Multivalent Random Walkers:A computational model of superdiffusive transport at the nanoscale

We present a stochastic model and numerical simulation framework for a synthetic nanoscale walker that can be used to transport materials and information at superdiffusive rates in artificial molecular systems. Our \emph{multivalent random walker} model describes the motion of a walker with a rigid, inert body and flexible, enzymatic legs. A leg can bind to and irreversibly modify surface-bound chemical substrate sites arranged as nanoscale tracks. As the legs attach to, modify, and detach from the sites, the walker moves along these tracks. Walkers are symmetrical and the tracks they walk on are unoriented, yet we show that under appropriate kinetic constraints the walkers can transform the chemical free energy in the surface sites into directional motion, and can do ordered work against an external load force. This shows that multivalent random walkers are a new type of molecular motor, useful for directional transport in nanoscale systems. We model the motion of multivalent random walkers as a continuous-time discrete-state Markov process. States in the process correspond to the chemical state of the legs and surface sites, and transitions represent discrete chemical changes of legs binding to, unbinding from, and modifying the surface sites. The Markov property holds because we let the mechanical motion of the body and unattached legs come to equilibrium in between successive chemical steps, thus the transitions depend only on the current chemical state of the surface sites and attached legs. This coarse-grained model of walker motion allows us to use both equilibrium and non-equilibrium Markov chain Monte Carlo simulation techniques. The Metropolis-Hastings algorithm approximates the motion of a walker\u27s body and legs at a mechanical equilibrium, while the kinetic Monte Carlo algorithm simulates the transient chemical dynamics of the walker stepping across the surface sites. Using these numerical techniques, we find that MVRWs move superdiffusively in the direction of unmodified substrate sites when there is a residence time bias between modified and unmodified sites. This superdiffusive motion persists when opposed by external load forces, showing that multivalent random walkers are \emph{molecular motors} that can transform chemical free energy into ordered mechanical work. To produce these results we devised a distributed object-oriented framework for parallel simulation and analysis of the MVRW model. We use an object-relational mapping to persistently maintain all simulation-related objects as tuples in a relational database. We present a new object-relational mapping technique called the \emph{natural entity framework} which disambiguates the semantics of object identity and uniqueness in the relational and object-oriented programming models. Using the natural entity framework we are able to guarantee the uniqueness of mappings between data stored as objects in the relational database and external data stored in non-transactionally-secured HDF5 data files

Quantum Complexity, Relativized Worlds, and Oracle Separations

Η κλάση πολυπλοκότητας QMA, που ορίσθηκε από τον Watrous, το 2000, είναι το κβαντικό ανάλογο της MA, που ορίσθηκε από τον Babai, το 1985, και η οποία είναι μία γενίκευση της κλάσης NP. Η κλάση MA γενικεύει την NP με την εξής έννοια: η επαληθευτική διαδικασία στην κλάση MA είναι πιθανοκρατική, ενώ στην NP είναι πλήρως ντετερμινιστική. Το 2014, οι Grilo, Kerenidis και Sikora, απέδειξαν ότι η κβαντική απόδειξη που ανακύπτει στον ορισμό της QMA μπορεί, σε κάθε περίπτωση, να αντικατασταθεί από μία, κατάλληλα ορισμένη, κβαντική κατάσταση-υποσύνολο. Οι Grilo κ.ά. ονόμασαν την κλάση αυτή SQMA, για ‘subset-state quantum Merlin-Arthur.’ ΄Αρα QMA ⊆ SQMA, και κάποιος θα μπορούσε να γράψει ότι QMA = SQMA, μιά και ο εγκλεισμός SQMA ⊆ QMA ισχύει τετριμμένα. Μετά από αυτό το αποτέλεσμα, από τους Grilo κ.ά., οι Fefferman και Kimmel, το 2015, απέδει- ξαν ότι υπάρχει κάποιο κβαντικό μαντείο A—παρόμοιο με αυτό που εισήγαγαν οι Aaronson και Kuperberg, το 2006, για να δείξουν ότι υπάρχει μαντείο A τέτοιο ώστε QMAA 1 6⊆ QCMAA—το οποίο είναι τέτοιο ώστε QMAA = SQMAA 6⊆ QCMAA. Σημειώνουμε εδώ ότι η QCMA είναι αυτή η έκδοση της QMA, που ορίσθηκε από τους Aharonov και Naveh, το 2002, σύμφωνα με την οποία η προς επαλήθευση απόδειξη είναι πλήρως κλασσική, π.χ. μία συμβολοσειρά 0-1-χαρακτήρων, και η QMA1 είναι η έκδοση τέλειας πληρότητας της QMA, δηλαδή είναι η έκδοση της QMA κατά την οποία για κάθε ΝΑΙ απάντηση, στο εξεταζόμενο πρόβλημα απόφασης, υπάρχει μία απόδειξη που κά- νει τον επαληθευτή να απαντήσει ΝΑΙ με πιθανότητα ίση με ένα. Στον μαντειακό τους διαχωρισμό οι Fefferman και Kimmel, εισήγαγαν, και χρησιμοποίησαν, μία ενδιαφέρουσα διαδικασία κατά την οποία κάποιος μπορεί να αποδείξει ότι L ∈/ QCMA, για κάποια γλώσσα L που ικανοποιεί κάποιες συγκεκριμένες ιδιότητες. Χρησιμοποιώντας αυτό το αποτέλεσμα των Fefferman και Kimmel, αποδεικνύουμε ότι υπάρχει κάποιο κβαντικό μαντείο τέτοιο ώστε SQMAA 1 6⊆ QCMAA. Σημειώνουμε εδώ ότι η κλάση SQMA1 είναι η έκδοση τέλειας πληρότητας της SQMA. Στην απόδειξή μας χρησιμοποιήσαμε την εν λόγω διαδικασία των Fefferman και Kimmel, μία εκδοχή των βασικών μαντειακών τους κατασκευών, όπως και το πρόβλημα απόφασης που χρησιμοποίησαν για την απόδειξη του διαχωρισμού τους. Σημειώνουμε εδώ ότι το αποτέλεσμά μας συνεπάγεται αυτό των Fefferman και Kimmel, μιά και ισχύει ότι SQMA1 ⊆ SQMA. Αφού διατυπώσουμε και αποδείξουμε το αποτέλεσμά μας, κάνουμε μία παράκαμψη για να εξερευνή- σουμε τον κόσμο των μαντειακών διαχωρισμών τόσο στον κλασσικό όσο και τον κβαντικό κόσμο. Εξερευνούμε κάποια αποτελέσματα, και τις υποβόσκουσες μεθόδους τους, που είναι σχετικά με την χρήση κλασσικών ή κβαντικών μαντείων σε μαντειακούς διαχωρισμούς που αφορούν σε κλασσικές ή κβαντικές κλάσεις πολυπλοκότητας. ΄Αρα εξερευνούμε κάποιες πολύ ενδιαφέρουσες πτυχές των διαχωριστικών αποτελεσμάτων που είναι σχετικά με σχετικιστικούς κόσμους. Τελικά, επιστρέφουμε, στο ερευνητικό τοπίο, ώστε να προσεγγίσουμε την ερώτηση σχετικά με την υποτιθέμενη ύπαρξη, ή όχι, ενός μαντείου A που είναι τέτοιο ώστε QMAA 1 6⊆ SQMAA 1 . Καταγρά- φουμε τις πρώτες μας προσπάθειες, και ιδέες, μέχρι τώρα.The complexity class QMA, defined by Watrous, in 2000, is the quantum analogue of MA, defined by Babai, in 1985, which, in turn, is a generalization of the class NP. The class MA generalizes the class NP in the sense that the verification procedure of the purported proof, put forth by the prover, is carried out by a probabilistic machine, rather than a deterministic one—as the definition of the class NP demands. In 2014, Grilo, Kerenidis, and Sikora, proved that the quantum proof, in the setting of QMA, may always be replaced by, an appropriately defined, quantum subset state—without any conceptual loss. That is, QMA ⊆ SQMA. Grilo et al., named their new class SQMA, for subset-state quantum MerlinArthur. Thus, one could write that SQMA = QMA, as the inclusion SQMA ⊆ QMA holds trivially. After this result, by Grilo, Kerenidis, and Sikora, Fefferman and Kimmel, in 2015, used this new characterization of QMA, and further proved that there exists some quantum oracle A—similar to that Aaronson and Kuperberg introduced, and used, in 2006, to show that QMAA 1 6⊆ QCMAA—which is such that QMAA = SQMAA 6⊆ QCMAA. Here, QCMA is that version of QMA, defined by Aharonov, and Naveh, in 2002, in which the purported proof is purely-classical, that is, a bitstring, and QMA1 is the perfect completeness version of QMA. In their separation, Fefferman and Kimmel introduced, and used, an interesting template to obtain oracle separations against the class QCMA. Drawing upon this recent result, by Fefferman and Kimmel, we prove that there exists some quantum oracle A, such that SQMAA 1 6⊆ QCMAA. We note that the class SQMA1 is the perfect completeness version of the class SQMA. In our proof, we used the template of Fefferman and Kimmel, a modified version of their basic quantum oracle construction, as well as the basic decision problem, that they themselves used for their separation. Note that our result implies that of Fefferman and Kimmel, as the inclusion xiii SQMA1 ⊆ SQMA holds. After we state and prove our result, we take a detour to explore a bit the world of oracle separations, both in the classical and the quantum setting. That is, we explore some results, and their underlying methods, about classical and quantum oracles being employed for proving separations— about classical, or quantum, complexity classes. Hence, we investigate some gems pertaining to the, not few at all, nor uninteresting, privileged relativized worlds. Finally, we return, to the research setting, to approach the open question of whether there exists some classical, or quantum, oracle A, such that QMAA 1 6⊆ SQMAA 1 , or not. We record our efforts, and some of our first ideas, thus far

The Relationship between Cardiometabolic Disorders and Schizophrenia: From Early-Life Origins to the Development of a Cardiometabolic Risk Prediction Algorithm for Young People with Psychosis

My thesis considers the theme of comorbidity between cardiometabolic disorders and schizophrenia by focussing on three key aspects: the nature of association between cardiometabolic disorders and schizophrenia; the potential for common underlying biological mechanisms for the comorbidity; and the prediction of cardiometabolic risk in young adults with psychosis. On the nature of association between cardiometabolic disorders and schizophrenia, using longitudinal repeat measure data from a large birth cohort, I found that disruption to glucose-insulin homeostasis through childhood/adolescence is associated with increased risk of psychosis in early-adulthood; may not be fully explained by common sociodemographic and lifestyle factors; and may be specific to it. On the mechanisms of association between cardiometabolic disorders and schizophrenia, I used a range of genetic and observational epidemiological methods to examine whether inflammation and shared genetic liability may be common underlying biological mechanisms for the comorbidity. Using birth cohort data, I show that genetic risk for type 2 diabetes is associated with psychosis-risk in adulthood, and vice versa. I also show that genetic risk for type 2 diabetes may influence psychosis risk by increasing systemic inflammation. Using summary data from large genome-wide association studies (GWAS), I show a thread of evidence for shared genetic overlap between schizophrenia, cardiometabolic and inflammatory traits. Finally, using Mendelian randomization, I show evidence supporting that inflammation may be a common cause for insulin resistance and schizophrenia. On the prediction of cardiometabolic risk in young adults with psychosis, I performed a systematic review of cardiometabolic risk prediction algorithms and explored their predictive performance in a sample of young people at risk of developing psychosis. In doing so, I show that none are likely to be suitable for this population. Then, using patient data, I developed and externally validated the Psychosis Metabolic Risk Calculator (PsyMetRiC), the first cardiometabolic risk prediction algorithm specifically tailored for young people with psychosis. Together, my work suggests that cardiometabolic disorders and schizophrenia share aetiologic mechanisms, namely inflammation and shared genetic liability. I have shown that it is possible to accurately predict cardiometabolic risk in young people with psychosis using a tool tailored for the population. Such tools can in future become valuable resources for clinicians to reduce the risk of long-term cardiometabolic morbidity and mortality in people with schizophrenia.National Institute for Health Research (NIHR) Doctoral Research Fellowshi

Genetic Insights into the Heterogeneity and Comorbidity of Substance Use Disorders

[eng] Substance use disorders (SUDs) are psychiatric disorders characterized by a recurring desire to continue taking a substance regardless of its destructive consequences. The etiology of SUDs is complex and multifactorial, where both genetic and environmental factors have an impact on the disease development. In addition, SUDs often co-occur at high prevalence with other psychiatric conditions, significantly impacting life expectancy, disease severity and societal burden. Over the past decade, genome-wide association studies (GWASs) have identified various risk loci for substance-specific SUD, as well as a shared genetic vulnerability for addiction. In addition, post-GWAS analyses have helped unravel the complex genetic architecture of SUDs, which can also involve an interplay of gene-environment interactions, and its relationship with comorbid mental health conditions. Current research in this field is making collective efforts to provide deeper and clearer knowledge into the genetic and environmental factors involved into the co-occurrence of SUDs and psychiatric disorders, which may be partially driving the high heterogeneity observed in SUDs, and the biological mechanisms driving these relationships. The present thesis comprises two studies that leverage in-house clinical cohorts, with both phenotypical and genetic data available, and state-of-the-art genomic techniques to investigate the shared genetic liability between SUDs and co-occurring traits, and to shed light into the genetic underpinnings of SUDs heterogeneity. The first study particularly focused on the relationship between SUDs and attention-deficit and hyperactivity disorder (ADHD). In this study, we tested whether the genetic liability to five SUD-related phenotypes share a common genetic background in both the general population and clinically diagnosed ADHD individuals, using an in-house sample of 989 subjects and polygenic scores (PGSs) analyses. We further explored the genetic overlap and the causal relationship between ADHD and SUDs using genetic correlation and Mendelian randomization analyses. Our results confirmed a significant genetic correlation between ADHD and SUDs and supported the current literature on the causal effect of the genetic liability to ADHD on the risk for SUDs. We provided novel findings on the effect of the genetic liability to lifetime cannabis use on an increased risk for ADHD and found evidence of a shared genetic background underlying SUDs between general population and ADHD, at least for lifetime cannabis use, alcohol dependence and smoking initiation. The second study aimed to disentangle SUDs heterogeneity using multidimensional data from a deeply phenotyped SUDs cohort of 1,427 individuals and PGSs for comorbid psychiatric disorders, behavioral and other related traits. We systematically explored the associations between the PGSs and 39 SUD-related phenotypes, and performed PGSs-environment interaction analyses using information on lifetime emotional, physical and/or sexual abuse. Our results revealed different patterns of associations between the genetic liability for mental health-related traits and SUD-related phenotypes, which may help explain part of the heterogeneity observed in SUDs. We also found evidence of a PGS-environment interaction showing that genetic liability for suicide attempt worsened the psychiatric status in SUDs individuals with a history of emotional physical and/or sexual abuse. Overall, the results of the present thesis provide new insights into the genetic overlap and causal relationships between SUDs and ADHD and contribute to a better understanding of the role of the genetic liability for psychiatric disorders and related traits, as well as its interaction with adverse life experiences, in the complexity of SUD heterogeneity. Lastly, this thesis provides a general discussion of the findings, which offers an extensive interpretation of the results in the context of existing literature, discusses the main methodological implications and outlines prospective directions for advancing in this line of research.[cat] Els trastorns per l'ús de substàncies (TUS) són trastorns psiquiàtrics caracteritzats per un desig recurrent de continuar prenent una o diverses substàncies, independentment de les seves conseqüències destructives. L'etiologia dels TUS és complexa i multifactorial, on tant factors genètics com ambientals tenen un impacte en el desenvolupament de la malaltia. A més, els TUS sovint es presenten simultàniament amb altres trastorns psiquiàtrics, afectant significativament la severitat de la malaltia, l’esperança de vida i la càrrega en la societat. Durant l'última dècada, els estudis d'associació del genoma complet (GWASs) han identificat diverses variants genètiques de risc per a TUS de substàncies específiques, així com una vulnerabilitat genètica compartida per a l'addicció. A més, les anàlisis post-GWAS han ajudat a desxifrar l'arquitectura genètica complexa dels TUS, que també pot implicar la interacció entre gens i ambient, i la seva relació amb trastorns de salut mental comòrbids. La recerca actual en aquest camp està focalitzada en profunditzar en el coneixement sobre els factors genètics i ambientals involucrats en la coexistència del TUS i trastorns psiquiàtrics, el qual pot ser parcialment responsable de l’alta heterogeneïtat observada en el TUS, i els mecanismes biològics implicats. La present tesi està composta per dos estudis que utilitzen cohorts clíniques, amb dades fenotípiques i genètiques disponibles, i tècniques genòmiques actuals per explorar la carga genètica compartida entre els TUS i els trets comòrbids, i per investigar la heterogeneïtat dels TUS des del punt de vista genètic. El primer estudi es centra particularment en la relació entre els TUS i el trastorn per dèficit d’atenció i hiperactivitat (TDAH). En aquest estudi, vam testar si la càrrega genètica per a cinc fenotips de TUS comparteixen una base genètica comuna en la població general i en individus amb TDAH, fent servir un mostra interna de 989 individus i anàlisis de puntuacions poligèniques (PGSs). Seguidament, vam explorar el solapament genètic i la relació causal entre el TDAH i els TUS utilitzant anàlisis de correlació genètica i de randomització mendeliana. Els nostres resultats confirmen una base genètic comuna entre el TDAH i els TUS i donen suport a la literatura actual sobre l'efecte causal de la càrrega genètica pel TDAH en el risc de TUS. A més, descrivim per primera vegada l'efecte causal de la càrrega genètica per a l'ús de cànnabis en el risc de TDAH i trobem evidències d'un component genètic compartit subjacent als TUS en la població general i en els individus amb TDAH, almenys per a l'ús de cànnabis, la dependència a l'alcohol i l'inici del consum de tabac. El segon estudi té com a objectiu desxifrar la heterogeneïtat dels TUS utilitzant dades multidimensionals d'una cohort de TUS de 1,427 individus dels quals es disposa una àmplia informació fenotípica, i PGSs per a trastorns psiquiàtrics comòrbids, trets del comportament i altres trets relacionats. Vam explorar les associacions entre els PGSs i 39 fenotips de TUS, i vam portar a terme anàlisis d’interacció PGS-ambient utilitzant informació sobre abús emocional, físic i/o sexual al llarg de la vida. Els nostres resultats revelen diferents patrons d'associacions entre la càrrega genètica per a trets relacionats amb la salut mental i fenotips de TUS, el que pot ajudar a explicar part de la heterogeneïtat observada en els TUS. També trobem evidència d'una interacció PGS-ambient que mostra que la càrrega genètica per a intents de suïcidi empitjora l'estat psiquiàtric en individus amb TUS que han patit abús emocional, físic i/o sexual. En conjunt, els resultats de la present tesi aporten noves perspectives sobre el solapament genètic i les relacions causals entre els TUS i el TDAH i contribueixen a una millor comprensió del paper de la càrrega genètica pels trastorns psiquiàtrics i trets relacionats, així com la seva interacció amb experiències adverses al llarg de la vida, en la complexitat de la heterogeneïtat dels TUS. Finalment, aquesta tesi ofereix una discussió general, la qual proporciona una extensa interpretació dels resultats en el context de la literatura existent, discuteix les principals implicacions metodològiques i detalla les futures direccions per avançar en aquesta línia de investigació

The design of 'possible worlds' as a contribution to the unfinished project of modernity: development of a reference architecture to support the decision-making processes of community-driven sustainable human development initiatives

This dissertation’s central ambitions are to point out and illustrate how design-oriented information systems research (ISR) can be utilized for critical and emancipatory (C&E) purposes as well as—although to a lesser extent—to offer a considerably different perspective on how ISR can contribute to the sustainable development (SD) research agenda. Research programs intending to remove entrenched inequalities by changing the status quo exhibit a C&E orientation. A design-oriented methodology tends to be predestinated as underpinning for such endeavors because of its explicitly stated aim of change. The omnipresent SD discussion, at least in its original conceptualization, is one of the most prominent areas where design-oriented research programs with C&E features are urgently needed. In particular, design science research in information systems (DSRIS), the design-oriented research program in ISR, is considered to be a vital ingredient: the design of appropriate technical systems is gaining in importance, because the complexity and dynamics of SD issues exceed human problem-solving capabilities. However, SD concerns cannot be addressed by isolated technical artifacts; technical systems have to be aligned with the social systems in which they are embedded. This broader endeavor is called the design of socio-technical systems. In comparison to research under this heading, DSRIS rarely strives for C&E goals. This curious situation can be traced back to the methodological suggestions given in the hope that they bridge the ‘relevance-rigor gap’: relevant research has to be carried out in response to problems articulated in practice and results have to be rigorously evaluated in practical settings to demonstrate their efficacy to solve the explicated issues. Besides the inherent challenges of both these prescriptions, from the stance of C&E research, it seems implausible that powerful actors would grant access to a setting and support projects that challenge their positions. Hence, the postulated aim of change is merely an euphemism for endeavors that reinforce and solidify the status quo—they, due to the lack of empowering potential, can solely further what Habermas termed the ‘colonization of the lifeworld’. The method for the design of ‘possible worlds’ proposed in the present inquiry not only helps to overcome this limitation, but it simultaneously integrates DSRIS more clearly with the overarching undertaking of devising socio-technical systems. Against this background, a designed `possible world’, seen from an explicated value position, is a more desirable, theoretically possible alternative to factual existing contexts in a particular domain. It functions as ‘crash barrier’ for the design of social systems and it can at the same time be leveraged as domain model from which it is possible to elicit requirements for the construction of a reference architecture that describes technical systems backing the processes of and within the ‘possible world’. However, in addition to the method’s development, the Ph.D. dissertation also illustrates the former’s application by designing a reference architecture for systems that support the decision-making processes of community-driven sustainable human development initiatives; one at least theoretically possible concretization of SD. As such, the inquiry makes three research contributions: its primary focus is a constructive extension of the disciplinary body of knowledge through the methodical guidance for C&E DSRIS; however, the reflection of SD as part of the exemplary application is also a critique of the way SD issues are currently tackled and of how they are integrated into the ISR canon. To realize these aims the study proceeds as follows: based on a critical reflection of the philosophical underpinnings of DSRIS, it explicates different routes to bridge the relevance-rigor gap. One of these avenues then serves as starting point for the construction of a method that specifically addresses the peculiarities of C&E DSRIS. The core derivation from the traditional conceptualization of design-oriented ISR lies within the sketch of a desirable, hypothetical alternative of factually existing social systems, which, through the contrasting with the latter, allows to carve out intervention entry points, i.e., aspects in which the ‘factual world’ has to change to become more like the ‘possible world’. To justify the claim that this transition, manifesting itself in the determined intervention entry points, is at least theoretically possible and not utopian, the ‘realist synthesis’ as a technique for the gathering of justificatory evidence from the existing body of knowledge is presented. Rooting endeavors of DSRIS in the scientific knowledge base is an important move to free them from being confined to those problems that are articulated by powerful gatekeepers in practical settings. However, for the design of ‘possible worlds’ to bear fruit in ISR, this step needs to be complemented. Therefore, the synthesis is adapted to also permit the extraction of, from the perspective of the underpinning normative stance, suitable ‘draft meanings’, because these progressive (social) structures or organizational options resulting from interventions provide the basis for the design of reference architectures that are aligned with the ‘possible world’. To illustrate this, from an ISR perspective, fundamental usage scenario, the inquiry, based on a devised preliminary reference architecture development approach, carries out the afore-mentioned exemplary application of the method for the design of ‘possible worlds’