A expansão das atividades humanas está associada a várias ameaças antrópicas que afetam a biodiversidade tropical, especialmente a perda e fragmentação de habitat, o continuado crescimento populacional humano e a expansão de infraestrutura, como estradas e rodovias. Embora seja esperado que as ameaças antrópicas interajam e criem mosaicos de manchas de habitat de diferentes qualidades, há ainda poucos estudos sobre os efeitos aditivos e interativos de diferentes ameaças sobre a biodiversidade ou sobre a capacidade de espécies nativas de usar remanescentes de diferentes qualidades. De fato, a maioria dos estudos focaram em apenas uma ou poucas ameaças isoladas, na escala do fragmento em vez da escala da paisagem e não consideraram as variações na qualidade dos remanescentes. Mamíferos de maior porte são um bom modelo de estudo porque possuem um conjunto de características que os tornam particularmente vulneráveis a várias ameaças antrópicas. Dada a dificuldade de obter dados sobre estas espécies elusivas em escalas espaciais adequadas, entrevistas com moradores locais vêm sendo cada vez mais usadas para acessar a distribuição de mamíferos de maior porte, e podem fornecer informações confiáveis. Através da estimativa da ocorrência de 15 espécies de mamíferos de maior porte por meio de entrevistas com o chefe de 12 unidades domésticas em cada uma de 20 paisagens em uma região de pós-fronteira de 1 milhão ha na Amazônia, investigamos: (i) que tipo de habitat e em qual escala espacial está associado com a ocorrência das espécies, e (ii) os efeitos, a importância relativa e as interações de quatro ameaças antrópicas - cobertura de habitat, fragmentação de habitat, densidade populacional humana e densidade de estrada - sobre a persistência das espécies. Dados de presença/ausência nos arredores de 227 unidades domésticas foram analisados usando modelos lineares generalizados mistos e seleção de modelos baseada no Critério de Informação de Akaike em duas etapas. A persistência das espécies maiores e ameaçadas não foi necessariamente afetada pela qualidade do habitat, mas elas responderam majoritariamente a cobertura de habitat em escalas maiores. A chance de persistência de todas as espécies - mesmo das duas menores, que não responderam à perda de habitat isoladamente - foi afetada por alguma combinação das quatro ameaças antrópicas. Efeitos aditivos entre as ameaças antrópicas foram mais importantes do que as interações entre elas na determinação da ocorrência de mamíferos de maior porte. Enquanto os efeitos da perda de habitat foram mais fortes do que os efeitos da fragmentação de habitat per se, a densidade de estradas foi tão importante quanto à perda de habitat para a ocorrência das espécies. Por último, não houve um padrão claro em termos do grau de ameaça e do tamanho corpóreo por trás da reposta dos mamíferos de maior porte a ameaças antrópicas combinadas. Nosso estudo sugere que áreas protegidas em terras públicas ou privadas na Amazônia devem ser grandes para assegurar a persistência de mamíferos de maior porte, mas podem incluir mosaicos de florestas primárias e secundárias. Os resultados também ressaltam a necessidade de considerar os impactos acumulados de múltiplas ameaças simultaneamente - em especial, as consequências da expansão da malha viária - em planejamentos e manejos, de maneira a evitar subestimar a chance de extinções. Evitar que paisagens na Amazônia se tornem muito desmatadas e alteradas é fundamental, dado que a persistência até mesmo das espécies mais comuns pode ser prejudicada, afetando um dos serviços ecossistêmicos mais importantes para moradores locais - a carne de caça - e potencialmente erodindo o valor que estes atribuem às florestas / The expansion of human activities is associated to a myriad of anthropogenic threats that affect tropical biodiversity, especially habitat loss and fragmentation, the continued human population growth and the expansion of infrastructure, as roads and highways. Although anthropogenic threats are expected to interact and to create mosaics of patches of varying quality, their additive and interaction effects on biodiversity, as well as the extent native species are able to use remnants of distinct quality, have yet been poorly studied. Indeed most studies focused on only one or few threats in isolation, on the patch rather than the landscape scale and did not considered the varying quality of remnants. Large mammals are a good study model as they have a set of traits that make them particularly vulnerable to several anthropogenic threats. Due to the difficulties in gathering data on these elusive species at adequate spatial scales, interviews with local residents have increasingly being used to access their distribution and can provide reliable information. By estimating the occurrence of 15 large mammal species through interviews with the head of 12 households within each of 20 landscapes across a 1-million ha post-frontier region in Amazonia, we investigated: (i) which habitat type at which spatial scale is associated with species occurrence, and (ii) the effects, relative importance and interactions of four anthropogenic threats - habitat cover, habitat fragmentation, human population density and road density - on species persistence. Presence/absence data across the surroundings of 227 households was analyzed using generalized linear mixed-effects models, and a two-step model selection based on Akaike’s Information Criteria. The persistence of larger and endangered species was not necessarily affected by habitat quality, but they responded to habitat cover mostly at larger spatial scales. The chance of persistence of all species - even the two smallest that were not affected by habitat loss alone - was disrupted by some combination of the four anthropogenic threats. Additive effects between anthropogenic threats were more important than their interaction in determining the occurrence of large mammals. While the effects of habitat loss were stronger than the effects of habitat fragmentation per se, road density was as important as habitat loss to species occurrence. Finally, there was no clear pattern in threat status or body size underlying the response of large mammals to combined anthropogenic threats. Our study suggest that protected areas in public or private lands in Amazonia should be large to secure the persistence of large mammals, but may include mosaics of primary and secondary forest. The findings also highlight the need to take into account the accumulated impacts of multiple threats simultaneously - particularly, the consequences of the expansion of the road network - in planning and management, as a way to avoid underestimating the chance of extinctions. Preventing Amazonian landscapes to become heavily deforested and altered is critical, as the persistence of even common species can be impaired, affecting one of the most important ecosystem services provided to local residents - bushmeat - and potentially eroding the value people attribute to forests

Expectations regarding the contributions of academics to entrepreneurial activity in addition to their primary role of carrying out teaching and research have increased in recent years. Nevertheless, research on academic entrepreneurship has, to date, been carried out mainly in developed nations and there has been little emphasis on developing countries, particularly low income ones. Developing countries, when compared with developed nations, have been reported to face relatively high levels of resource scarcity that involve shortages of skills, finance, physical infrastructure, technology, and institutions needed for innovation and entrepreneurship. This gap in our knowledge leads to the main objective of this study, which is to investigate academic entrepreneurship in a resource constrained environment. Referring to the entrepreneurship and diversification literature, the current study argues that, as a strategy to extract value from a resource constrained environment, academic entrepreneurs may diversify their entrepreneurial engagements, which is named in this research as ‘plural activity’. In order to achieve the main objective, this thesis derives four specific objectives; namely, investigating the ‘plural activities’ of academic entrepreneurs, studying the motivations of academic entrepreneurs, examining the influence of multilevel causal factors on ‘plural activities’, and investigating the impacts of academic entrepreneurship on universities and wider economy. Sequential mixed methods were adopted in three stages; namely, an initial context specific data gathering stage, an on-line survey, and in-depth interviews. Initial context specific data were used to design two subsequent data collection phases. This approach was believed to improve the construct validity of the study. The main purpose of the on-line survey was to obtain a broad understanding of the entrepreneurial engagements of academics, while that of in-depth interviews was to obtain detailed context specific data, required to achieve research objectives. This sequential mixed method design of a survey being followed up by in-depth interviews was also considered to improve the internal validity of this research.The results suggested that entrepreneurial activity was a means of overcoming resource barriers in a resource constrained environment as opposed to resources are a means of becoming entrepreneurial in a resource rich environment. The majority of academic entrepreneurs had overcome resource and opportunity constraints by diversifying their entrepreneurial engagements. ‘Plural activity’ was found to generate synergies between multiple academic entrepreneurial activities. Diversifying into a greater number of different activities was found to generate more synergistic effects than diversifying into a limited number of similar activities. Nevertheless, there remained synergies between those who adopted different diversification strategies. Moreover, academic entrepreneurship was found to enable the overcoming of resource barriers to university teaching and research as well as deliver positive outcomes to universities and wider economy. Furthermore, it was evident that academics were initially motivated by ‘push’ motives and over time the influence of ‘push’ factors declined, while the impact of ‘pull’ motives increased. As a result of a lack of research capabilities of industry and funding for universities, there was a higher mutual interdependence between universities and industry. However, due to the unavailability of supportive mechanisms or formal institutional infrastructure to promote academic entrepreneurship, university-industry interactions were driven by individuals, and thus, were scattered and isolated. Policy implications and future research avenues were considered in conclusion.

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L’expression aromatique fruitée des vins rouges a été le sujet de nombreuses études qui démontrent qu’au moins une composante de cette expression est le reflet d’interactions perceptives impliquant des esters. La plupart des travaux concernant les interactions perceptives jusqu’à ce jour se sont avérés descriptifs, très peu ayant cherché à déterminer leurs origines. Dans ce but, un outil analytique a été développé afin d’apprécier les changements de volatilité d’esters représentatifs de l’arôme fruité des vins rouges. Ainsi, les coefficients de partage de 9 esters ont pu être déterminés aussi bien dans une solution hydroalcoolique que dans un vin rouge désaromatisé. L’application de cet outil analytique aux interactions perceptives préalablement mises en évidence a permis d'observer des changements de volatilité des esters lors de leur mise en mélange avec d'autres composés volatils en solution. Ces changements de volatilité, synonymes de potentiels effets pré-sensoriels, vont dans le même sens que ceux observés lors de l’analyse sensorielle. L’utilisation d’un verre de dégustation possédant deux compartiments a permis de mettre en lumière le fait que certaines modifications sensorielles pouvaient être expliquées, pour partie au moins, par des effets pré-sensoriels. L'impact olfactif de 5 alcools supérieurs ainsi que de 15 composés issus du bois de chêne a pu être démontré grâce à de nombreuses reconstitutions aromatiques, et leur rôle de masquage de l’arôme fruité des vins rouges a pu être souligné. Le calcul des coefficients de partage des esters a permis de montrer que des changements de volatilité ont lieu au sein de la solution. Ces modifications peuvent être corrélées aux résultats obtenus lors de l’analyse sensorielle. Ainsi, il est possible d’expliquer, en partie, les effets de masquage de l’arôme fruité observés grâce aux seuils de détection et aux profils sensoriels, du fait de la diminution de la présence d’esters dans l’espace de tête venant stimuler le dégustateur. Globalement, nos travaux ont permis de mettre en évidence que la mise en mélange en solution de composés volatils pouvait se traduire par la modification de la volatilité des constituants du mélange et que certaines de ces interactions pré-sensorielles pouvaient conditionner l'expression aromatique fruitée due aux esters. / A lot of studies highlighted the perceptual role of esters in fruity aromatic expression of red wines, demonstrating that at least partially it was due to perceptive interactions. Indeed, a lot of synergistic and masking effects have been brought to light in the past. However, the origin of these interactions remains unknown, although some authors suggested several levels where they can take place. In this goal, an analytical tool was developed to study the possible occurrence of esters volatility modifications. The application of this tool allowed determining partition coefficients of 9 esters in dilute alcohol solution and in dearomatized red wine. Thanks to perceptive interactions previously demonstrated by various authors, the application of this analytical tool highlighted modifications of esters volatility when compounds were mixed together in the solution. These modifications support the observations made with sensory analysis, indicating the existence of pre-sensorial effects. The use of a new tool consisting in a tasting glass with 2 compartments, reveals that these volatility changes may led to true sensorial modifications. Masking effect of fruity aroma due to 5 higher alcohols but also 15 wood by-products was highlighted using various aromatic reconstitutions. Esters partition coefficients calculation showed volatility modifications from the matrix to the gas phase. These data may be correlated with sensorial analysis results. Thus, it is possible to explain, at least partially, fruity aroma masking effect highlighted through detection threshold and sensory profile thanks to decrease in esters presence in headspace, and so a decline of taster’s olfactory stimulation. To conclude, our work showed that the mixture of volatile compounds in solution may result in modification of molecules volatility, and furthermore highlighted that these pre-sensorial interactions may impact fruity aromatic expression related to esters

Cancer is a leading cause of death that affects millions of people across the globe each year. Photodynamic therapy (PDT) is a relatively new treatment approach for cancer in which anticancer drugs are activated by light at an appropriate wavelength to generate highly cytotoxic reactive oxygen species (ROS) and achieve tumor destruction. Compared with conventional chemo- and radiotherapy, PDT can be performed with minimal invasiveness, local targeting and reduced side effects. However, most of the currently available PDT drugs mainly absorb in the visible part of the spectrum, where light penetration depth into human tissues is very limited. Therefore, increasing the treatment depth of PDT has been considered to be an important approach to improve the effectiveness of PDT for treating larger and thicker tumor masses. In this thesis, we present our investigation into the potential of two-photon activated PDT (2-γ PDT), combination therapy of PDT and chemotherapy, and bioluminescence-activated PDT as a means to increase the treatment depth of this modality. In 2-γ PDT, the photosensitizing agents are activated through simultaneous absorption of two photons. This approach allows the use of near-infrared (NIR) light that can penetrate deeper into tissues and thus, has the potential of treating deep-seated tumors and reducing side effects, while the non-linear nature of two-photon excitation (TPE) may improve tumor targeting. We have evaluated the PDT efficacy of a second-generation photosensitizer derived from chlorophyll a, pyropheophorbide a methyl ester (MPPa), through both one- and two-photon activation. We observed that MPPa had high one-photon (1-γ PDT efficacy against both cisplatin-sensitive human cervical (HeLa) and cisplatin-resistant human lung (A549) and ovarian (NIH:OVCAR-3) cancer cells when activated by femtosecond (fs) laser pulses at 674 nm. At a low light dose of 0.06 J cm-2, the MPPa concentration required to produce a 50% cell killing effect (IC50) was determined to be 5.3 ± 0.3, 3.4 ± 0.3 and 3.6 ± 0.4 μM in HeLa, A549 and NIH:OVCAR-3 cells, respectively. More significantly, we also found that MPPa could be effectively activated at the optimal tissue-penetrating wavelength of 800 nm through TPE. At a light dose of 886 J cm-2, where no measurable photodamage was observed in the absence of MPPa, the IC50 values were measured to be 4.1 ± 0.3, 9.6 ± 1.0 and 1.6 ± 0.3 μM in HeLa, A549 and NIH:OVCAR-3 cells, respectively. We obtained corresponding LD50 (the light dose required to produce a 50% killing effect) values of 576 ± 13, 478 ± 18 and 360 ± 16 J cm-2 for 10 μM MPPa, which were approximately 3-5 times lower than the published 2-γ LD50 of Visudyne® and 20-30 times lower than that of Photofrin®. These results indicate that MPPa may serve as a photosensitizer for both 1- and 2-γ activated PDT treatment of difficult-to-treat tumors by conventional therapies. Indocyanine green (ICG), a dye having an absorption maximum near 800 nm, has been considered to be a potential NIR PDT agent. However, the PDT efficacy of ICG has been found to be very limited probably due to the low yield of cytotoxic ROS. In the present work, we have evaluated the combination effects of ICG-mediated PDT with conventional chemotherapy mediated by two types of chemotherapeutic drugs, namely the type II topoisomerase (TOPII) poisons etoposide (VP-16)/teniposide (VM-26) and the platinum-based drugs cisplatin (CDDP)/oxaliplatin (OXP). Synergistic enhancement of cytotoxicity and increased yields of DNA double strand breaks (DSBs) were observed in HeLa, A549 and NIH:OVCAR-3 cancer cells treated with the combination of ICG-PDT and VP-16. The presence of VP-16 during the laser irradiation process was found to be critical for producing a synergistic effect. An electron-transfer-based mechanism, in which ICG could increase the yield of highly cytotoxic VP-16 metabolites, was proposed for the observed synergistic effects, although direct spectroscopic detection of the reaction products was found to be very challenging. Moreover, we observed a much lower degree of synergy in the human normal fibroblast GM05757 cells than that in the three cancer cell lines investigated. Synergistic effects were also observed in A549 cells treated with the combination of ICG-PDT and VM-26 (i.e. an analog of VP-16). Furthermore, the combination of low-dose CDDP/OXP and ICG-PDT was demonstrated to produce an additive or synergistic effect in selected cancer cell lines. These preliminary results suggest that the combination of ICG-PDT with VP-16/VM-26 or CDDP/OXP chemotherapy may offer the advantages of enhancing the therapeutic effectiveness of ICG-PDT and lowering the side effects associated with the chemotherapeutic drugs. Bioluminescence, the generation of light in living organisms through chemical reactions, has been explored as an internal light source for PDT in recent years. This approach, in principle, does not suffer from the limited tissue penetration depth of light. In the present project, we have evaluated the effectiveness of luminol bioluminescence in activating the porphyrin photosensitizers meso-tetra(4-sulfonatophenyl)porphine dihydrochloride (TPPS4) and Fe(III) meso-tetra(4-sulfonatophenyl)porphine chloride (FeTPPS). The combination treatment induced significant killing of HeLa cells, while additive effects were observed in two normal human fibroblast cell lines (GM05757 and MRC-5). Our observations indicate that bioluminescence of luminol may generate sufficient light for intracellular activation of PDT sensitizers. Furthermore, the combination treatment may have intrinsic selectivity towards cancerous tissues. In summary, we have demonstrated effective killing of cancer cells by MPPa-mediated 1- and 2-γ PDT, combination of ICG-PDT and VP-16/VM-26 or CDDP/OXP chemotherapy, and bioluminescence of luminol activated PDT mediated by TPPS4/FeTPPS. These positive preliminary results indicate that all these three approaches have the potential of increasing the treatment depth of PDT and facilitating the development of more effective PDT treatment strategies.

The main objective of this thesis work was to gain understanding of the principles of biolubrication, focusing on synergistic effects between biolubricants. To this end surface force and friction measurements were carried out by means of Atomic Force Microscopy, using hydrophilic and hydrophobic model surfaces in salt solutions of high ionic strength (≈ 150 mM) in presence of different biolubricants. There was also a need to gain information on the adsorbed layers formed by the biolubricants. This was achieved by using a range of methods such as Atomic Force Microscopy PeakForce imaging, Quartz Crystal Microbalance with Dissipation, Dynamic Light Scattering and X-Ray Reflectometry. By combining data from these techniques, detailed information about the adsorbed layers could be obtained.The biolubricants that were chosen for investigation were a phospholipid, hyaluronan, lubricin, and cartilage oligomeric matrix protein (COMP) that all exist in the synovial joint area. First the lubrication ability of these components alone was investigated, and then focus was turned to two pairs that are known or assumed to associate in the synovial area. Of the biolubricants that were investigated, it was only the phospholipid 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) that was found to be an efficient lubricant on its own. Deposited DPPC bilayers on silica surfaces were found to be able to provide very low friction coefficients (≈ 0.01) up to high pressures, ≈ 50 MPa. A higher load bearing capacity was found for DPPC in the liquid crystalline state compared to in the gel state.The first synergy pair that was explored was DPPC and hyaluronan, that is known to associate on the cartilage surface, and we also noticed association between hyaluronan and DPPC vesicles as well as with adsorbed DPPC bilayers. By combining these two components a lubrication performance similar to that of DPPC alone could be achieved, even though the friction coefficient in presence of hyaluronan was found to be slightly higher. The synergy here is thus not in form of an increased performance, but rather that the presence of hyaluronan allows a large amount of the phospholipid lubricant to accumulate where it is needed, i.e. on the sliding surfaces.The other synergy pair was lubricin and COMP that recently has been shown to be co-localized on the cartilage surface, and thus suggested to associate with each other. Lubricin, as a single component, provided poor lubrication of PMMA surfaces, which we utilized as model hydrophobic surfaces. However, if COMP first was allowed to coat the surface, and then lubricin was added a low friction coefficient (≈ 0.03) was found. In this case the synergy arises from COMP facilitating strong anchoring of lubricin to the surface in conformations that provide good lubrication performance. / Huvudsyftet med det här avhandlingsarbetet var att öka förståelsen för den låga friktion som finns i vissa biologiska system, med fokus på synergistiska effekter mellan de smörjande molekylerna. För detta ändamål studerades ytkrafter och friktion med hjälp av atomkraftsmikroskopi. Mätningarna utfördes med hydrofila och hydrofoba modellytor i lösningar med hög salthalt (≈ 150 mM) i närvaro av smörjande biomolekyler. Det var också nödvändigt att få information om de adsorberade skikten av biomolekyler. Det åstadkoms med hjälp av en rad tekniker så som AFM PeakForce avbildning, kvartskristallmikrovåg, dynamisk ljusspridning och röntgen reflektometri. Genom att kombinera data från dessa tekniker erhölls detaljerad information om de smörjande skikten.De smörjande biomolekyler som valdes ut för studierna var en fosfolipid, hyaluronan, lubricin, and cartilage oligomeric matrix protein (COMP) vilka alla finns i synovialledsområdet. Först undersöktes den smörjande förmågan hos dessa komponenter var för sig, och sedan fokuserade vi på två par av biomolekyler som man vet eller antar bildar associationsstrukturer i synovialleder. Av de enskilda biomolekyler som undersöktes var det endast fosfolipiden 1,2-dipalmitoyl-sn-glycero-3-fosfokoline (DPPC) som visade sig vara en effektivt smörjande molekyl. Deponerade biskikt av DPPC på silikaytor gav upphov till mycket låga friktionskoefficienter (≈ 0.01) upp till höga pålagda tryck, ≈ 50 MPa. DPPC bilager i flytande kristallin fas visade sig ha högre lastbärande förmåga än DPPC bilager i geltillstånd.Det första synergistiska par som undersöktes var DPPC och hyaluronan vilka man vet associerar på broskytan, och vi visade att hyaluronan associerar med såväl DPPC vesiklar som med DPPC bilager. Genom att kombinera dessa två komponenter uppmättes en smörjande förmåga som var jämförbar med den som DPPC ensam uppvisar. Även om friktionskoefficienten var något högre i närvaro av hyaluronan. Synergieffekten här består inte av en bättre smörjande förmåga, utan istället gör närvaron av hyaluronan att de smörjande fosfolipiderna kan ansamlas i stora mängder där de behövs, dvs. på de glidande ytorna.Det andra synergiparet var lubricin och COMP vilka nyligen har visats vara lokaliserade på samma platser på broskytan, vilket tyder på att de associerar med varandra. På egen hand var lubricins smörjande förmåga av PMMA, våra hydrofoba modellytor, dålig. Emellertid, om COMP först adsorberades på PMMA och sedan lubricin tillsattes uppmättes en låg friktionskoefficient (≈ 0.03). I det här fallet består synergin av att COMP möjliggör en stark inbindning till ytan av lubricin i konformationer som ger god smörjande förmåga. / <p>QC 20141202</p> / Stiftelsen för strategisk forskning - SSF