Constraints that Bind? A Comparison of Ruler Longevity in Merit and Feudal Institutions

This study examines the theory that veto players constrain executives and create a more stable political environment. This study extends previous research by looking at two new cases, the empires of China and Japan. I focus on the unconstrained rule of Chinese Emperors compared to their Japanese counterparts in part because of the existence of a developed feudal society in Medieval Japan, but also because China represents one of the earliest forms of meritocratic recruitment for higher offices in the government. Using data on imperial rule, this thesis analyzes the constraining effect of feudal institutions in a context found outside typical literature. I show that constraining the executive this way decreases the probability of being removed from office in both cases, yet has an ambiguous effect on duration of rule once time trends are taken into account. Unexpectedly, the effect of other institutions—namely merit-based—increased the duration of rule for Chinese Emperors. In times when bureaucrats were recruited solely based on merit, Chinese emperors ruled for a longer duration of time and enjoyed a decreased probability of being removed from office. I conclude by theorizing that the merit system created an independent power base that insulated the bureaucracy from executive reprisal, yet still created a powerful centralized state apparatus that undermined feudal elites

Electric Vehicles

This chapter regards the current state of electric vehicles in society today: the pros and cons, areas that need to improve, etc. The chapter starts by discussing some of the unethical practices that go into creating commodities of electric vehicles. From there, we explore the short, yet rapidly changing history of electric vehicles. Topics explored throughout its history include early inefficiencies, the introduction of hybrids that led to major improvements, and the increase in availability. The chapter then explores markets and commodities of electric vehicles, which explores the supply and demand side of this technology. We will show how growing demand has lead to improved government action, and how production methods must be improved for a sustainable future of electric vehicles. Finally, we test the ethics of electric vehicles, challenging the notion of nothing but the most ethical environmental standards. We will show how ways of metal mining and electricity generation actually do more bad than good for our environment. By reading this chapter, you will become more knowledgeable of how impactful electric vehicles are, and also you will get a grasp on whether or not you want to support this practice.Angela Person, Ph.D.N

Genetically Increasing Flux Through b-Oxidation in Skeletal Muscle Increases Mitochondrial Reductive Stress and Glucose Intolerance

Elevated mitochondrial hydrogen peroxide (H(2)O(2)) emission and an oxidative shift in cytosolic redox environment have been linked to high-fat-diet-induced insulin resistance in skeletal muscle. To test specifically whether increased flux through mitochondrial fatty acid oxidation, in the absence of elevated energy demand, directly alters mitochondrial function and redox state in muscle, two genetic models characterized by increased muscle β-oxidation flux were studied. In mice overexpressing peroxisome proliferator-activated receptor-α in muscle (MCK-PPARα), lipid-supported mitochondrial respiration, membrane potential (ΔΨ(m)), and H(2)O(2) production rate (JH(2)O(2)) were increased, which coincided with a more oxidized cytosolic redox environment, reduced muscle glucose uptake, and whole body glucose intolerance despite an increased rate of energy expenditure. Similar results were observed in lipin-1-deficient, fatty-liver dystrophic mice, another model characterized by increased β-oxidation flux and glucose intolerance. Crossing MCAT (mitochondria-targeted catalase) with MCK-PPARα mice normalized JH(2)O(2) production, redox environment, and glucose tolerance, but surprisingly, both basal and absolute insulin-stimulated rates of glucose uptake in muscle remained depressed. Also surprising, when placed on a high-fat diet, MCK-PPARα mice were characterized by much lower whole body, fat, and lean mass as well as improved glucose tolerance relative to wild-type mice, providing additional evidence that overexpression of PPARα in muscle imposes more extensive metabolic stress than experienced by wild-type mice on a high-fat diet. Overall, the findings suggest that driving an increase in skeletal muscle fatty acid oxidation in the absence of metabolic demand imposes mitochondrial reductive stress and elicits multiple counterbalance metabolic responses in an attempt to restore bioenergetic homeostasis. NEW & NOTEWORTHY Prior work has suggested that mitochondrial dysfunction is an underlying cause of insulin resistance in muscle because it limits fatty acid oxidation and therefore leads to the accumulation of cytotoxic lipid intermediates. The implication has been that therapeutic strategies to accelerate β-oxidation will be protective. The current study provides evidence that genetically increasing flux through β-oxidation in muscle imposes reductive stress that is not beneficial but rather detrimental to metabolic regulation

Ultra-deep sequencing reveals the mutational landscape of classical Hodgkin lymphoma

UNLABELLED: The malignant Hodgkin and Reed Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) are scarce in affected lymph nodes, creating a challenge to detect driver somatic mutations. As an alternative to cell purification techniques, we hypothesized that ultra-deep exome sequencing would allow genomic study of HRS cells, thereby streamlining analysis and avoiding technical pitfalls. To test this, 31 cHL tumor/normal pairs were exome sequenced to approximately 1,000× median depth of coverage. An orthogonal error-corrected sequencing approach verified \u3e95% of the discovered mutations. We identified mutations in genes novel to cHL including: CDH5 and PCDH7, novel stop gain mutations in IL4R, and a novel pattern of recurrent mutations in pathways regulating Hippo signaling. As a further application of our exome sequencing, we attempted to identify expressed somatic single-nucleotide variants (SNV) in single-nuclei RNA sequencing (snRNA-seq) data generated from a patient in our cohort. Our snRNA analysis identified a clear cluster of cells containing a somatic SNV identified in our deep exome data. This cluster has differentially expressed genes that are consistent with genes known to be dysregulated in HRS cells (e.g., PIM1 and PIM3). The cluster also contains cells with an expanded B-cell clonotype further supporting a malignant phenotype. This study provides proof-of-principle that ultra-deep exome sequencing can be utilized to identify recurrent mutations in HRS cells and demonstrates the feasibility of snRNA-seq in the context of cHL. These studies provide the foundation for the further analysis of genomic variants in large cohorts of patients with cHL. SIGNIFICANCE: Our data demonstrate the utility of ultra-deep exome sequencing in uncovering somatic variants in Hodgkin lymphoma, creating new opportunities to define the genes that are recurrently mutated in this disease. We also show for the first time the successful application of snRNA-seq in Hodgkin lymphoma and describe the expression profile of a putative cluster of HRS cells in a single patient

Revisiting the Historic Distribution and Habitats of the Whooping Crane

Understanding the historic range and habitats of an endangered species can assist in conservation and reintroduction efforts for that species. Individuals reintroduced into a species’ historic core range have a higher survival rate compared to individuals introduced near the periphery or outside the historic range (Falk and Olwell, 1992; Griffith et al., 1989). Individuals on the periphery of a species’ range tend to occupy less favorable habitats and have lower and more variable densities than those near the core of their range (Brown, 1984; Brown et al., 1995, 1996). Such conclusions, however, presume that historic habitats have not changed since a species was extirpated from core areas – a difficult assumption for many areas, and particularly for wetland habitat (Prince, 1997). Many endangered species persist only on the periphery of their historic range because of habitat loss or modification in their core range (Channell and Lomolino, 2000), which can bias our understanding of the species’ habitat preferences. Further, habitat models based on locations where species persist necessarily emphasize local conditions rather than historical conditions (Kuemmerle et al., 2011). For example, habitat models for the European bison (Bison bonasus) suggested it was a woodland species, but assessment of the bison’s historic range indicated it preferred mosaictype landscapes and had a more eastern and northern distribution than previously reported (Kuemmerle et al., 2011, 2012). Hence, accurate determination of the historic range and habitat conditions for endangered species can improve our understanding of their ecology and assist in conservation and reintroduction efforts. Examining the historic range from an ecological perspective can also help identify where appropriate habitat still exists that could sustain a population

Novel Anti-bacterial Activities of β-defensin 1 in Human Platelets: Suppression of Pathogen Growth and Signaling of Neutrophil Extracellular Trap Formation

Human β-defensins (hBD) are antimicrobial peptides that curb microbial activity. Although hBD's are primarily expressed by epithelial cells, we show that human platelets express hBD-1 that has both predicted and novel antibacterial activities. We observed that activated platelets surround Staphylococcus aureus (S. aureus), forcing the pathogens into clusters that have a reduced growth rate compared to S. aureus alone. Given the microbicidal activity of β-defensins, we determined whether hBD family members were present in platelets and found mRNA and protein for hBD-1. We also established that hBD-1 protein resided in extragranular cytoplasmic compartments of platelets. Consistent with this localization pattern, agonists that elicit granular secretion by platelets did not readily induce hBD-1 release. Nevertheless, platelets released hBD-1 when they were stimulated by α-toxin, a S. aureus product that permeabilizes target cells. Platelet-derived hBD-1 significantly impaired the growth of clinical strains of S. aureus. hBD-1 also induced robust neutrophil extracellular trap (NET) formation by target polymorphonuclear leukocytes (PMNs), which is a novel antimicrobial function of β-defensins that was not previously identified. Taken together, these data demonstrate that hBD-1 is a previously-unrecognized component of platelets that displays classic antimicrobial activity and, in addition, signals PMNs to extrude DNA lattices that capture and kill bacteria