Mechanisms of Regulatory Adaptation in the Evolving Genome

The development from a single cell into a complex organism requires the precise control of gene expression in space and time. To achieve this, the activity of genes is governed by large regulatory chromatin landscapes that when disrupted can cause gene mis-regulation and disease. However, at the same time, the successful modification of these landscapes is thought to be a major driver of phenotypic innovation during evolution. Given the vulnerability of these landscapes in disease settings, it remains largely unknown how their integrity is maintained when novel genes are “safely” incorporated during evolution, which is addressed in this work. Specifically, here, multiple mechanisms are dissected that adapted the Fat1 regulatory landscape to maintain its integrity while simultaneously incorporating a novel gene, Zfp42, during evolution. First, comparative evolutionary genomics was used to reconstruct the history of the locus (section 1). Second, the three-dimensional chromatin configuration of the locus was examined in relationship to the gene activities using genomics-technologies (HiC, DamID) combined with super resolution microscopy and in silico modeling (section 2). Finally, the mechanisms that adapted the landscape in ESCs (section 3) and embryonic limbs (section 4) for the emergence of Zfp42 were investigated using genome engineering and genomics. Two tissue-specific mechanisms were identified that enabled the independent activities of Zfp42 and Fat1 despite sharing the same regulatory chromatin landscape: In ESCs, the landscape physically restructures and isolates the genes together with their regulatory information, from one another, thereby allowing their independent regulation. Surprisingly, this restructuring is not driven by the most recognized chromatin structuring force, loop extrusion, but rather by the underlying epigenetic state of chromatin. A different mechanism operates in embryonic mouse limbs where both genes are exposed to the same regulatory information driving Fat1 activation, but surprisingly not Zfp42. The inactivity of Zfp42 cannot be explained by nuclear envelopment attachment nor by enhancer-promoter specificity. Instead, Zfp42 is kept inactive by a highly context-dependent silencing mechanism driven by DNA methylation. As such, Zfp42 is ectopically active and responsive to the surrounding regulatory information when DNA methylation is removed or when the gene is slightly repositioned within its domain. Combined, we find that 3D-restructuring and context-dependent silencing adapted the Fat1 landscape to integrate Zfp42. More generally, this demonstrates that even single regulatory landscapes harbor an enormous regulatory complexity and, thus can accommodate multiple independently regulated genes. We believe that this has significant consequences for human genetics where similar genomic alterations do not drive disease in patients. This is possible, because additional, yet still unknown, mechanisms control how regulatory information is used in the genome

ABILITY OF PHENOLICS IN ISOLATION, COMPONENTS PRESENT IN SUPINA TURF GRASS TO REMEDIATE \u3ci\u3eCANDIDA ALBICANS\u3c/i\u3e (A72 and SC5314) ADHESION AND BIOFILM FORMATION

Candida albicans inhabits the gastrointestinal tract dormant commensal member but can become an opportunistic pathogen when the host microflora or immune system is compromised. Adhesion to a biological or synthetic surface, followed by a morphological change from the yeast to hyphae phenotype. Biofilm formation is becoming a common occurrence on types of medical devices. Because C. albicans resistant to commonly available anti-fungal drugs is increasing, innovative treatments are critically needed. Phenolic compounds are promising anti-fungal synergists. Supina grass was used as the complex matrix as it is abundant and highly sustainable source of phytochemicals even though grass cuttings are typically disposed. Therefore, the objective of this research is to determine the potential of phenolic compounds in isolation, as a combination and in present matrix, supina turf grass, to act synergistically in remediating C. albicans adhesion and biofilm formation from a synthetic surface. Chapter 1 of this study focused on the ability of 7 phenols (ferulic, gallic, sinapic, coumaric, epicatechin, catechin and quercetin) and 2 non-phenolic (farnesol and chlorophyll) common in natural systems to combat the cited virulent factors using different incubation times, 1, 3, 6 and 24 h, and treatment dosages (0.06-4.00 mM). The highest potency for occurred at 6 h post treatment but only chlorophyll, farnesol, and catechin were effective against adhesion while all the compounds were able to act against biofilm formation. However, percent remediation ranged from \u3c 0 to 40% with C. albicans (A72) being more stable and G, F being the most effective phenol. Interestingly, the lower dosages resulted in the greatest effectiveness. Chapter 2 describes the ability of two phenols to act synergistically to remediate adhesion and biofilm formation. After screening combination of compounds described above, the same 6 sets were the most effective against adhesion and biofilms, and included F-G, S-Q, F-E, E-C, CAT-Q, and CAT-C. In combination, the non-phenolic compounds in combination were not as effective as in isolation. The efficacy of the phenol combination was 20-60%, which again occurred with the lower dosages, (0.03 0.25) while the higher concentration (up to 4 mM) resulted in limited or no inhibition. The phenols acted synergistically to detach bound cells as the factionary inhibitory concentrations (FIC) was less than 0.05. For the biofilm experiments, with the FIC was 0.51.0 indicating partial synergy. Lastly, Chapter 3 demonstrated that a supina grass extract (at ng levels) was able to remediate C. albicans cellular adhesion and biofilm formation (50-70%). This study therefore generated information on the ability from a readily available agricultural stream, which then is expected to facilitate the development of efficacious anti-fungal treatments capable of remediating potentially life-threatening C. albicans infections. Advisor: Vicki Schlege

In Search of a Standard: Why Michigan\u27s Legal Loophole in Sole Legal Custody Situations Should Be Closed

Article published in the Michigan State University School of Law Student Scholarship Collection

An "All Hands" Call to the Social Science Community: Establishing a Community Framework for Complexity Modeling Using Agent Based Models and Cyberinfrastructure

To date, many communities of practice (COP) in the social sciences have been struggling with how to deal with rapidly growing bodies of information. Many CoPs across broad disciplines have turned to community frameworks for complexity modeling (CFCMs) but this strategy has been slow to be discussed let alone adopted by the social sciences communities of practice (SS-CoPs). In this paper we urge the SS-CoPs that it is timely to develop and establish a CBCF for the social sciences for two major reasons: the rapid acquisition of data and the emergence of critical cybertools which can facilitate agent-based, spatially-explicit models. The goal of this paper is not to prescribe how a CFCM might be set up but to suggest of what components it might consist and what its advantages would be. Agent based models serve the establishment of a CFCM because they allow robust and diverse inputs and are amenable to output-driven modifications. In other words, as phenomena are resolved by a SS-CoP it is possible to adjust and refine ABMs (and their predictive ability) as a recursive and collective process. Existing and emerging cybertools such as computer networks, digital data collections and advances in programming languages mean the SS-CoP must now carefully consider committing the human organization to enabling a cyberinfrastructure tool. The combination of technologies with human interfaces can allow scenarios to be incorporated through 'if' 'then' rules and provide a powerful basis for addressing the dynamics of coupled and complex social ecological systems (cSESs). The need for social scientists to be more engaged participants in the growing challenges of characterizing chaotic, self-organizing social systems and predicting emergent patterns makes the application of ABMs timely. The enabling of a SS-CoP CFCM human-cyberinfrastructure represents an unprecedented opportunity to synthesize, compare and evaluate diverse sociological phenomena as a cohesive and recursive community-driven process.Community-Based Complex Models, Mathematics, Social Sciences

Lumbar Posture and Tissue Loading During Short-Term Static Trunk Bending

Low back pain (LBP) is among the most prevalent occupational health problems worldwide and is a leading cause of lost work days. Previous studies have suggested that static prolonged trunk bending could generate lumbar muscle fatigue and introduce creep to the lumbar posterior tissues. Such physical changes could lead to alterations to the lumbar active and passive tissue sharing mechanism and also elevate spinal loading, which is highly associated with the risk of LBP. In the past, most occupational ergonomic studies focused on the instantaneous spine biomechanical responses during task performance. A few studies assessed the changes of spine biomechanics due to spinal tissue creep (introduced by prolonged trunk full flexion) and lumbar muscle fatigue (introduced by prolonged or repetitive trunk bending). However, the dynamic changes of lumbar and trunk postures and spinal tissue loadings during the performance of relatively short-term trunk bending tasks are still unclear. Therefore, the purpose of the current study was to investigate the changes of lumbar biomechanics during short-term, sustained trunk bending.;In the present study, fifteen participants performed short-term (40 seconds) static trunk bending tasks in two different trunk postures (30° or 60°) with two different hand load levels (0 or 15lbs). Results of the current study revealed significant reduction of lumbar muscle activities during the course of task performance. This change was coupled with significant increase of lumbar flexion angle and lumbar passive moment. Such increase of lumbar passive tissue loading could help relief/delay lumbar muscle fatigue by compensating the reduced lumber active tissue loading. Findings of this study suggest that, during the performance of sustained trunk bending, there is an internal mechanism to shift loading from lumbar active tissues to passive tissues by increasing the lumbar flexion. This mechanism is beneficial in reducing the amount of lumbar muscle fatigue; however, lumbar passive tissue creep could be generated at a faster rate

Education as a Positional Good? Evidence from the German Socio-Economic Panel

People care about their relative standing in society and therefore compare themselves to relevant others. Empirical findings suggest that there are concerns for relative standing for different goods and life domains such as income, cars, attractiveness, and supervisor’s praise. Even education has been mentioned as having a (partially) positional character. However, there has been only small consideration of education as a positional good in the empirical literature so far. Based on the literature on positional concerns and the role of education on relative position, I use German panel data to investigate the relationship between education and life satisfaction beyond the effect education might have through other variables such as income, health, or occupational prestige. Additionally, I consider the possibility that the consumption of education is subject to positional concerns. I discover a positive relationship between education and life satisfaction, indicating that education has a consumption component. Moreover, the relationship depends on the distribution of particular levels of education, suggesting that education has a positional character. © 2021, The Author(s)

ABILITY OF PHENOLICS IN ISOLATION, COMPONENTS PRESENT IN SUPINA TURF GRASS TO REMEDIATE \u3ci\u3eCANDIDA ALBICANS\u3c/i\u3e (A72 and SC5314) ADHESION AND BIOFILM FORMATION

Candida albicans inhabits the gastrointestinal tract dormant commensal member but can become an opportunistic pathogen when the host microflora or immune system is compromised. Adhesion to a biological or synthetic surface, followed by a morphological change from the yeast to hyphae phenotype. Biofilm formation is becoming a common occurrence on types of medical devices. Because C. albicans resistant to commonly available anti-fungal drugs is increasing, innovative treatments are critically needed. Phenolic compounds are promising anti-fungal synergists. Supina grass was used as the complex matrix as it is abundant and highly sustainable source of phytochemicals even though grass cuttings are typically disposed. Therefore, the objective of this research is to determine the potential of phenolic compounds in isolation, as a combination and in present matrix, supina turf grass, to act synergistically in remediating C. albicans adhesion and biofilm formation from a synthetic surface. Chapter 1 of this study focused on the ability of 7 phenols (ferulic, gallic, sinapic, coumaric, epicatechin, catechin and quercetin) and 2 non-phenolic (farnesol and chlorophyll) common in natural systems to combat the cited virulent factors using different incubation times, 1, 3, 6 and 24 h, and treatment dosages (0.06-4.00 mM). The highest potency for occurred at 6 h post treatment but only chlorophyll, farnesol, and catechin were effective against adhesion while all the compounds were able to act against biofilm formation. However, percent remediation ranged from \u3c 0 to 40% with C. albicans (A72) being more stable and G, F being the most effective phenol. Interestingly, the lower dosages resulted in the greatest effectiveness. Chapter 2 describes the ability of two phenols to act synergistically to remediate adhesion and biofilm formation. After screening combination of compounds described above, the same 6 sets were the most effective against adhesion and biofilms, and included F-G, S-Q, F-E, E-C, CAT-Q, and CAT-C. In combination, the non-phenolic compounds in combination were not as effective as in isolation. The efficacy of the phenol combination was 20-60%, which again occurred with the lower dosages, (0.03 0.25) while the higher concentration (up to 4 mM) resulted in limited or no inhibition. The phenols acted synergistically to detach bound cells as the factionary inhibitory concentrations (FIC) was less than 0.05. For the biofilm experiments, with the FIC was 0.51.0 indicating partial synergy. Lastly, Chapter 3 demonstrated that a supina grass extract (at ng levels) was able to remediate C. albicans cellular adhesion and biofilm formation (50-70%). This study therefore generated information on the ability from a readily available agricultural stream, which then is expected to facilitate the development of efficacious anti-fungal treatments capable of remediating potentially life-threatening C. albicans infections. Advisor: Vicki Schlege