Using Helix-coil Models to Study Protein Unfolded States

An abstract of a thesis devoted to using helix-coil models to study unfolded states.\\

Research on polypeptide unfolded states has received much more attention in the last decade or so than it has in the past. Unfolded states are thought to be implicated in various

misfolding diseases and likely play crucial roles in protein folding equilibria and folding rates. Structural characterization of unfolded states has proven to be

much more difficult than the now well established practice of determining the structures of folded proteins. This is largely because many core assumptions underlying

folded structure determination methods are invalid for unfolded states. This has led to a dearth of knowledge concerning the nature of unfolded state conformational

distributions. While many aspects of unfolded state structure are not well known, there does exist a significant body of work stretching back half a century that

has been focused on structural characterization of marginally stable polypeptide systems. This body of work represents an extensive collection of experimental

data and biophysical models associated with describing helix-coil equilibria in polypeptide systems. Much of the work on unfolded states in the last decade has not been devoted

specifically to the improvement of our understanding of helix-coil equilibria, which arguably is the most well characterized of the various conformational equilibria

that likely contribute to unfolded state conformational distributions. This thesis seeks to provide a deeper investigation of helix-coil equilibria using modern

statistical data analysis and biophysical modeling techniques. The studies contained within seek to provide deeper insights and new perspectives on what we presumably

know very well about protein unfolded states. \\

Chapter 1 gives an overview of recent and historical work on studying protein unfolded states. The study of helix-coil equilibria is placed in the context

of the general field of unfolded state research and the basics of helix-coil models are introduced.\\

Chapter 2 introduces the newest incarnation of a sophisticated helix-coil model. State of the art modern statistical techniques are employed to estimate the energies

of various physical interactions that serve to influence helix-coil equilibria. A new Bayesian model selection approach is utilized to test many long-standing

hypotheses concerning the physical nature of the helix-coil transition. Some assumptions made in previous models are shown to be invalid and the new model

exhibits greatly improved predictive performance relative to its predecessor. \\

Chapter 3 introduces a new statistical model that can be used to interpret amide exchange measurements. As amide exchange can serve as a probe for residue-specific

properties of helix-coil ensembles, the new model provides a novel and robust method to use these types of measurements to characterize helix-coil ensembles experimentally

and test the position-specific predictions of helix-coil models. The statistical model is shown to perform exceedingly better than the most commonly used

method for interpreting amide exchange data. The estimates of the model obtained from amide exchange measurements on an example helical peptide

also show a remarkable consistency with the predictions of the helix-coil model. \\

Chapter 4 involves a study of helix-coil ensembles through the enumeration of helix-coil configurations. Aside from providing new insights into helix-coil ensembles,

this chapter also introduces a new method by which helix-coil models can be extended to calculate new types of observables. Future work on this approach could potentially

allow helix-coil models to move into use domains that were previously inaccessible and reserved for other types of unfolded state models that were introduced in chapter 1.

[N]pT ensemble and finite-size-scaling study of the critical isostructural transition in the generalized exponential model of index 4.

First-order transitions of system where both lattice site occupancy and lattice spacing fluctuate, such as cluster crystals, cannot be efficiently studied by traditional simulation methods, which necessarily fix one of these two degrees of freedom. The difficulty, however, can be surmounted by the generalized [N]pT ensemble [J. Chem. Phys. 136, 214106 (2012)]. Here we show that histogram reweighting and the [N]pT ensemble can be used to study an isostructural transition between cluster crystals of different occupancy in the generalized exponential model of index 4 (GEM-4). Extending this scheme to finite-size scaling studies also allows us to accurately determine the critical point parameters and to verify that it belongs to the Ising universality class.

Numerical detection of the Gardner transition in a mean-field glass former.

Recent theoretical advances predict the existence, deep into the glass phase, of a novel phase transition, the so-called Gardner transition. This transition is associated with the emergence of a complex free energy landscape composed of many marginally stable sub-basins within a glass metabasin. In this study, we explore several methods to detect numerically the Gardner transition in a simple structural glass former, the infinite-range Mari-Kurchan model. The transition point is robustly located from three independent approaches: (i) the divergence of the characteristic relaxation time, (ii) the divergence of the caging susceptibility, and (iii) the abnormal tail in the probability distribution function of cage order parameters. We show that the numerical results are fully consistent with the theoretical expectation. The methods we propose may also be generalized to more realistic numerical models as well as to experimental systems.

Universal Non-Debye Scaling in the Density of States of Amorphous Solids.

At the jamming transition, amorphous packings are known to display anomalous vibrational modes with a density of states (DOS) that remains constant at low frequency. The scaling of the DOS at higher packing fractions remains, however, unclear. One might expect to find a simple Debye scaling, but recent results from effective medium theory and the exact solution of mean-field models both predict an anomalous, non-Debye scaling. Being mean-field in nature, however, these solutions are only strictly valid in the limit of infinite spatial dimension, and it is unclear what value they have for finite-dimensional systems. Here, we study packings of soft spheres in dimensions 3 through 7 and find, away from jamming, a universal non-Debye scaling of the DOS that is consistent with the mean-field predictions. We also consider how the soft mode participation ratio evolves as dimension increases.

The Evolution of Chimpanzee Sanctuaries in the United States

Chimpanzees are native only to the jungles of equatorial Africa, but for the last hundred years, they have also lived in captivity in the United States, most commonly in biomedical research laboratories, but also at Air Force bases for experiments for the space program, at accredited and unaccredited zoos, at circuses, as performers in Hollywood and even in private homes and backyards as pets. But that has been gradually evolving over the last few decades, as more and more chimpanzees move to newly-established chimpanzee sanctuaries. That transition was already underway even before the announcement by the National Institutes of Health (NIH) last year that it will retire all of its remaining chimpanzees from labs to sanctuaries. By thoroughly examining the evolution of these sanctuaries leading up to that seminal decision, along with the many challenges they face, including money, medical care, conflicting philosophies on the treatment of animals and the pitfalls that have led other sanctuaries to the brink of ruin, we can take away a better understanding of why chimpanzee sanctuaries are needed and why caretakers of other animal species are now looking to the chimpanzee sanctuary movement as a model to show how animals can be cared for in retirement.

Reconfiguring the contours of statehood and the rights of the peoples of disappearing states

Many of the elements that have traditionally supported state level normative self-organization, most notably territory, are being actively undermined by rising sea levels, flooding, desertification, amongst other climate change effects. As more and more states come to be redefined as â disappearingâ , that is, states losing their territories to the natural environment through no specific fault of their own, a question arises as to how displaced communities will be assisted in their desire (and right) to continue to practice principles of self-determination and self-government? What is clear is that the international community can no longer continue with the fiction of a unified or unchanging model of the liberal democratic state. Instead, alternative ontological models of sovereign community are required, as is a re-imagining of how statehood might be re-constituted in the future in response to deepening ecological problems. The international community must now begin to address the immanent nature of threats posed to disappearing states and consider how a model of statehood that does not privilege territory as a fixed component of state identity could be operationalized. This paper considers how a democratic reform of statehood might proceed and resettlement agreements for displaced communities determined. The transition to an era of peaceful sovereign relations under deteriorating global climate conditions and growing natural resource scarcity, it argues, will require a significant extension of established traditions of democratic compromise, human rights solidarity and cosmopolitan justice.

From Scarcity to Overload: Finding “Good Enough” Public Information in Myanmar’s Transition Information Symposium Summary Report

The Myanmar Book Aid Preservation Foundation (MBAPF) and Enlightened Research Myanmar (EMR) held an Information Symposium titled, From Scarcity to Overload: Finding “Good Enough” Public Information in Myanmar’s Transition in Yangon, Myanmar on January 28-29, 2016. The Symposium was co-sponsored by the University of Washington’s Henry M. Jackson School of International Studies (JSIS) and the Technology & Social Change Group (TASCHA) of the University’s Information School with support from the United States Agency for International Development (USAID), Microsoft, the Bill & Melinda Gates Foundation, and the Asia Foundation. The Information Symposium was held as part of a larger project supported by USAID, Microsoft, the Bill & Melinda Gates Foundation, and the Tableau Foundation implemented by the University of Washington’s JSIS and TASCHA, along with Myanmar partners, MBAPF and EMR. This project, Information Strategies for Societies in Transition, was developed largely because of the staggering challenges Myanmar is facing as it seeks to “catch-up” in the world’s most economically competitive region.

THE HEALTH OF YOUNG ADULTS WITH DISABILITIES IN THE UNITED STATES: THE COLLECTIVE ROLES OF RISK FACTORS IN SOCIAL ECOLOGIC FRAMEWORK

Background: Over the last few decades, the prevalence of young adults with disabilities (YAD) has steadily risen as a result of advances in medicine, clinical treatment, and biomedical technologythat enhanced their survival into adulthood. Despite investments in services, family supports, and insurance, they experience poor health status and barriers to successful transition into adulthood. Objectives: We investigated the collective roles of multi-faceted factors at intrapersonal, interpersonal and community levels within the social ecological framework on health related outcome including self-rated health (SRH) of YAD. The three specific aims are: 1) to examine sociodemographic differences and health insurance coverage in adolescence; 2) to investigate the role of social skills in relationships with family and peers developed in adolescence; and 3) to collectively explore the association of sociodemographic characteristics, social skills, and community participation in adolescence on SRH. Methods: Using longitudinal data (N=5,020) from the National Longitudinal Transition Study (NLTS2), we conducted multivariate logistic regression analyses to understand the association between insurance status as well as social skills in adolescence and YAD’s health related outcomes. Structural equation modeling (SEM) assessed the confluence of multi-faceted factors from the social ecological model that link to health in early adulthood. Results: Compared with YAD who had private insurance, YAD who had public health insurance in adolescence are at higher odds of experiencing poorer health related outcomes in self-rated health [adjusted odds ratio (aOR=2.89, 95% confidence interval (CI): 1.16, 7.23), problems with health (aOR=2.60, 95%CI: 1.26, 5.35), and missing social activities due to health problems (aOR=2.86, 95%CI: 1.39, 5.85). At the interpersonal level, overall social skills developed through relationship with family and peers in adolescence do not appear to have association with health related outcomes in early adulthood. Finally, at the community level, community participation in adolescence does not have an association with SRH in early adulthood. Conclusions: Having public health insurance coverage does not equate to good health. YAD need additional supports to achieve positive health outcomes. The findings in social skills and community participation suggest other potential factors may be at play for health related outcomes for YAD and the need for further investigation.

Ready for Transition: Factors that facilitate transfer to undergraduate engineering programs among Black African and American students

This study examines the factors facilitating the transfer admission of students broadly classified as Black from a single community college into a selective engineering college. The work aims to further research on STEM preparation and performance for students of color, as well as scholarship on increasing access to four-year institutions from two-year schools. Factors illuminating Underrepresented Racial and Ethnic Minority (URM) student pathways through Science, Technology, Engineering, and Mathematics (STEM) degree programs have often been examined through large-scale quantitative studies. However, this qualitative study complements quantitative data through demographic questionnaires, as well as semi-structured individual and group. The backgrounds and voices of diverse Black transfer students in four-year engineering degree programs were captured through these methods. Major findings from this research include evidence that community college faculty, peer networks, and family members facilitated transfer. Other results distinguish Black African from Black American transfers; included in these distinctions are depictions of different K-12 schooling experiences and differences in how participants self-identified. The findings that result from this research build upon the few studies that account for expanded dimensions of student diversity within the Black population. Among other demographic data, participants’ countries of birth and years of migration to the U.S. (if applicable) are included. Interviews reveal participants’ perceptions of factors impacting their educational trajectories in STEM and subsequent ability to transfer into a competitive undergraduate engineering program. This study is inclusive of, and reveals an important shifting demographic within the United States of America, Black Africans, who represent one of the fastest-growing segments of the immigrant population.

Unemployed, Now What? The Effect of Immigration on Unemployment Transitions of Native-born Workers in the United States

Although one would expect the unemployed to be the population most likely affected by immigration, most of the studies have concentrated on investigating the effects immigration has on the employed population. Little is known of the effects of immigration on labor market transitions out of unemployment. Using the basic monthly Current Population Survey from 2001 and 2013 we match data for individuals who were interviewed in two consecutive months and identify workers who transition out of unemployment. We employ a multinomial model to examine the effects of immigration on the transition out of unemployment, using state-level immigration statistics. The results suggest that immigration does not affect the probabilities of native-born workers finding a job. Instead, we find that immigration is associated with smaller probabilities of remaining unemployed, but it is also associated with higher probabilities of workers leaving the labor force. This effect impacts mostly young and less educated people.

Jiao Tong: A Grounded Theory of Chinese International Students' Transition to American Tertiary Education

University students are more globally mobile than ever before, increasingly receiving education outside of their home countries. One significant student exchange pattern is between China and the United States; Chinese students are the largest population of international students in the U.S. (Institute of International Education, 2014). Differences between Chinese and American culture in turn influence higher education praxis in both countries, and students are enculturated into the expectations and practices of their home countries. This implies significant changes for students who must navigate cultural differences, academic expectations, and social norms during the process of transition to a system of higher education outside their home country. Despite the trends in students’ global mobility and implications for international students’ transitions, scholarship about international students does not examine students’ experiences with the transition process to a new country and system of higher education. Related models were developed with American organizations and individuals, making it unlikely that they would be culturally transferable to Chinese international students’ transitions. This study used qualitative methods to deepen the understanding of Chinese international students’ transition processes. Grounded theory methods were used to invite the narratives of 18 Chinese international students at a large public American university, analyze the data, and build a theory that reflects Chinese international students’ experiences transitioning to American university life. Findings of the study show that Chinese international students experience a complex process of transition to study in the United States. Students’ pre-departure experiences, including previous exposure to American culture, family expectations, and language preparation, informed their transition. Upon arrival, students navigate resource seeking to fulfill their practical, emotional, social, intellectual, and ideological needs. As students experienced various positive and discouraging events, they developed responses to the pivotal moments. These behaviors formed patterns in which students sought familiarity or challenge subsequent to certain events. The findings and resulting theory provide a framework through which to better understand the experiences of Chinese international students in the context of American higher education.

Insulator-to-metal transition in vanadium supersaturated silicon: variable-range hopping and Kondo effect signatures

We report the observation of the insulator-to-metal transition in crystalline silicon samples supersaturated with vanadium. Ion implantation followed by pulsed laser melting and rapid resolidification produce high quality single-crystalline silicon samples with vanadium concentrations that exceed equilibrium values in more than 5 orders of magnitude. Temperature-dependent analysis of the conductivity and Hall mobility values for temperatures from 10K to 300K indicate that a transition from an insulating to a metallic phase is obtained at a vanadium concentration between 1.1 × 10^(20) and 1.3 × 10^(21) cm^(−3) . Samples in the insulating phase present a variable-range hopping transport mechanism with a Coulomb gap at the Fermi energy level. Electron wave function localization length increases from 61 to 82 nm as the vanadium concentration increases in the films, supporting the theory of impurity band merging from delocalization of levels states. On the metallic phase, electronic transport present a dispersion mechanism related with the Kondo effect, suggesting the presence of local magnetic moments in the vanadium supersaturated silicon material.

Shaken not stirred: creating exotic angular momentum states by shaking an optical lattice

We propose a method to create higher orbital states of ultracold atoms in the Mott regime of an optical lattice. This is done by periodically modulating the position of the trap minima (known as shaking) and controlling the interference term of the lasers creating the lattice. These methods are combined with techniques of shortcuts to adiabaticity. As an example of this, we show specifically how to create an anti-ferromagnetic type ordering of angular momentum states of atoms. The specific pulse sequences are designed using Lewis-Riesenfeld invariants and a fourlevel model for each well. The results are compared with numerical simulations of the full Schrodinger equation.

State-narco networks and the ‘War on Drugs’ in post-transition Bolivia, with special reference to 1989-1993

This thesis examines the development of state-narco networks in post-transition Bolivia. Mainstream discourses of drugs tend to undertheorise such relationships, holding illicit economies, weak states and violence as synergistic phenomena. Such assumptions fail to capture the nuanced relations that emerge between the state and the drug trade in different contexts, their underlying logics and diverse effects. As an understudied case, Bolivia offers novel insights into these dynamics. Bolivian military authoritarian governments (1964-1982), for example, integrated drug rents into clientelistic systems of governance, helping to establish factional coalitions and reinforce regime authority. Following democratic transition in 1982 and the escalation of US counterdrug efforts, these stable modes of exchange between the state and the coca-cocaine economy fragmented. Bolivia, though, continued to experience lower levels of drug-related violence than its Andean neighbours, and sustained democratisation despite being a major drug producer. Focusing on the introduction of the Andean Initiative (1989-1993), I explore state-narco interactions during this period of flux: from authoritarianism to (formal) democracy, and from Cold War to Drug War. As such, the thesis transcends the conventional analyses of the drugs literature and orthodox readings of Latin American narco-violence, providing insights into the relationship between illicit economies and democratic transition, the regional role of the US, and the (unintended) consequences of drug policy interventions. I utilise a mixed methods approach to offer discrete perspectives on the object of study. Drawing on documentary and secondary sources, I argue that state-narco networks were interwoven with Bolivia’s post-transition political settlement. Uneven democratisation ensured pockets of informalism, as clientelistic and authoritarian practices continued. This included police and military autonomy, and tolerance of drug corruption within both institutions. Non-enforcement of democratic norms of accountability and transparency was linked to the maintenance of fragile political equilibrium. Interviews with key US and Bolivian elite actors also revealed differing interpretations of state-narco interactions. These exposed competing agendas, and were folded into alternative paradigms and narratives of the ‘war on drugs’. The extension of US Drug War goals and the targeting of ‘corrupt’ local power structures, clashed with local ambivalence towards the drug trade, opposition to destabilising, ‘Colombianised’ policies and the claimed ‘democratising mission’ of the Bolivian government. In contrasting these US and Bolivian accounts, the thesis shows how real and perceived state-narco webs were understood and navigated by different actors in distinct ways. ‘Drug corruption’ held significance beyond simple economic transaction or institutional failure. Contestation around state-narco interactions was enmeshed in US-Bolivian relations of power and control.