Proton channels are essential for many of the processes of life. The influenza A viral protein M2 is responsible for sensing the conditions necessary for viral RNA release. The proton-translocating FoF1 ATPase (ATP synthase) uses a proton gradient to drive adenosine triphosphate (ATP) synthesis. We have directly measured proton uptake in vesicles containing reconstituted M2 or FO by monitoring external pH after addition of valinomycin to vesicles with 100-fold diluted external [K+]. This proton flux assay was utilized to quantify proton flux through single M2 and Fo channels. Contrary to previous reports, proton uptake by M2 was not significantly altered by acidification of the extravesicular pH. We conclude that pH only weakly affects proton flux through M2 in the pH range of 5.4 - 7.0. Theoretical analysis utilized for such vesicle uptake assays illuminates the appropriate time scale of the initial slope and an important limitation that must be placed on inferences about channel ion selectivity. The rise in pH over 10 seconds after ionophore addition yielded time-averaged single channel conductances of 0.35±0.2 aS and 0.72±0.4 aS at pH 5.4 and 7.0 respectively. Such a low time-average conductance implies that M2 is only conductive 10^-6 to 10^-4 of the time. M2 selectivity for hydrogen over potassium is ~10^7. Fo translocates protons across membranes, converting electrochemical energy to rotational inertia. Previous experiments have been partially confounded by a contaminating channel, CL, which co-purifies with Fo and leaks cations. CL activity is shown to not decrease following deletion of the previously uncharacterized yraM open reading frame of E. coli. Fo purified from a deletion strain lacking yraM is just as active as Fo purified from the wild-type strain. Using Fo from the deletion strain, the single-hit hypothesis of DCCD inhibition of passive proton flux through Fo was examined. A DCCD-induced reduction in ATP synthase activity correlates with a reduction in the total initial slope, the number of functional Fo per µg protein, and the single channel proton flux. At least 2 DCCD per Fo are required to totally inactivate passive proton flux. M2 and Fo have similar single channel conductances but different open probabilities.

A library of 25 novel 3,6-disubstituted and 3-substituted pyrazolo[1,5-a]pyrimidines were synthesized using a microwave chemical reactor in 3 steps with a total reaction time of 1 hour. The products were obtained in good to excellent yields (20-93%, ave. = 62%). The synthesis began with the reaction of aryl acetonitriles with dimethylformamide-dimethylacetal (120C, 20 min), followed by treatment of the resulting 2-arylacrylonitrile with H2NNH2 • HBr (120C, 20 min). The intermediate 4-arylpyrazol-5-amine obtained was finally reacted with either 2-aryl-substituted malondialdehydes or 1,1,3,3-tetramethoxypropane (120C, 20 min) to give the final products. The products were either collected directly on a Buchner funnel or purified via flash chromatography. The compounds were screened for anti-cancer activity against the A2780 Ovarian cancer cell line in vitro at 10 µM. The most active compound was the 2-(pyrazolo[1,5-a]pyrimidin-3-yl)benzothiazole, herein referred to as RD-I-53, which had an EC50 value of 0.9 µM nearly mirroring the experimental control, Dorsomorphin, which had an EC50 of 1.1 µM. RD-I-53 was screened against a panel of 453 kinases by DiscoverX in a KinomeScan™, a competitive binding inhibition assay wherein RD-I-53 selectively inhibited VPS34 kinase and JAK1-JH2 pseudokinase (Kd VPS34 = 0.4µM, Kd JAK-1 JH2 = 0.5µM). NCI-60 data revealed selective anticancer activity of RD-I-53 against the MCF-7 and MDA-MB-468 breast cancer cell lines. Virtual docking studies of RD-I-53 against the VPS34 active site and its derivatives resulted in the creation of a virtual library of new compounds with potentially improved anticancer activity. A highly convergent route was developed to facilitate the ease of access to derivatives of RD-I-53. In the process, new methodologies for the synthesis of 2-aminobenzothiazoles and the thiocyanation of non-C4-substituted anilines and heterocycles were investigated and reported. A library of derivatives of RD-I-53 has been synthesized to be screened for potentially improved kinase inhibitory and anti-cancer activity.

No description available.

No description available.

<p>Flotation is a critical operation in the isolation of valuable minerals from natural ore. Before flotation, chemical collectors are routinely added to ground ore slurries. Collectors selectively bind to mineral-rich particles, increasing their hydrophobicity thus promoting selective flotation. Conventional collectors are small surfactants with a short hydrocarbon tail (2-6 carbons) and a head group, such as xanthate. In this work, much larger hydrophobic polystyrene nanoparticles are evaluated as potential flotation collectors. Experiments involving both clean model mineral suspensions and complex ultramafic nickel ores confirm that conventional water-soluble molecular collectors could be partially or completely replaced by colloidal hydrophobic nanoparticle flotation collectors.</p> <p>The ability of nanoparticles to induce flotation has been demonstrated by floating hydrophilic, negatively charged glass beads with cationic polystyrene nanoparticle collectors. Mechanisms and key parameters such as nanoparticle hydrophobicity and nanoparticle adsorption density have been identified. Electrostatic attraction promotes the spontaneous deposition of the nanoparticles on the glass surfaces raising the effective contact angle to facilitate the adhesion of beads to air bubbles. The pull-off force required to detach a glass sphere from the air/water interface of a bubble into the water was measured by micromechanics. Coating with nanoparticles allows the beads to attach remarkably firmly on the air bubble. As little as 10% coverage of the bead surfaces with the most effective nanoparticles could promote high flotation efficiencies, whereas conventional molecular collector requires 25% or higher coverage for a good recovery. Contact angle measurements of modified glass surfaces with a series of nanoparticles that covered a range of surface energies were used to correlate the nanoparticle surface properties with their ability to promote flotation of glass beads. Factors influencing nanoparticle deposition on glass, such as nanoparticle dosage, nanoparticle size, conditioning time have been investigated with a quartz crystal microbalance (QCM). Deposition kinetics has been analyzed according to Langmuir kinetics model.</p> <p>Surface functionalized nanoparticles enhance the ability of nanoparticle collectors to selectively deposit onto surfaces of the desired mineral particles in the presence of gangue materials. Poly (styrene-co-vinylimidazole) based nanoparticle collectors have been developed to selectively deposit onto nickel mineral (pentlandite) in the presence of Mg/Si slime. Flotation tests of ultramafic nickel ores with these nanoparticle collectors have shown improvements in both pentlandite recovery and selectivity.</p> / Doctor of Philosophy (PhD)

<p>Sensorineural hearing loss imparts two serious hearing deficits in hearing-impaired people: reduced dynamic range of hearing and reduced frequency selectivity. Psychophysically, these deficits render loss of speech audibility and speech intelligibility to a hearing-impaired person. Studies of an impaired cochlea in cats have shown that the hearing loss originates from damage to or complete loss of inner and outer hair cells. Neurophysiology of an impaired cochlea in cats shows that the tuning curves of the auditory nerve fibers become elevated and broadened. Amplification in hearing aids has been used to restore audibility in hearing-impaired people. Multiband compression has been commercially available in conventional hearing aids to compensate for the reduced dynamic range of hearing. However, little has been achieved to improve the intelligibility of speech in the hearing-impaired people. The aim of this thesis is to restore not only the speech audibility in a hearing-impaired person, but also to improve their speech intelligibility through some hearing-aid signal processing. The compensation technique used in this thesis for speech intelligibility is based on the hypothesis that a narrowband response of the auditory nerve fibers to speech signals ensure phonemic discriminability in the central nervous system.</p><p>Miller et al. [1999] have proposed contrast-enhancing frequency shaping ( CEFS) to compensate for the broadband responses of the fibers to first and second formants (Fl and F2) of a speech stimulus. Bruce [2004] has shown that the multiband compression can be combined with CEFS without counteracting each other. In Bruce's algorithm, a multiband compressor is serially combined with a time-domain CEFS filter. The MICEFS algorithm, herein presented, is a combination of multiband compression and an improved version of CEFS implemented in the frequency domain. The frequency domain implementation of MICEFS has improved the time delay response of the algorithm by 10 ms as compared to series implementation proposed by Bruce. The total time delay of the MICEFS algorithm is 16 ms, which is still longer than the standard time delay of 10 ms in hearing aids. The MICEFS algorithm was tested on a computational model of auditory periphery [Bruce et al., 2003] using a synthetic vowel and a synthetic sentence. The testing paradigm consisted of five conditions: 1) unmodified speech presented to a normal cochlea; 2) speech modified with halfgain rule presented to an impaired cochlea; 3) CEFS modified speech presented to the impaired cochlea; 4) speech modified with MICEFS presented to the impaired cochlea, and; 5) MICEFS-modified speech with some added noise in the formant estimation presented to an impaired cochlea. The spectral enhancement filter used in MICEFS has improved the synchrony capture of the fibers to the first three formants of a speech stimulus. MICEFS has also restored the correct tonotopic representation in the average discharge rate of the fibers at the first three formants of the speech.</p> / Thesis / Master of Applied Science (MASc)

Commodity projection studies anticipate an exponential increase in copper demand and decreasein mill grade of deposits currently exploited globally. Most of this demand is driven by theindispensable use of copper in electrification and currently, the growing demand in the contextof the green transition. To meet this challenge while supplying society with copper, producerssuch as Boliden AB have plans for exploration and expansion projects to increase their reservesand in turn increase production through efficient measures. As grinding is a bottleneck to mineralprocessing and the most energy intensive, more efficient comminution systems are beingconsidered for environmental sustainability. These are required to have lower energyconsumption while achieving the required liberation or better for subsequent processing byflotation. Consequently, the literature review shows there is a research query on whether more can beexpected from comminution to optimise for downstream processing. With most publishedresearch being on particles with a P80 less than 100 μm, there exists a gap in investigating theeffect of grinding on flotation for coarser size fractions which this degree project focuses on.Importantly, it includes evaluating chalcopyrite liberation and flotation performance when usinga Novel Comminution Device. Three grinding mills were considered, a vertical roller mill (VRM),a Novel Comminution Device (NCD), with a rod mill as the reference mill. The scope of this studywas an analysis of the mill products’ particle size distribution, chalcopyrite liberation andinvestigation of the flotation performance of the products from the three mills. This was done ona Cu-Au-Ag ore from the Boliden Aitik mine in northern Sweden. Particle size distribution (PSD) analysis revealed that at comparable P80 values, the VRMproduced particles had broader PSD curves than the rod mill, while the NCD provided a steeperproduct size distribution than its reference rod mill products. The chalcopyrite liberation analysisusing QEMSCAN automated mineralogy showed that for samples split into three size fractions, -45 μm, +45/-90 μm and +90 μm, the VRM and rod mill products had their highest proportion offree to liberated particles within the intermediate size fraction while for the NCD sample this waswithin the fine fraction. Overall, the NCD product had the highest free to liberated particles acrossall fractions. From shape analysis based on scanning electron microscopy (SEM) images, it wasobserved that the NCD produced particles with the higher elongation than the VRM and rod mill. The flotation performance was assessed with respect to the mass pull, kinetics, grade andrecovery in the concentrate and separation efficiency. The rougher batch flotation tests indicatedthat flotation of the VRM ground samples had higher mass pull, Cu recovery, faster kinetics andlower Cu grade than the samples from the reference rod mill. This was also a similar outcome forthe NCD with the exception of higher mass pull at an increased collector dosage in the rod millcase. For all the mills, the general trend showed that an increase in P80 was associated withreduced mass pull. Overall, at similar flotation conditions, despite having one of the coarsest P80s,the NCD product showed the fastest Cu recovery kinetics, highest total recovery and selectivityindex. The rod mill reference test samples gave the highest grade but the lowest recovery. The findings illustrate that there is a significant difference in PSD broadness between productsfrom different mills at comparable P80. The differences in flotation performance between thethree mill products were mainly attributed to differences in liberation, potential differences insurface activation between wet and dry grinding methods and to some extent, steepness of thePSD curve. Based on the high recovery yet low grade of the NCD ground product, this is best suitedfor the rougher flotation stage. Future studies should therefore include cleaner stage flotation andoptimisation tests for the NCD with respect to reagent dosages and hydrodynamic conditions.

The spin dynamics within a chiral and achiral molecule was investigated. It was investigated through a diminishing periodic potential, depicting the molecules being dropped onto a substrate. Born-Oppenheimers approximation and a tight-binding model was used to describe the molecules. Moreover, Schrödingers equation was defined for the problem and an iterative approach was used to solve it. The results indicated an induced spin selectivity for the chiral molecule, which varied over time. In contrast, the achiral molecule exhibited weaker spin selectivity. This difference might lie in how the spin couples to the linear momentum in the different structures.

Syfte: Företagsledningen har stor möjlighet att påverka innehållet i årsredovisningen eftersom delar av den saknar regleringar. Detta gör att det finns en problematik om årsredovisningen ger en trovärdig bild av företaget. Enligt tidigare forskning används grafer i årsredovisningar för att påverka läsarens uppfattning om företaget och det har visat sig att företagen snedvrider graferna för att grafen ska se bättre ut. Syftet med denna studie är därmed att undersöka användningen av grafer för finansiella nyckelvariabler i årsredovisningar och snedvridningar av dessa variabler för medelstora företag. Metod: Studien har ett positivistiskt och objektivt synsätt och en deduktiv ansats. Utifrån den teoretiska referensramen formulerades hypoteser som sedan testades mot det empiriska materialet. Det empiriska materialet bestod av grafer från årsredovisningar och detta samlades in genom en kvantitativ innehållsanalys. Studien har en longitudinell design där vi studerade 39 medelstora företag listade på Nasdaq OMX Stockholm under två olika år, vilket resulterade i att 78 årsredovisningar studerades. Det empiriska materialet testades genom statistiska tester för att kunna undersöka hypotesernas acceptans. Resultat &amp; slutsats: Studien har visat att medelstora företag har en hög grafanvändning i årsredovisningar och att de använder sig av grafer för finansiella nyckelvariabler konsekvent över tid. Företagen tenderar att visa positiva trender för finansiella nyckelvariabler men studien har även visat att mer än hälften av dessa variabler presenteras felaktigt genom snedvridningar. Denna studie har visat på en högre andel snedvridna finansiella nyckelvariabler jämfört med tidigare forskning som har undersökt stora företag. Förslag till fortsatt forskning: Eftersom denna studie har visat att det finns snedvridningar i grafer för finansiella nyckelvariabler för medelstora företag listade på Nasdaq OMX Stockholm vore det intressant med ytterligare studier inom området för små och stora företag. Detta för att undersöka om små respektive stora företag skiljer sig från medelstora företag gällande snedvridningar för finansiella nyckelvariabler. Vidare vore det även intressant att undersöka snedvridningar för samtliga grafer i årsredovisningar.  Uppsatsens bidrag: Studien bidrar till att öka förståelsen för hur medelstora företag använder grafer för finansiella nyckelvariabler i sina årsredovisningar. Den bidrar även till nya kunskapsområden eftersom inga tidigare studier har undersökt varken svenska eller medelstora företag. Studien visar att grafer för finansiella nyckelvariabler tenderar att visas på ett felaktigt sätt för att ge en bättre bild av företaget. Denna studie ökar därför medvetenheten hos läsare av årsredovisningar att grafer inte alltid presenteras på ett tillförlitligt sätt. / Aim: The management has a great opportunity to influence the content of annual reports as there are elements that do not adhere to regulations. Hence there is a concern whether the annual report is a reliable representation of a company. According to previous research, graphs are used in annual reports with the purpose of influencing the reader’s perception about the company. Furthermore, it has been demonstrated that some companies distort the graphs with the purpose of improving their appearance. Thus, the purpose of this study is to investigate the use of graphical representations of key financial variables in annual reports, and the distortion of these variables in mid size companies. Method: The study has a positivist and objective approach with a deductive undertaking. Hypotheses has been formulated based on the theoretical framework, they have thereafter been tested against the empirical findings. The empirical material consisted of various graphs from annual reports which were collected through a quantitative content analysis. The study has a longitudinal design in which we have studied 39 mid size companies during two different years, in total 78 annual reports have been studied. The empirical material has been analyzed through statistical tests with the purpose of investigating the acceptance of the hypotheses. Result &amp; conclusions: The study has shown that mid size companies has an elevated usage of graphs in annual reports, and that they use graphical representations of key financial variables consistently over time. The companies tend to show positive trends for key financial variables, however the study has shown that a majority of these variables are erroneously represented due to distortions. The study has demonstrated a higher share of distorted key financial variables compared to earlier research which has been focused on large companies. Suggestions for future research: As this study has demonstrated the existence of distortions in graphical representations of key financial variables in mid size companies, it would be interesting to conduct further studies in the area of Swedish small and large size companies. Hence investigating if small and large size companies are any different compared to mid size companies regarding distortions of key financial variables. Furthermore it would be interesting to investigate distortions of all graphical representations in annual reports. Contribution of the thesis: The study contributes to an increased understanding of how mid size companies use key financial variables in their annual reports. It also contributes to new knowledge areas as no previous studies has investigated Swedish nor mid size companies. The study shows that graphical representations of key financial variables tend to be exposed erroneously in order to improve the image of the company. Thus, this study increases the awareness of the reader’s of annual reports and alerts them that graphs are not always presented in a reliable way.

Diseases such as malaria and dengue impose great economic burdens and are a serious threat to public health, with young children being among the worst affected. These diseases are transmitted by mosquitoes, also called disease vectors, which are able to transmit both parasitic and viral infections. One of the most important strategies in the battle against mosquito-borne diseases is vector control by insecticides and the goal is to prevent people from being bitten by mosquitoes. Today’s vector control methods are seriously threatened by the development and spread of insecticide-resistant mosquitos warranting the search for new insecticides. This thesis has investigated the possibilities of vector control using non-covalent inhibitors targeting acetylcholinesterase (AChE); an essential enzyme present in mosquitoes as well as in humans and other mammals. A key requirement for such compounds to be considered safe and suitable for development into new public health insecticides is selectivity towards the mosquito enzyme AChE1. The work presented here is focused on AChE1 from the disease transmitting mosquitoes Anopheles gambiae (AgAChE1) and Aedes aegypti (AaAChE1), and their human (hAChE) and mouse (mAChE) counterparts. By taking a medicinal chemistry approach and utilizing high throughput screening (HTS), new chemical starting points have been identified. Analysis of the combined results of three different HTS campaigns targeting AgAChE1, AaAChE1, and hAChE allowed the identification of several mosquito-selective inhibitors and a number of compound classes were selected for further development. These compounds are non-covalent inhibitors of AChE1 and thereby work via a different mechanism compared to current anti-cholinergic insecticides, whose activity is the result of a covalent modification of the enzyme. The potency and selectivity of two compound classes have been explored in depth using a combination of different tools including design, organic synthesis, biochemical assays, protein X-ray crystallography and homology modeling. Several potent inhibitors with promising selectivity for the mosquito enzymes have been identified and the insecticidal activity of one new compound has been confirmed by in vivo experiments on mosquitoes. The results presented here contribute to the field of public health insecticide discovery by demonstrating the potential of selectively targeting mosquito AChE1 using non-covalent inhibitors. Further, the presented compounds can be used as tools to study mechanisms important in insecticide development, such as exoskeleton penetration and other ADME processes in mosquitoes.