Light or photons can excite electrons in a molecule, leading to creation of electronically excited states. Such processes are ubiquitous in nature, such as, vision, photo-protection of DNA/RNA nucleobases, light harvesting, energy and charger transfer etc. This photoexcitation induces nuclear motion on the excited states, leading the excess energy to dissipate either non-radiatively via internal conversion back down to the ground state, isomerization, and dissociation, or radiatively via fluorescence and phosphorescence. In this dissertation, we investigate the non-radiative processes in organic chromophores that ensue in an ultrafast manner, mediated via conical intersections (CoIn). Description of such excited state processes generally require multi-reference treatment because of quasi-degeneracy near CoIns. Hence, most insight about these processes is typically gained by constructing potential energy surface (PES) using multi-reference electronic structure methods along important reaction coordinates. Nonetheless, the aforementioned static treatment fails to provide any dynamical information, such as, excited state lifetime, state populations, branching ratio, quantum yield etc. In this dissertation, we have gone beyond the static treatment by undertaking computationally expensive non-adiabatic excited state molecular dynamics simulations employing trajectory surface hopping (TSH) methodology on PESs created on-the-fly using multi-reference electronic structure methods. This allows us to compare theoretical results to experimental observables, when possible, strengthening the explanations underlying those processes. Our goal is to examine the effect of structure, and of electronic structure methods on the excited state dynamics. We have examined the non-adiabatic excited state dynamics of cis,cis-1,3-cyclooctadiene (cc-COD), a cyclic diene, in an effort to systematically compare and contrast the dynamics of cc-COD to that of other well studied conjugated molecules. Such exploration is very significant, since the majority of the molecules involved in natural photoexcited processes, include an ethylenic double bond or alternating double bonds creating conjugation. Our calculations have revealed ultrafast sub-ps decay for cc-COD, and have illustrated that the internal conversion dynamics is facilitated by CoIns, dominated by twisting of one of the double bonds and pyramidalization of one of the carbons of that double bond, similar to trans-1,3-butadiene and unlike 1,3-cyclohexadiene (CHD). Our high-level electronic structure calculations have also explained the features in the experimental time-resolved photoelectron spectrum of cc-COD. Another molecule of biological importance, uracil, was also investigated using TSH simulations, by systematically increasing dynamical correlation. We have found that the inclusion of dynamical correlation for uracil leads to an almost barrierless PES on S2, leading to a faster decay and no population trap on this state. Uracil also contains a double bond and the simulations have revealed that the ultrafast relaxation is dominated by an ethylenic twist and pyramidalization of a carbon of that bond, increasing importance of such nuclear motion in photoexcited molecular dynamics. A comparison of the molecules studied have illustrated that the rigid molecules, such as uracil, CHD, have a very local CoIn seam space, whereas cc-COD, which is flexible having many low frequency degrees of freedom, has a non-local or extended CoIn seam space. Overall, the work performed in this dissertation, elucidates the significance of structure and conjugation, in the photoinduced coupled electron-nuclear dynamics in organic molecules. / Chemistry

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Bakgrund: Lateral fotledsstukning är en av de vanligaste traumatiska muskuloskeletala skadorna och av alla som ådrar sig denna skada utvecklar upp till 40 procent något som kallas kronisk ankelinstabilitet. Det är en skadeform som förekommer inom nästan alla idrotter. Typiskt är en kraftig stukning som följs av ytterligare stukningar och instabilitetskänsla. Konsekvenser är ofta nedsatt kraft, balans och prestationsförmåga. Syftet med denna studie var således att undersöka fotledsfunktion med avseende på styrka, balans och funktionella tester hos personer med kronisk ankelinstabilitet. Metod: Studien genomfördes som en tvärsnittsstudie med tester vid ett tillfälle. Deltagare söktes via idrottsföreningar och distriktsmottagning. Totalt inkluderades 17 personer (10 kvinnor och sju män), med kronisk fotledsinstabilitet, vilka utförde fem tester för att utvärdera balans, styrka och funktionell prestationsförmåga. Testerna utgjordes av enbentstående, isometrisk styrka i inversion och eversion i liggande, samt enbent längdhopp och sidohopp.  Resultat:  Skadad sida var signifikant svagare jämfört med frisk sida i både eversion (75N respektive 92N, p=0,001) och inversion (75N respektive 85N, p=0,002). Deltagarna visade också sämre prestation, på skadad sida jämfört med frisk sida, vid enbentshopp (101cm respektive 107cm, p=0,05) samt i sidohopptestet (antal 30 respektive 39, p<0,001). Balansen var också nedsatt i skadad jämfört med frisk sida (poäng 17 respektive 11, p<0,001). Det fanns en signifikant korrelation mellan styrka i eversion och inversion (r=0,731, p=0,001). Inversion hade, utöver eversion, signifikanta korrelationer med enbentshopp (r=0,517, p=0,033), och med sidohopp (r=0,644, p=0,005). Enbentshopp korrelerade även med sidohopp (r=0,650, p=0,005). Antal sidohopp hade en hög korrelation, (p <0.01), med samtliga övriga parametrar, undantagen balans. Det förelåg ingen korrelation mellan balansen och några av övriga parametrar (p ≥0,600). Konklusion: Den här studien visar att individer med kronisk ankelinstabilitet har sämre funktion i skadad jämfört med frisk fot. Funktionell prestationsförmåga, i form av sidohopp, och balans var de variabler som var mest påverkade. Det faktum att det fanns en 50-procentig skillnad i balans tyder på att utvärdering av balans är av betydelse i denna grupp av patienter och att rehabilitering bör syfta till att förbättra balansförmågan. / Background: Lateral ankle sprain is one of the most common traumatic musculoskeletal injuries, is present in almost all fields of sport, and up to 40 percent of everyone that is injured developes something called chronic ankle instability. A typical description is a severe strain followed by more straines and a sense of instability. Strenght, balance and performance deficits are often seen consequences of the disorder. Objective: The aim of this study was to survey the function concerning strenght, balance and functional ability within this group. Methods: This study was conducted as a cross-sectional study with participants recruited through various sport clubs and at a clinical practice. A total of 17 persons with chronic ankle instability were included (10 women and seven men). The test battery consisted of five tests for assessment of balance, strength and functional performance; Single leg balance, isometric strength in inversion and eversion, single leg hop and side hop test Result: The affected side was signifikantly weaker compared to the non-affected side in both eversion (75N vs. 92N, p=0,001) and inversion (57N vs 85N, p=0,002). The same pattern was seen, with a lesser performance on the affected side in, single leg hop (101cm vs. 107cm p=0,05) and number of sidehops (30 vs. 39, p <0,001). The balance was also lesser in the affected versus non-affected side (17 vs. 11, p <0,001). There were a signifikant correlation between strenght in eversion and inversion (r=0,731, p=0,001). Inversion strenght had also signifikant correlationes with the performance in the single leg hop (r=0,517, p=0,033), and the side hop tests (r=0,644, p=0,005). Single leg hop also correlated with the side hop performance (r=0,650, p=0,005). The performance in the side hop test had high correlation, (p <0.010), with every other parameter except balance which did not correlate with any of the other tests (p ≥0,600).  Conklusion: In this study, strength, balance and functional performance were all impaired at the injured side, compared to the non-injured side. The fact that there was a 50% difference between sides in balance performance suggests that evaluation of balance is of importance in this group of patients and rehabilitation should aim to improve balance.

Cognitive radio (CR) is seen as one of the enabling technologies for realizing a new regulatory spectrum management paradigm, viz. opportunistic spectrum sharing (OSS). In the OSS paradigm, unlicensed users (a.k.a. secondary users) opportunistically operate in fallow licensed spectrum on a non-interference basis to licensed users (a.k.a. incumbent or primary users). Incumbent users have absolute priority in licensed bands, and secondary users must vacate the channel where incumbent user signals are detected. A CR network is composed of secondary users equipped with CRs and it can coexist with incumbent users in licensed bands under the OSS paradigm. The coexistence between incumbent users and secondary users is referred to as incumbent coexistence, and the coexistence between CR networks of the same type is referred to as self-coexistence. In this dissertation, we address three coexistence-related problems at the medium access control (MAC) layer in CR networks: (1) the rendezvous (control channel) establishment problem, (2) the channel assignment problem in an ad hoc CR network, and (3) the spectrum sharing problem between infrastructure-based CR networks, i.e., the 802.22 wireless regional area networks (WRANs). Existing MAC layer protocols in conventional wireless networks fail to adequately address the key issues concerning incumbent and self coexistence that emerge in CR networks. To solve the rendezvous establishment problem, we present a systematic approach, based on quorum systems, for designing channel hopping protocols that ensure a pair of CRs to "rendezvous" within an upper-bounded time over a common channel that is free of incumbent user signals. In a single radio interface, ad hoc CR network, we propose a distributed channel assignment scheme that assigns channels at the granularity of "segments" for minimizing the channel switching overhead. By taking into account the coexistence requirements, we propose an inter-network spectrum sharing protocol that enables the sharing of vacant TV white space among coexisting WRANs. Our analytical and simulation results show that these proposed schemes can effectively address the aforementioned MAC layer coexistence problems in CR networks. / Ph. D.

The current state of the art in structural health monitoring is primarily reliant on sensing deformation of structures at discrete locations using sensors and detecting damage using techniques such as X-ray, microCT, acoustic emission, impedance methods etc., primarily employed at specified intervals of service life. There is a need to develop materials and structures with self-sensing capabilities such that deformation and damage state can be identified in-situ real time. In the current work, the inherent deformation and damage sensing capabilities of carbon nanotube (CNT) based nanocomposites are explored starting from the nanoscale electron hopping mechanism to effective macroscale piezoresistive response through finite elements based computational micromechanics techniques. The evolution of nanoscale conductive electron hopping pathways which leads to nanocomposite piezoresistivity is studied in detail along with its evolution under applied deformations. The nanoscale piezoresistive response is used to evaluate macroscale nanocomposite response by using analytical micromechanics methods. The effective piezoresistive response, obtained in terms of macroscale effective gauge factors, is shown to predict the experimentally obtained gauge factors published in the literature within reasonable tolerance. In addition, the effect of imperfect interface between the CNTs and the polymer matrix on the mechanical and piezoresistive properties is studied using coupled electromechanical cohesive zone modeling. It is observed that the interfacial separation and damage at the nanoscale leads to a larger nanocomposite irreversible piezoresistive response under monotonic and cyclic loading because of interfacial damage accumulation. As a sample application, the CNT-polymer nanocomposites are used as a binding medium for polycrystalline energetic materials where the nanocomposite binder piezoresistivity is exploited to provide inherent deformation and damage sensing. The nanocomposite binder medium is modeled using electromechanical cohesive zones with properties obtained through the Mori-Tanaka method allowing for different local CNT volume fractions and orientations. Finally, the traditional implementation of Material Point Method (MPM) is extended for composite problems with large deformation (e.g. large strain nanocomposite sensors with elastomer matrix) allowing for interfacial discontinuities appropriately. Overall, the current work evaluates nanocomposite piezoresistivity using a multiscale modeling framework and emphasizes through a sample application that nanocomposite piezoresistivity can be exploited for inherent sensing in materials. / Ph. D.

Yes / The aldo-keto reductase 1C3 (AKR1C3) isoform plays a vital role in the biosynthesis of androgens and is considered an attractive target in prostate cancer (PCa). No AKR1C3-targeted agent has to date been approved for clinical use. Flufenamic acid and indomethacine are non-steroidal anti-inflammatory drugs known to inhibit AKR1C3 in a non-selective manner as COX off-target effects are also observed. Recently, we employed a scaffold hopping approach to design a new class of potent and selective AKR1C3 inhibitors based on a N-substituted hydroxylated triazole pharmacophore. Following a similar strategy, we designed a new series focused around an acidic hydroxybenzoisoxazole moiety, which was rationalised to mimic the benzoic acid role in the flufenamic scaffold. Through iterative rounds of drug design, synthesis and biological evaluation, several compounds were discovered to target AKR1C3 in a selective manner. The most promising compound of series (6) was found to be highly selective (up to 450-fold) for AKR1C3 over the 1C2 isoform with minimal COX1 and COX2 off-target effects. Other inhibitors were obtained modulating the best example of hydroxylated triazoles we previously presented. In cell-based assays, the most promising compounds of both series reduced the cell proliferation, prostate specific antigen (PSA) and testosterone production in AKR1C3-expressing 22RV1 prostate cancer cells and showed synergistic effect when assayed in combination with abiraterone and enzalutamide. Structure determination of AKR1C3 co-crystallized with one representative compound from each of the two series clearly identified both compounds in the androstenedione binding site, hence supporting the biochemical data. / University of Turin (Ricerca Locale grant 2015-2017) and Prostate Cancer UK grant S12-027.

The doctoral thesis deals with design of coding for frequency hopping stations in band with intensive jamming. In digital modulations erroneous determination of the modulation state occurs due to jam at the receiver side. The result is erroneously transferred symbols of the message. Errors created during the transmission can be eliminated by using error control systems. It is also possible to prevent these errors by using algorithms (techniques) of frequency hopping which select the appropriate channel. Appropriate communication channel is a channel with a lower probability of erroneous symbol in the message. The main contribution of this thesis is to design a new frequency hopping technique with collision avoidance (FH/CA). The station with FH/CA technique measures signal levels in the considered several channels before every jump. Based on the measurements the most appropriate channel with the lowest value of measured signal level is selected. Therefore, it is more probable that a jump to an unoccupied channel with a transmission will occur. Using a mathematical model, the performance of the newly proposed FH/CA technique is compared with the currently used techniques FH and AFH. Comparison criteria are the probability of a collision between an FH/CA communication system and a static (device transmitting continuously at a fixed frequency) or dynamic jammer (i.e. other FH or AFH systems). By comparing the values of the probability of jammed transmission, indisputable theoretical advantages of the new FH/CA technique were found, compared to the currently used FH and AFH techniques. The FH/CA technique always has better or equal results compared with the FH technique in the case of interference by static and dynamic jammers. The FH/CA technique in a band with static and dynamic jammers usually has better results than the AFH technique. A significant contribution of the FH/CA technique can be seen in the case of dynamic jammers. On the other hand, in the case of static jammers the FH/CA technique is in certain situations worse than the AFH technique. The accuracy of the mathematical models were successfully verified on a simulation model that was created as a part of this thesis in the MATLAB environment. Based on the obtained data from the model there was designed coding for frequency hopping stations with the new technique of frequency hopping FH/CA which is designed for small-volume data transfer in a band with intensive jamming.

Une communication est impulsive chaque fois que le signal portant des informations est intermittent dans le temps et que la transmission se produit à rafales. Des exemples du concept impulsife sont : les signaux radio impulsifs, c’est-à-dire des signaux très courts dans le temps; les signaux optiques utilisé dans les systèmes de télécommunications; certains signaux acoustiques et, en particulier, les impulsions produites par le système glottale; les signaux électriques modulés en position d’impulsions; une séquence d’événements dans une file d’attente; les trains de potentiels neuronaux dans le système neuronal. Ce paradigme de transmission est différent des communications continues traditionnelles et la compréhension des communications impulsives est donc essentielle. Afin d’affronter le problème des communications impulsives, le cadre de la recherche doit inclure les aspects suivants : la statistique d’interférence qui suit directement la structure des signaux impulsifs; l’interaction du signal impulsif avec le milieu physique; la possibilité pour les communications impulsives de coder l’information dans la structure temporelle. Cette thèse adresse une partie des questions précédentes et trace des lignes indicatives pour de futures recherches. En particulier, nous avons étudié: un système d'accès multiple où les utilisateurs adoptent des signaux avec étalement de spectre par saut temporel (time-hopping spread spectrum) pour communiquer vers un récepteur commun; un système avec un préfiltre à l'émetteur, et plus précisément un transmit matched filter, également connu comme time reversal dans la littérature de systèmes à bande ultra large; un modèle d'interférence pour des signaux impulsifs. / A communication is impulsive whenever the information-bearing signal is burst-like in time. Examples of the impulsive concept are: impulse-radio signals, that is, wireless signals occurring within short intervals of time; optical signals conveyed by photons; speech signals represented by sound pressure variations; pulse-position modulated electrical signals; a sequence of arrival/departure events in a queue; neural spike trains in the brain. Understanding impulsive communications requires to identify what is peculiar to this transmission paradigm, that is, different from traditional continuous communications.In order to address the problem of understanding impulsive vs. non-impulsive communications, the framework of investigation must include the following aspects: the different interference statistics directly following from the impulsive signal structure; the different interaction of the impulsive signal with the physical medium; the actual possibility for impulsive communications of coding information into the time structure, relaxing the implicit assumption made in continuous transmissions that time is a mere support. This thesis partially addresses a few of the above issues, and draws future lines of investigation. In particular, we studied: multiple access channels where each user adopts time-hopping spread-spectrum; systems using a specific prefilter at the transmitter side, namely the transmit matched filter (also known as time reversal), particularly suited for ultrawide bandwidhts; the distribution function of interference for impulsive systems in several different settings.

Une communication est impulsive chaque fois que le signal portant des informations est intermittent dans le temps et que la transmission se produit à rafales. Des exemples du concept impulsife sont : les signaux radio impulsifs, c’est-à-dire des signaux très courts dans le temps; les signaux optiques utilisé dans les systèmes de télécommunications; certains signaux acoustiques et, en particulier, les impulsions produites par le système glottale; les signaux électriques modulés en position d’impulsions; une séquence d’événements dans une file d’attente; les trains de potentiels neuronaux dans le système neuronal. Ce paradigme de transmission est différent des communications continues traditionnelles et la compréhension des communications impulsives est donc essentielle. Afin d’affronter le problème des communications impulsives, le cadre de la recherche doit inclure les aspects suivants : la statistique d’interférence qui suit directement la structure des signaux impulsifs; l’interaction du signal impulsif avec le milieu physique; la possibilité pour les communications impulsives de coder l’information dans la structure temporelle. Cette thèse adresse une partie des questions précédentes et trace des lignes indicatives pour de futures recherches. En particulier, nous avons étudié: un système d'accès multiple où les utilisateurs adoptent des signaux avec étalement de spectre par saut temporel (time-hopping spread spectrum) pour communiquer vers un récepteur commun; un système avec un préfiltre à l'émetteur, et plus précisément un transmit matched filter, également connu comme time reversal dans la littérature de systèmes à bande ultra large; un modèle d'interférence pour des signaux impulsifs. / A communication is impulsive whenever the information-bearing signal is burst-like in time. Examples of the impulsive concept are: impulse-radio signals, that is, wireless signals occurring within short intervals of time; optical signals conveyed by photons; speech signals represented by sound pressure variations; pulse-position modulated electrical signals; a sequence of arrival/departure events in a queue; neural spike trains in the brain. Understanding impulsive communications requires to identify what is peculiar to this transmission paradigm, that is, different from traditional continuous communications.In order to address the problem of understanding impulsive vs. non-impulsive communications, the framework of investigation must include the following aspects: the different interference statistics directly following from the impulsive signal structure; the different interaction of the impulsive signal with the physical medium; the actual possibility for impulsive communications of coding information into the time structure, relaxing the implicit assumption made in continuous transmissions that time is a mere support. This thesis partially addresses a few of the above issues, and draws future lines of investigation. In particular, we studied: multiple access channels where each user adopts time-hopping spread-spectrum; systems using a specific prefilter at the transmitter side, namely the transmit matched filter (also known as time reversal), particularly suited for ultrawide bandwidhts; the distribution function of interference for impulsive systems in several different settings.

The process of protein and RNA folding has been understood in general terms through the principle of minimal frustration, and is usually thought of as being guided by a folding funnel on the energy landscape, which is based around the native structure. However, more recently, various biomolecules have been associated with multifunnel energy landscapes, where each funnel exhibits a distinct structural ensemble and function. This work explores how the principle of minimal frustration may be extended to multifunnel energy landscapes that are associated with multifunctional biomolecules. To achieve this aim, the computational potential energy landscape framework is employed to analyse four example systems. Additionally, this study analyses mutants for all four systems, where the mutations are chosen to change properties of the systems without destabilising the native sequence ensemble entirely. The first system considered is a two-state coiled-coil. It is shown how mutations fundamentally change the energy landscape from the minimal frustrated organisation necessary to fulfil biological function. These changes can introduce alternative pathways for folding, as well as new structural ensembles. Similar effects are observed for ubiquitin. In addition, the landscape exploration allows us to calculate a number of experimentally determined properties for this protein, which exhibit excellent agreement, and we characterise folding at an atomistic level of detail. Next we consider the hormones oxytocin and vasopressin, which are themselves mutants of each other, along with a number of other mutants for both molecules. Again, the frustration in the landscape increases due to mutations, and a greater variety in the resulting structural ensembles is observed, leading to changes in binding affinities. Finally, the HP1 loop of RNA 7SK is analysed, revealing that the principles established for the energy landscapes of proteins extend to nucleic acids. Overall, the results indicate that sequences have evolved to exhibit the minimum number of funnels on the energy landscape to support multiple functions, extending the principle of minimal frustration to multifunnel energy landscapes.