan kuormauselimeen nosturin liikkeelle lähdöstä ja pysähtymisestä syntyvät herätteet ja voimat. Nosturin liikenopeus on kyettävä pitämään mahdollisimman suurena lyhyen rullienkäsittelyajan saavuttamiseksi. Liitynnältä vaaditaan kykyä ottaa kuormauselin vastaan mahdollisimman suurella nostonopeudella. Lisäksi kuorman ja kuormauselimen oskillaatio on vaimennettava mahdollisimman nopeasti samalla rajoittaen heilunnasta aiheutuvaa maksimi siirtymää. Liitynnän suunnittelu pohjautuu nosturin, kuormauselimen ja paperirullan muodostaman systeemin teoreettiseen tarkasteluun. Systeemistä laadittiin dynaaminen malli, jonka avulla tutkittiin oskillaation ja syntyvien kiihtyvyyksien suuruutta. Näiden teoriaan perustuvien tuloksien pohjalta suunniteltiin vaimennukseen tarvittavat vaimennuselementit ja liitynnän rakenne. Suunnittelutyön tuloksena saatiin liitynnälle alustava rakenne, joka mahdollistaa käytettävien vaimennuselementtien vaihtamisen ja siten tehokkaan heilunnan vaimmennuksen. Suunnittelutyön lähtökohtana oleva teoreettinen tarkastelu vaatii tuekseen esim. prototyypin kokeellisten tulosten saamiseksi ennen lopullisen tuotteen valmistamista. Suunnitteluprosessissa noudatettiin järjestelmällisen tuotesuunnittelun vaiheita ja menetelmiä.

Prolegomenon for an ethics of visibility in Hannah Arendt

This paper aims to discuss the Arendtian notions of appearance and perception in order to promote a displacement of those conceptions from the generally associated domain of passive apprehension of the faculty of knowledge towards the domain of a praxiology of action and language, based on an active perception. Arendt's appropriations on the Heideggerian "to take one's place" (sich hin-stellen) will be discussed, as well as the Augustinian "finding oneself in the world" (diligere). A twofold disposition of appearance will be distinguished: producing and position, whose transposed to the Arendtian notion of world correspond, respectively, to fabrication (poiesis) of the world, man's objective in-between space, and to action (praxis) in the world, man's subjective in-between space. Those conceptual replacements, in a broad sense, uphold a closer imbrication between the activities of the mind and acting, stricto sensu, and consequently, foment not only the valorization of the public space, but the visibility of our acts and deeds as well, calling out the dignity of appearance in ethics.