Neurotrophic Factor Signaling Mechanisms Underlying the Development of Peripheral Neural Circuits

The first discovery of a growth-regulating signaling molecule was more than 65 years ago, when the work of Rita Levi-Montalcini, Viktor Hamburger, and Stanley Cohen led to the identification and purification of nerve growth factor (NGF). As the prototypical growth factor, the identification of NGF was a milestone in developmental biology, leading to the subsequent discovery of hundreds of additional secreted growth factors. Many decades later, NGF is now recognized as one of many neurotrophic factors (NTFs) and the founding member of the neurotrophin family, which includes NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4), and neurotrophin-3 (NT-3). The physiologic functions of these factors are mediated by the tropomyosin-related kinase (Trk) receptor family as well as the p75 neurotrophin receptor (p75). A more recently identified family of neurotrophic factors is the the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs), which are potent growth factors that promote the survival of numerous populations of neurons in both the peripheral nervous system and central nervous system. The GFLs consist of four homologous ligands: GDNF, neurturin, artemin, and persephin, and signal by binding to one of four GDNF family co-receptors (GFRαs), which subsequently bind to and activate the tyrosine kinase Ret to initiate downstream signaling. This thesis work collectively sought to understand the functions of Ret signaling in peripheral nervous system development. In the first investigation (Chapter 2), we explored the function of a newly identified p75-Ret receptor complex in the development of nociceptive sensory neurons of the dorsal root ganglion (DRG), known to be dependent on GFL-Ret signaling for their survival and maintenance. In our investigation we found that p75 is required for cell surface localization of Ret. In the absence of p75, GFL-dependent, but not NGF-dependent, nociceptors are specifically reduced, with sensory populations that normally express lower levels of Ret being most greatly affected by p75 deletion. Based on these data, we conclude that p75 has a surprising role in augmenting GFL signaling, and collectively serves to promote the establishment of postnatal sensory neuron diversity. In the second study (Chapter 3), we investigated the function of this p75-Ret receptor complex in developing sympathetic neurons of the superior cervical ganglion (SCG). Interestingly, p75 signaling regulates programmed cell death (PCD) during perinatal development. In this investigation, we found that Ret expression is restricted to a subpopulation of apoptotic neurons that are rapidly eliminated. Ret and p75 form a complex induced by pro-apoptotic stimuli both in vitro and in vivo. Importantly, p75 deletion specifically within Ret-expressing neurons, and Ret deletion specifically during PCD, result in a significant abrogation in apoptosis. These studies collectively revealed a surprising non-canonical function of Ret in augmenting apoptotic signaling through p75 during PCD in vivo. In the last study (Chapter 4), we explored the function of Ret in the development of the peripheral taste system, focusing our studies on the geniculate ganglion (GG) which afferently innervates taste buds within fungiform papillae on the anterior 2/3 of the dorsal tongue. We identified a novel, biphasic function for GDNF-Ret signaling in the peripheral taste system, initially acting to promote the chemosensory phenotype of all GG neurons, while acting postnatally to define a unique subpopulation of lingual mechanoreceptors. These findings collectively broaden our understanding of the cues responsible for taste neuron development, and bring to light new information regarding taste neuron heterogeneity.PHDOral Health SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttps://deepblue.lib.umich.edu/bitstream/2027.42/144146/1/chdonnel_1.pd

Dynamics and control of a single-line maneuverable kite

Through simulation, an automated control system for a single-line maneuverable kite is developed for application in kite wind energy production. The kite used in this study is a small, tension-controlled, single-line kite, commonly known as a fighter kite. These kites have a simple design, but flying them requires complex control of line tension and visual input. At low tether tension, the kite is unstable; spinning about the tether. Increasing tension in the tether causes the kite to deform and fly in the direction it was facing. Experienced fliers can produce intricate maneuvers and often participate in competitions with other fliers. A simplified physical and behavioral numeric simulation of the kite\u27s dynamics was created and shown to closely approximate the actual kite\u27s flight characteristics. This model was used to develop successful control algorithms for autonomous flight. Information of the kite\u27s state and orientation used by the controller was gradually reduced to that which is physically measurable from the ground. An experimental test rig was designed and constructed for future testing in real wind conditions

Protection of Children from Use in Pornography: Toward Constitutional and Enforceable Legislation

This article will begin with an overview of the child pornography problem, then move to a more detailed discussion of the harms wrought upon children and society by the production and distribution of such material. A discussion of prior law will follow, detailing the need for legislation aimed specifically at the child pornography industry. The majority of the article will undertake a critical examination of existing child pornography legislation. The various elements of the offenses will be discussed and recommendations will be made to assure the effectiveness and constitutionality of child pornography statutes. In addition, provisions designed to facilitate easier enforcement of the statutes will be considered. Provisions seeking to protect and rehabilitate the victimized child will also be considered. Finally, recommendations made throughout this analysis will be summarized for the benefit of legislators and others seeking to improve the effectiveness of child pornography laws

What is pathogen-mediated insect superabundance?

When increasing abundance of insect vectors is manifest across multiple fields of a crop at the landscape scale, the phenomenon is sometimes referred to as insect superabundance. The phenomenon may reflect environmental factors (i.e. environmentally mediated insect superabundance, EMiS), including climatic change. A number of pathogens, however, are also known to modify the quality of infected plants as a resource for their insect vectors. In this paper, we term increasing vector abundance when associated with pathogen modification of plants as pathogen-mediated insect superabundance (henceforth PMiS). We investigate PMiS using a new epidemiological framework. We formalize a definition of PMiS and indicate the epidemiological mechanism by which it is most likely to arise. This study is motivated by the occurrence of a particularly destructive cassava virus epidemic that has been associated with superabundant whitefly populations in sub-Saharan Africa. Our results have implications for how PMiS can be distinguished from EMiS in field data. Above all, they represent a timely foundation for further investigations into the association between insect superabundance and plant pathogens.Bill and Melinda Gates Foundatio

Estimating epidemiological parameters from experiments in vector access to host plants, the method of matching gradients.

Estimation of pathogenic life-history values, for instance the duration a pathogen is retained in an insect vector (i.e., retention period) is of particular importance for understanding plant disease epidemiology. How can we extract values for these epidemiological parameters from conventional small-scale laboratory experiments in which transmission success is measured in relation to durations of vector access to host plants? We provide a solution to this problem by deriving formulae for the empirical curves that these experiments produce, called access period response curves (i.e., transmission success vs access period). We do this by writing simple equations for the fundamental life-cycle components of insect vectors in the laboratory. We then infer values of epidemiological parameters by matching the theoretical and empirical gradients of access period response curves. Using the example of Cassava brown streak virus (CBSV), which has emerged in sub-Saharan Africa and now threatens regional food security, we illustrate the method of matching gradients. We show how applying the method to published data produces a new understanding of CBSV through the inference of retention period, acquisition period and inoculation period parameters. We found that CBSV is retained for a far shorter duration in its insect vector (Bemisia tabaci whitefly) than had previously been assumed. Our results shed light on a number of critical factors that may be responsible for the transition of CBSV from sub- to super-threshold R0 in sub-Saharan Africa. The method is applicable to plant pathogens in general, to supply epidemiological parameter estimates that are crucial for practical management of epidemics and prediction of pandemic risk

Pathogenic modification of plants enhances long-distance dispersal of non-persistently transmitted viruses to new hosts.

Aphids spread the majority of plant viruses through ‘non-persistent’ transmission (NPT) whereby virus particles attach transiently to these insects’ probing mouthparts. Virus acquisition from infected plants and inoculation to healthy host plants is favored when aphids briefly probe plant epidermal cells. It is well established that NPT virus infection can alter plant-vector interactions, and moreover such pathogen modifications are found in a range of plant and animal systems. In particular, viruses can make plants more attractive to aphids but inhibit aphid settling on infected plants. It is hypothesized that this viral ‘reprogramming’ of plants promotes virus acquisition and encourages dispersal of virus-bearing aphids to fresh hosts. In contrast, it is hypothesized that virus-induced biochemical changes encouraging prolonged feeding on infected hosts inhibit NPT. To understand how these virus-induced modifications affect epidemics, we developed a modeling framework accounting for important but often neglected factors, including: feeding behaviors (probing or prolonged feeding) and distinct spatial scales of transmission (as conditioned by wingless or winged aphids). Analysis of our models confirmed that when viruses inhibit aphid settling on infected plants this initially promotes virus transmission. However, initially enhanced transmission is self-limiting because it decreases vector density. Another important finding is that virus-induced changes encouraging settling will stimulate birth of winged aphids, which promotes epidemics of NPT viruses over greater distances. Thus our results illustrate how plant virus modifications influence epidemics by altering vector distribution, density, and even vector form. Our insights are important for understanding how pathogens in general propagate through natural plant communities and crops

miR-34a-/- mice are susceptible to diet-induced obesity

Objective: MicroRNA (miR)−34a regulates inflammatory pathways, and increased transcripts have been observed in serum and subcutaneous adipose of subjects who have obesity and type 2 diabetes. Therefore, the role of miR-34a in adipose tissue inflammation and lipid metabolism in murine diet-induced obesity was investigated. Methods: Wild-type (WT) and miR-34a−/− mice were fed chow or high-fat diet (HFD) for 24 weeks. WT and miR-34a−/− bone marrow-derived macrophages were cultured in vitro with macrophage colony-stimulating factor (M-CSF). Brown and white preadipocytes were cultured from the stromal vascular fraction (SVF) of intrascapular brown and epididymal white adipose tissue (eWAT), with rosiglitazone. Results: HFD-fed miR-34a−/− mice were significantly heavier with a greater increase in eWAT weight than WT. miR-34a−/− eWAT had a smaller adipocyte area, which significantly increased with HFD. miR-34a−/− eWAT showed basal increases in Cd36, Hmgcr, Lxrα, Pgc1α, and Fasn. miR-34a−/− intrascapular brown adipose tissue had basal reductions in c/ebpα and c/ebpβ, with in vitro miR-34a−/− white adipocytes showing increased lipid content. An F4/80high macrophage population was present in HFD miR-34a−/− eWAT, with increased IL-10 transcripts and serum IL-5 protein. Finally, miR-34a−/− bone marrow-derived macrophages showed an ablated CXCL1 response to tumor necrosis factor-α. Conclusions: These findings suggest a multifactorial role of miR-34a in controlling susceptibility to obesity, by regulating inflammatory and metabolic pathways