Seeing the light : experimental signatures of emergent electromagnetism in a quantum spin ice

The "spin ice" state found in the rare earth pyrochlore magnets Ho2Ti2O7 and Dy2Ti2O7 offers a beautiful realisation of classical magnetostatics, complete with magnetic monopole excitations. It has been suggested that in "quantum spin ice" materials, quantum-mechanical tunnelling between different ice configurations could convert the magnetostatics of spin ice into a quantum spin liquid which realises a fully dynamical, lattice-analogue of quantum electromagnetism. Here we explore how such a state might manifest itself in experiment, within the minimal microscopic model of a such a quantum spin ice. We develop a lattice field theory for this model, and use this to make explicit predictions for the dynamical structure factor which would be observed in neutron scattering experiments on a quantum spin ice. We find that "pinch points", seen in quasi-elastic scattering, which are the signal feature of a classical spin ice, fade away as a quantum ice is cooled to its zero-temperature ground state. We also make explicit predictions for the ghostly, linearly dispersing magnetic excitations which are the "photons" of this emergent electromagnetism. The predictions of this field theory are shown to be in quantitative agreement with Quantum Monte Carlo simulations at zero temperature.Comment: 26 pages, 18 figures, minor revision

Master of Science

thesisVirtual point lights (VPLs) provide an effective solution to global illumination computation by converting the indirect illumination into direct illumination from many virtual light sources. This approach results in a less noisy image compare to Monte Carlo methods. In addition, the number of VPLs to generate can be specified in advance; therefore, it can be adjusted depending on the scene, desired quality, time budget, and the available computational power. In this thesis, we investigate a new technique that carefully places VPLs for providing improved rendering quality for computing global illumination using VPLs. Our method consists of three different passes. In the first pass, we randomly generate a large number of VPLs in the scene starting from the camera to place them in positions that can contribute to the final rendered image. Then, we remove a considerable number of these VPLs using a Poisson disk sample elimination method to get a subset of VPLs that are uniformly distributed over the part of the scene that is indirectly visible to the camera. The second pass is to estimate the radiant intensity of these VPLs by performing light tracing starting from the original light sources in the scene and scatter the radiance of light rays at a hit-point to the VPLs close to that point. The final pass is rendering the scene, which consists of shading all points in the scene visible to the camera using the original light sources and VPLs

Development of Container Free Sample Exposure for Synchrotron X-ray Footprinting.

The method of X-ray footprinting and mass spectrometry (XFMS) on large protein assemblies and membrane protein samples requires high flux density to overcome the hydroxyl radical scavenging reactions produced by the buffer constituents and the total protein content. Previously, we successfully developed microsecond XFMS using microfluidic capillary flow and a microfocused broadband X-ray source at the Advanced Light Source synchrotron beamlines, but the excessive radiation damage incurred when using capillaries prevented the full usage of a high-flux density beam. Here we present another significant advance for the XFMS method: the instrumentation of a liquid injection jet to deliver container free samples to the X-ray beam. Our preliminary experiments with a liquid jet at a bending magnet X-ray beamline demonstrate the feasibility of the approach and show a significant improvement in the effective dose for both the Alexa fluorescence assay and protein samples compared to conventional capillary flow methods. The combination of precisely controlled high dose delivery, shorter exposure times, and elimination of radiation damage due to capillary effects significantly increases the signal quality of the hydroxyl radical modification products and the dose-response data. This new approach is the first application of container free sample handling for XFMS and opens up the method for even further advances, such as high-quality microsecond time-resolved XFMS studies

Mechanisms of neuronal pathology in a model of grey matter inflammation

Multiple sclerosis (MS) is a chronic, inflammatory, and demyelinating disease of the central nervous system (CNS). It is characterized by formation of lesions both in white and grey matter. Upon disease evolution into progressive stages, grey matter pathology plays a larger role and permanent disability ensues. Grey matter pathology of MS has been widely characterized through histopathological studies in terms of demyelination, neuronal pathology, and inflammation. However, the mechanisms that play a role in pathology development and progression are not fully understood. Furthermore, treatment options for progressive stages of MS are limited and we have no way of effectively blocking ongoing cortical neurodegeneration. Thus, my PhD project focused on modeling, visualizing, understanding, and therapeutic targeting of cortical grey matter pathology. To address these questions, I used a combination of confocal microscopy, multiphoton in vivo microscopy, bioinformatic transcriptomic analysis, CRISPR/Cas9 gene editing, and PET imaging. The first part of my thesis aimed to establish a mouse model of grey matter pathology that resembled cortical pathology in MS. This model was induced in BiozziABH mice, which is a strain characterized by high antibody response and susceptibility to chronic CNS inflammation. Mice were immunized with MOG, followed by an intracerebral injection of pro-inflammatory cytokines to induce cortical lesions. Results suggest that our mouse model indeed presents with cortical grey matter demyelination, synapse loss and inflammatory lesions, which in turn, resembles previously described grey matter pathology in MS. Moreover, an age effect was observed in pathology resolution, with older mice displaying a more sustained neuroinflammatory response while younger mice spontaneously resolved inflammation. Further analysis of grey matter lesions revealed a potential role of synaptic calcium accumulation and phagocyte engulfment in neuronal pathology. In the second part of the thesis, the focus was on investigating pathways and mechanisms underlying neuronal pathology in grey matter of MS. For this purpose, we utilized single nuclei transcriptomic analysis of our mouse model, which was further mapped together with data sets from MS patients. We aimed at determining a MS specific gene signature that was present both in our model as well as in patients with MS. To ensure MS specificity, we further analysed the enrichment of our cortical MS-related gene signature in an Alzheimer’s disease patient data set. Our results demonstrated a species conservation of a cortical MS-related gene signature with five genes that are highly upregulated in neurons in the inflamed cortex of mice and humans that are interesting targets for further mechanistic analysis. We subsequently aimed to establish a CRISPR/Cas9 system for neuron-specific gene knockout which could then be used for investigation of mechanisms and pathways by which our candidate genes might play a role in MS pathology. Using two of the target genes, we demonstrated that the CRISPR/Cas9 system was successful in knocking out genes in neurons. However, we were up to now not able to conclusively resolve the role our selected genes played in MS grey matter pathology. In the next part of my thesis, we aimed to test different therapeutic strategies in our mouse model to determine if they would inhibit neuronal pathology in the inflamed grey matter or could rescue existing pathology. We tested immunomodulatory therapies targeting microglia activation as a strategy to limit the induction of neuronal pathology and could show that CSF1R inhibition can prevent synapse loss in the cortical MS model. Finally, we investigated imaging based approaches that could be used to track synaptic pathology in MS. For this purpose we performed a preclinical study with a SV2a specific PET tracer in our cortical MS model. PET imaging of mice demonstrated that the PET tracer was able to sensitively detect synapse loss in our model with the reduction in tracer uptake corresponding to the synaptic density decrease that was observed by histological examinations in situ. Overall, the results obtained of my thesis provide new insights into the pathomechanisms undelying neuronal pathology in the grey matter, the therapeutic strategies that can be used to prevent it and the imaging strategies that can be used to track it in MS patients

Brain serotonin synthesis capacity in obsessive-compulsive disorder: effects of cognitive behavioral therapy and sertraline.

Cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) are both effective treatments for some patients with obsessive-compulsive disorder (OCD), yet little is known about the neurochemical changes related to these treatment modalities. Here, we used positron emission tomography and the α-[11C]methyl-L-tryptophan tracer to examine the changes in brain regional serotonin synthesis capacity in OCD patients following treatment with CBT or SSRI treatment. Sixteen medication-free OCD patients were randomly assigned to 12 weeks of either CBT or sertraline treatment. Pre-to-post treatment changes in the α-[11C]methyl-L-tryptophan brain trapping constant, K* (ml/g/min), were assessed as a function of symptom response, and correlations with symptom improvement were examined. Responders/partial responders to treatment did not show significant changes in relative regional tracer uptake; rather, in responders/partial responders, 12 weeks of treatment led to serotonin synthesis capacity increases that were brain-wide. Irrespective of treatment modality, baseline serotonin synthesis capacity in the raphe nuclei correlated positively with clinical improvement. These observations suggest that, for some patients, successful remediation of OCD symptoms might be associated with greater serotonergic tone

Rare quantum metastable states in the strongly dispersive Jaynes-Cummings oscillator

We present evidence of metastable rare quantum-fluctuation switching for the driven dissipative Jaynes-Cummings oscillator coupled to a zero-temperature bath in the strongly dispersive regime. We show that single-atom complex amplitude bistability is accompanied by the appearance of a low-amplitude long-lived transient state, hereinafter called `dark state', having a distribution with quasi-Poissonian statistics both for the coupled qubit and cavity mode. We find that the dark state is linked to a spontaneous flipping of the qubit state, detuning the cavity to a low-photon response. The appearance of the dark state is correlated with the participation of the two metastable states in the dispersive bistability, as evidenced by the solution of the Master Equation and single quantum trajectories.Comment: Extensively revised text, 18 revised figures (16 in main and 2 in appendix), 38(+1) references, appendi

Ultrasmall Mixed Eu−Gd Oxide Nanoparticles for Multimodal Fluorescence and Magnetic Resonance Imaging of Passive Accumulation and Retention in TBI

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. TBI can have a long-term impact on the quality of life for survivors of all ages. However, there remains no approved treatment that improves outcomes following TBI, which is partially due to poor delivery of therapies into the brain. Therefore, there is a significant unmet need to develop more effective delivery strategies that increase the accumulation and retention of potentially efficacious treatments in the injured brain. Recent work has revealed that nanoparticles (NPs) may offer a promising approach for site-specific delivery; however, a detailed understanding of the specific NP properties that promote brain accumulation and retention are still being developed. Multimodal imaging plays a vital role in the understanding of physicochemical properties that initiate the uptake and accumulation of NPs in the brain at both high spatial (e.g., fluorescence imaging) and temporal (e.g., magnetic resonance imaging, MRI) frequency. However, many NP systems that are currently used in TBI only provide contrast in a single imaging modality limiting the imaging data that can be obtained, and those that offer multimodal imaging capabilities have complicated multistep synthesis methods. Therefore, the goal of this work was to develop an ultrasmall NP with simple fabrication capable of multimodal imaging. Here, we describe the development, characterization, accumulation, and retention of poly(ethylene glycol) (PEG)-coated europium−gadolinium (Eu−Gd) mixed magnetic NPs (MNPs) in a controlled cortical impact mouse model of TBI. We find that these NPs having an ultrasmall core size of 2 nm and a small hydrodynamic size of 13.5 nm can be detected in both fluorescence and MR imaging modalities and rapidly accumulate and are retained in injured brain parenchyma. These NPs should allow for further testing of NP physicochemical properties that promote accumulation and retention in TBI and other disease models

Circuit Dynamics of Adult Visual Cortex

Learning and other forms of plasticity result from changes in transmission at existing synapses or the construction or elimination of synapses. Synapses occur at the juxtaposition of boutons, with their postsynaptic partners, dendrites and cell bodies. It has been assumed that connections in the primary visual cortex (V1) become static after the critical period. Recent studies show, however, that dendritic spines appear and disappear during adulthood in the normal brain. Our first objective was then to determine whether axonal branches and boutons also undergo morphological changes. To do so, we performed longitudinal studies of virally labeled neurons and their processes. An adeno-associated virus bearing the gene for enhanced green fluorescent protein (AAV.EGFP) provided long-term labeling of axons and their boutons in adult Macaque V1. To image the neurons in vivo, a custom-designed two-photon microscope and viewing chamber provided repeated imaging of selected locations. We examined the same EGFP-labeled axonal arbors at several time points over periods of weeks in the adult normal cortex. We found that axons are dynamic entities, in which a subset of boutons appeared and disappeared overtime, and that though axonal length and branching was largely stable, a small subset of terminals underwent elongation, retraction or appeared de novo. These results suggest an ongoing process of synaptogenesis and synapse elimination in adult V1. To further investigate structural plasticity in the adult V1, we studied the cortical reorganization that accompanies retinal lesions. Removal of visual input cause axonal sprouting of long-range horizontal connections from pyramidal cells in layer 2/3. Our in vivo approach allowed us to determine the dynamics of the process of sprouting. Immediately following retinal lesions, there was a remarkable rise in axonal density. In the following weeks, the massive increase in axon collaterals was accompanied by a comparable rate of axonal elimination. Also, boutons increased their rate of appearance and elimination beyond the rates seen in normal cortex. These data indicate that the initial sprouting of axons followed by the subsequent refinement, may account for the dynamics of receptive field changes observed during the course of topographic reorganization of visual cortex