A Systems Biology Approach to Epigenetic Gene Regulation

The ability to control when, and how much of the genetic code is being expressed is the underlying principle behind gene regulation. Control of gene production is able to influence a cell's phenotype by determining which structural components of the cell's observable traits (shape, growth, and behavior) are made. In multicellular organism’s different cell types are able to arise from the same genetic code due to a difference in the patterns of genes being expressed. Essentially anywhere in the process of gene expression from transcription, RNA processing, translation, and post-translational modifications of the protein is subject to regulation. As transcription is the first step in the process of gene expression, it is the first level of regulation for influencing the cell phenotype. The actions of transcription factors, histone modifiers, and other proteins work together to influence RNA polymerase's ability to complete the process of transcription. The actions of transcription factors are able to influence transcription by controlling the ability of RNA polymerase to be recruited to the start of a protein coding region and histone modifiers can rearrange the histones of the chromatin causing entire regions of a chromosome to become exposed or sequestered. These transcriptional regulators are able to work in a combinatorial fashion with one another to either activate and/or repress wide repertoires of transcriptional targets. Mapping out a network of interactions between these transcriptional regulators in gene expression programs allows researchers to understand how each protein is able to influence the phenotype of the cell, and how mutations to any of these transcriptional regulators are able to drive the cell into a diseased state. In the case of cancer, changes in the mechanisms of gene regulation brought on by mutations to these transcriptional regulators may drive the cell's hyper proliferative state. With the creation of next generation sequencing researchers are now better able to define where regulation is taking place in the genome, and how much it is able to influence gene expression. This gives researchers the ability to build these gene regulatory networks and evaluate their impact on gene expression. The subsequent chapters of this dissertation are a reflection of my published work investigating the contribution of oncogenic processes to gene regulatory networks in cancer through the study of hyperactivating somatic mutation of a histone modifier, changes in transcription factor response element specificity, epigenetic regulation of transcription factor signaling, and a transcription factor coactivation network

New Constraints on the Structure and Evolution of the Pulsar Wind Nebula 3C 58

We present an investigation of the spectral and spatial structure of the X-ray emission from 3C 58 based on a 350 ks observation with the Chandra X-ray Observatory. This deep image, obtained as part of the Chandra Large Project program, reveals new information on nearly all spatial scales in the pulsar wind nebula (PWN). On the smallest scales we derive an improved limit of T < 1.02 X 10^6 K for blackbody emission from the entire surface of the central neutron star (NS), confirming the need for rapid, nonstandard cooling in the stellar interior. Furthermore, we show that the data are consistent with emission from a light element atmosphere with a similar temperature. Surrounding the NS, a toroidal structure with a jet is resolved, consistent with earlier measurements and indicative of an east-west orientation for the projected rotation axis of the pulsar. A complex of loop-like X-ray filaments fills the nebula interior, and corresponds well with structures seen in the radio band. Several of the structures coincide with optical filaments as well. The emission from the interior of the PWN, including the pulsar, jet, and filaments, is primarily nonthermal in nature. The power law index steepens with radius, but appears to also show small azimuthal variations. The outermost regions of the nebula require a thermal emission component, confirming the presence of an ejecta-rich swept up shell.Comment: 12 pages, 9 figures. Accepted for Publication in ApJ. Fixed several incorrect east/west designations and revised treatment of column density. The latter results in minor changes to some derived spectral parameter

Food Distribution and Consumption in Knoxville: Exploring Food-Related Local Planning Issues

Summary: City planners have traditionally made an effort to understand the interrelationships between urban activities and various support systems, such as transportation, water and sewer, waste management, communications and energy. Food is also an important urban support system with a complex system of supply, distribution, and consumption. An understanding of the nature of the food supply and distribution system seems important, but in the past has not been an area of concern for the planning profession. It was the intent of this project to develop a basis from which to seek an understanding of the Knoxville food support system and its implications for local planning policy in Knoxville. The thrust of the study was three-fold. First, food-related problems and issues were identified. Then, further work was undertaken in order to propose remedial measures or public programs that might be initiated by local units of government. Finally, the group considered the possibility of establishing some kind of public oversight of the local food supply and distribution function. The approach has been general and comprehensive. One assumption here is that before public action can be initiated, those with responsibility for maintaining the public interest must understand the system. Thus, an analysis which would describe the system comprehensively, while allowing an opportunity to detect interrelationships among system components, was utilized. Patterns of consumption, food services and programs, and marketing channels by food types were also explored. The development of information involves consultation with literature, academicians, public officials, and industry representatives

Host-linked soil viral ecology along a permafrost thaw gradient

Climate change threatens to release abundant carbon that is sequestered at high latitudes, but the constraints on microbial metabolisms that mediate the release of methane and carbon dioxide are poorly understood1,2,3,4,5,6,7. The role of viruses, which are known to affect microbial dynamics, metabolism and biogeochemistry in the oceans8,9,10, remains largely unexplored in soil. Here, we aimed to investigate how viruses influence microbial ecology and carbon metabolism in peatland soils along a permafrost thaw gradient in Sweden. We recovered 1,907 viral populations (genomes and large genome fragments) from 197 bulk soil and size-fractionated metagenomes, 58% of which were detected in metatranscriptomes and presumed to be active. In silico predictions linked 35% of the viruses to microbial host populations, highlighting likely viral predators of key carbon-cycling microorganisms, including methanogens and methanotrophs. Lineage-specific virus/host ratios varied, suggesting that viral infection dynamics may differentially impact microbial responses to a changing climate. Virus-encoded glycoside hydrolases, including an endomannanase with confirmed functional activity, indicated that viruses influence complex carbon degradation and that viral abundances were significant predictors of methane dynamics. These findings suggest that viruses may impact ecosystem function in climate-critical, terrestrial habitats and identify multiple potential viral contributions to soil carbon cycling

Disorder Induced Power-law Gaps in an Insulator-metal Mott Transition

A correlated material in the vicinity of an insulator-metal transition (IMT) exhibits rich phenomenology and variety of interesting phases. A common avenue to induce IMTs in Mott insulators is doping, which inevitably leads to disorder. While disorder is well known to create electronic inhomogeneity, recent theoretical studies have indicated that it may play an unexpected and much more profound role in controlling the properties of Mott systems. Theory predicts that disorder might play a role in driving a Mott insulator across an IMT, with the emergent metallic state hosting a power law suppression of the density of states (with exponent close to 1; V-shaped gap) centered at the Fermi energy. Such V-shaped gaps have been observed in Mott systems but their origins are as yet unknown. To investigate this, we use scanning tunneling microscopy and spectroscopy to study isovalent Ru substitutions in Sr3(Ir1-xRux)2O7 (0≤x≤0.5) which drives the system into an antiferromagnetic, metallic state. Our experiments reveal that many core features of the IMT such as power law density of states, pinning of the Fermi energy with increasing disorder, and persistence of antiferromagnetism can be understood as universal features of a disordered Mott system near an IMT and suggest that V-shaped gaps may be an inevitable consequence of disorder in doped Mott insulators

Silent progression in disease activity-free relapsing multiple sclerosis.

ObjectiveRates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pretreatment era. Nonetheless, in our recently reported prospective cohort, more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, "no evidence of disease activity" at 2 years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation.MethodsDisability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0, or 0.5 (or greater) from baseline EDSS = 0, 1.0-5.0, and 5.5 or higher, respectively, assessed from baseline to year 5 (±1 year) and sustained to year 10 (±1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates.ResultsRelapses were associated with a transient increase in disability over 1-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p &lt; 0.05).InterpretationLong-term worsening is common in relapsing MS patients, is largely independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing-remitting MS. Ann Neurol 2019;85:653-666

Magnetic Quantum Tunneling: Insights from Simple Molecule-Based Magnets

This article takes a broad view of the understanding of magnetic bistability and magnetic quantum tunneling in single-molecule magnets (SMMs), focusing on three families of relatively simple, low-nuclearity transition metal clusters: spin S = 4 Ni4, Mn(III)3 (S = 2 and 6) and Mn(III)6 (S = 4 and 12). The Mn(III) complexes are related by the fact that they contain triangular Mn3 units in which the exchange may be switched from antiferromagnetic to ferromagnetic without significantly altering the coordination around the Mn(III) centers, thereby leaving the single-ion physics more-or-less unaltered. This allows for a detailed and systematic study of the way in which the individual-ion anisotropies project onto the molecular spin ground state in otherwise identical low- and high-spin molecules, thus providing unique insights into the key factors that control the quantum dynamics of SMMs, namely: (i) the height of the kinetic barrier to magnetization relaxation; and (ii) the transverse interactions that cause tunneling through this barrier. Numerical calculations are supported by an unprecedented experimental data set (17 different compounds), including very detailed spectroscopic information obtained from high-frequency electron paramagnetic resonance and low-temperature hysteresis measurements. Diagonalization of the multi-spin Hamiltonian matrix is necessary in order to fully capture the interplay between exchange and local anisotropy, and the resultant spin-state mixing which ultimately gives rise to the tunneling matrix elements in the high symmetry SMMs (ferromagnetic Mn3 and Ni4). The simplicity (low-nuclearity, high-symmetry, weak disorder, etc..) of the molecules highlighted in this study proves to be of crucial importance.Comment: 32 pages, incl. 6 figure

Paroxetine in human milk

Aims The primary aims of the study were to estimate the exposure of infants to paroxetine via breast milk and to determine the maternal milk:plasma ratio (M/P) of paroxetine. Secondary aims were to compare single point and area under the curve (AUC) estimates of M/P, to assess variability of M/P in fore and hind milk, and to compare the observed M/P with that predicted by a model. Methods Two studies were performed. In one study, six nursing mothers who were being treated with paroxetine were studied over a 24 h dose interval at steady-state. The total amount of paroxetine in the milk was measured, which represented the &apos;dose&apos; to the infant. The M/P AUC was calculated and compared with a predicted value. In the second study, four nursing mothers who were being treated with paroxetine, were studied at steady-state, around a normal infant feeding time. A single plasma sample and a prefeed milk sample were taken approximately 3 h after the morning dose of paroxetine, and a postfeed milk sample taken around 1 h later. The dose received by the infant was estimated from the average milk concentrations of the pre and postfeed samples using standard assumptions, and M/P calculated directly. Plasma concentrations of paroxetine were measured in 8 of the 10 infants in the two studies. Results The mean dose of paroxetine received by the infants in the first study was 1.13% (range 0.5-1.7) of the weight adjusted maternal dose. The mean M/P AUC was 0.39 (range 0.32-0.51). The predicted M/P was 0.22. The mean dose of paroxetine received by the infants in the second study was 1.25% (range 0.38-2.24) of the weight adjusted maternal dose. The mean M/P was 0.96 (range 0.31-3.33) and did not differ between fore and hind milk. The drug was not detected in the plasma of seven of the infants studied and was detected but not quantifiable (&lt;4 mg l −1 ) in one infant. No adverse effects were observed in any of the infants. Conclusions Measured M/P and estimated infant dose were similar in the two studies, although the range was wider for the single point study. Paroxetine can be considered &apos;safe&apos; during breast feeding because the dose transferred to the infant is well below the recommended safety limit of 10% of the weight adjusted maternal dose, concentrations in the infants were generally undetectable, and no adverse effects were reported

The success of the Montreal Protocol in mitigating interactive effects of stratospheric ozone depletion and climate change on the environment

The Montreal Protocol and its Amendments have been highly effective in protecting the stratospheric ozone layer, preventing global increases in solar ultraviolet-B radiation (UV-B; 280-315 nm) at Earth's surface, and reducing global warming. While ongoing and projected changes in UV-B radiation and climate still pose a threat to human health, food security, air and water quality, terrestrial and aquatic ecosystems, and construction materials and fabrics, the Montreal Protocol continues to play a critical role in protecting Earth's inhabitants and ecosystems by addressing many of the United Nations Sustainable Development Goals.Non peer reviewe