Inferring structures, free energy differences, and kinetic rates of biological macromolecular assemblies by integrative modeling

Biological macromolecular assemblies play crucial roles in most cellular processes. The determination of their structures, thermodynamics, and kinetics is essential to understand their function, evolution, modulation, and design. Determining such models, however, remains challenging. One particularly powerful approach to constructing models in general is integrative modeling. Integrative modeling aims to maximize the accuracy, precision, and completeness of models, by simultaneously utilizing all available information, including experimental data, physical principles, statistical analyses, and other prior models. The goal of this thesis is to expand the scope of integrative modeling to the inference of spatial, thermodynamic, and kinetic aspects of macromolecular assemblies. In Chapter I, I introduce the integrative modeling framework for spatiotemporal modeling of biological macromolecular assemblies. In Chapter II, I demonstrate how the synergy between multi-chemistry cross-linking mass spectrometry and integrative modeling can map the structural dynamics of macromolecular assemblies, by application to the human Cop9 signalosome complex. In Chapter III, I present a method for determining structures, free energy differences, and kinetic rates of macromolecular assemblies along their functional cycle, mainly from negative stain electron microscopy (EM). We apply the method to the yeast Hsp90 to estimate the free energy differences and kinetic parameters along its nucleotide hydrolysis cycle, which includes open and closed states of Hsp90. In Chapter IV, I describe a validation of stochastic sampling in integrative modeling. The remaining chapters describe applications of integrative modeling to assemblies of various sizes and scales, using various sources of information, thus illustrating the flexibility of the integrative modeling approach. Specifically, I apply integrative modeling to the human ECM29-Proteasome assembly under oxidative stress (Chapter V), the yeast nuclear pore complex (NPC) cytoplasmic mRNA export platform (Chapter VI), the major membrane ring component of the yeast NPC (Chapter VII), the entire yeast NPC (Chapter VIII), and the reconstruction of 3D structures of MET antibodies (Chapter IX)

Pumping conductance, the intrinsic anomalous Hall effect, and statistics of topological invariants

The pumping conductance of a disordered two-dimensional Chern insulator scales with increasing size and fixed disorder strength to sharp plateau transitions at well-defined energies between ordinary and quantum Hall insulators. When the disorder strength is scaled to zero as system size increases, the "metallic" regime of fluctuating Chern numbers can extend over the whole band. A simple argument leads to a sort of weighted equipartition of Chern number over minibands in a finite system with periodic boundary conditions: even though there must be strong fluctuations between disorder realizations, the mean Chern number at a given energy is determined by the {\it clean} Berry curvature distribution expected from the intrinsic anomalous Hall effect formula for metals. This estimate is compared to numerical results using recently developed operator algebra methods, and indeed the dominant variation of average Chern number is explained by the intrinsic anomalous Hall effect. A mathematical appendix provides more precise definitions and a model for the full distribution of Chern numbers.Comment: 12 page

Taking pleasure seriously: the political significance of subcultural practice

This paper demonstrates that subcultural theory continues to provide a relevant and useful analysis of youth leisure practices and their political significance in contemporary society. It achieves this by analysing the theoretical antecedents to both subcultural theory and the post-subcultural theory that followed it. It is argued that the post-subcultural turn to studying affects and everyday lives resonates deeply with the Gramscian perspective informing subcultural theory. It is thus possible to interpret post-subculturalism as augmenting rather than negating its predecessor. Deploying an analysis that combines these perspectives allows for an account of contemporary youth leisure practices that demonstrates a number of different forms of politics explicated within the paper: a politics of identity and becoming; a politics of defiance; a politics of affective solidarity and a politics of different experience. Whilst not articulated or necessarily conscious, there is a proto-politics to youth leisure that precludes it from being dismissed as entirely empty, hedonistic and consumerist. This paper demonstrates how the lens of post-subculturalism focuses on the affective spaces where this politics is most apparent and provides a means of updating subcultural theory to understand contemporary youth practices

State-space based mass event-history model I: many decision-making agents with one target

A dynamic decision-making system that includes a mass of indistinguishable agents could manifest impressive heterogeneity. This kind of nonhomogeneity is postulated to result from macroscopic behavioral tactics employed by almost all involved agents. A State-Space Based (SSB) mass event-history model is developed here to explore the potential existence of such macroscopic behaviors. By imposing an unobserved internal state-space variable into the system, each individual's event-history is made into a composition of a common state duration and an individual specific time to action. With the common state modeling of the macroscopic behavior, parametric statistical inferences are derived under the current-status data structure and conditional independence assumptions. Identifiability and computation related problems are also addressed. From the dynamic perspectives of system-wise heterogeneity, this SSB mass event-history model is shown to be very distinct from a random effect model via the Principle Component Analysis (PCA) in a numerical experiment. Real data showing the mass invasion by two species of parasitic nematode into two species of host larvae are also analyzed. The analysis results not only are found coherent in the context of the biology of the nematode as a parasite, but also include new quantitative interpretations.Comment: Published in at http://dx.doi.org/10.1214/08-AOAS189 the Annals of Applied Statistics (http://www.imstat.org/aoas/) by the Institute of Mathematical Statistics (http://www.imstat.org

Enhancing the work of the Islington Integrated Gangs Team: A pilot study on the response to serious youth violence in Islington

This report is the result of research conducted by the Centre for City Criminology at City, University of London, in partnership with Islington’s Integrated Gangs Team (IGT) and the Metropolitan Police Service (MPS). The research was co-funded by MPS and the School of Arts and Social Sciences, City, University of London. Following a collaborative research event in October 2017, City Criminologists were commissioned to carry out a small-scale research project to capture the work of the IGT and to make recommendations regarding its operations, coherence, effectiveness and sustainability. The research team conducted semi-structured interviews over several months with 23 practitioners across the services that constitute the IGT. This report presents the findings and recommendations

Predicted signatures of p-wave superfluid phases and Majorana zero modes of fermionic atoms in RF absorption

We study the superfluid phases of quasi-2D atomic Fermi gases interacting via a p-wave Feshbach resonance. We calculate the absorption spectra of these phases under a hyperfine transition, for both non-rotating and rotating superfluids. We show that one can identify the different phases of the p-wave superfluid from the absorption spectrum. The absorption spectrum shows clear signatures of the existence of Majorana zero modes at the cores of vortices of the weakly-pairing $p_x+ip_y$ phase

Percolation in living neural networks

We study living neural networks by measuring the neurons' response to a global electrical stimulation. Neural connectivity is lowered by reducing the synaptic strength, chemically blocking neurotransmitter receptors. We use a graph-theoretic approach to show that the connectivity undergoes a percolation transition. This occurs as the giant component disintegrates, characterized by a power law with critical exponent $\beta \simeq 0.65$ is independent of the balance between excitatory and inhibitory neurons and indicates that the degree distribution is gaussian rather than scale freeComment: PACS numbers: 87.18.Sn, 87.19.La, 64.60.Ak http://www.weizmann.ac.il/complex/tlusty/papers/PhysRevLett2006.pd