The Enteric Network: Interactions between the Immune and Nervous Systems of the Gut

Interactions between the nervous and immune systems enable the gut to respond to the variety of dietary products that it absorbs, the broad spectrum of pathogens that it encounters, and the diverse microbiome that it harbors. The enteric nervous system (ENS) senses and reacts to the dynamic ecosystem of the gastrointestinal (GI) tract by translating chemical cues from the environment into neuronal impulses that propagate throughout the gut and into other organs in the body, including the central nervous system (CNS). This review will describe the current understanding of the anatomy and physiology of the GI tract by focusing on the ENS and the mucosal immune system. We highlight emerging literature that the ENS is essential for important aspects of microbe-induced immune responses in the gut. Although most basic and applied research in neuroscience has focused on the brain, the proximity of the ENS to the immune system and its interface with the external environment suggest that novel paradigms for nervous system function await discovery

Host-Microbe Interactions Impacting and Mediated by Nervous Systems

Animals and microbes coevolved, and thus it is not surprising that the trillions of microorganisms that harmoniously inhabit the mammalian gastrointestinal tract (GIT), collectively termed the gut microbiome, continue to be implicated in healthy and disease states. However, less is known about the mechanisms by which these states are maintained, and how deviations from homeostasis (i.e., dysbiosis) occurr. This thesis explores the relationship between host-microbe interactions and the central and peripheral nervous systems. Specifically, the first chapter of this thesis explores how the microbiome differs is patients with multiple sclerosis and how these differences alter diseases outcomes in a mouse model of the disease. Next, we introduce the enteric nervous system (ENS), the intrinsic nervous system of the GI tract which is supposed as a major conduit of the bidirectional communication between the gut and the brain. Lastly, by adopting biotechnologies in gene delivery and genetically encoded tools for neuroscience, we introduce a molecular toolkit to characterize the ENS in a robust and efficient manner and modulate the ENS to uncover novel mechanisms by which innervation of the GI mediates host-microbe interactions

Gut-seeded α-synuclein fibrils promote gut dysfunction and brain pathology specifically in aged mice

Parkinson’s disease is a synucleinopathy that is characterized by motor dysfunction, death of midbrain dopaminergic neurons and accumulation of α-synuclein (α-Syn) aggregates. Evidence suggests that α-Syn aggregation can originate in peripheral tissues and progress to the brain via autonomic fibers. We tested this by inoculating the duodenal wall of mice with α-Syn preformed fibrils. Following inoculation, we observed gastrointestinal deficits and physiological changes to the enteric nervous system. Using the AAV-PHP.S capsid to target the lysosomal enzyme glucocerebrosidase for peripheral gene transfer, we found that α-Syn pathology is reduced due to the increased expression of this protein. Lastly, inoculation of α-Syn fibrils in aged mice, but not younger mice, resulted in progression of α-Syn histopathology to the midbrain and subsequent motor defects. Our results characterize peripheral synucleinopathy in prodromal Parkinson’s disease and explore cellular mechanisms for the gut-to-brain progression of α-Syn pathology

Predictors of the Change in the Expression of Emotional Support within an Online Breast Cancer Support Group: A Longitudinal Study

OBJECTIVES: To explore how the expression of emotional support in an online breast cancer support group changes over time, and what factors predict this pattern of change. METHODS: We conducted growth curve modeling with data collected from 192 participants in an online breast cancer support group within the Comprehensive Health Enhancement Support System (CHESS) during a 24-week intervention period. RESULTS: Individual expression of emotional support tends to increase over time for the first 12 weeks of the intervention, but then decrease slightly with time after that. In addition, we found that age, living situation, comfort level with computer and the Internet, coping strategies were important factors in predicting the changing pattern of expressing emotional support. CONCLUSIONS: Expressing emotional support changed in a quadratic trajectory, with a range of factors predicting the changing pattern of expression. PRACTICAL IMPLICATIONS: These results can provide important information for e-health researchers and physicians in determining the benefits individuals can gain from participation in should CMSS groups as the purpose of cancer treatment

A quantitative explanation of the observed population of Milky Way satellite galaxies

We revisit the well known discrepancy between the observed number of Milky Way (MW) dwarf satellite companions and the predicted population of cold dark matter (CDM) sub-halos, in light of the dozen new low luminosity satellites found in SDSS imaging data and our recent calibration of the SDSS satellite detection efficiency, which implies a total population far larger than these dozen discoveries. We combine a dynamical model for the CDM sub-halo population with simple, physically motivated prescriptions for assigning stellar content to each sub-halo, then apply observational selection effects and compare to the current observational census. As expected, models in which the stellar mass is a constant fraction F(Omega_b/Omega_m) of the sub-halo mass M_sat at the time it becomes a satellite fail for any choice of F. However, previously advocated models that invoke suppression of gas accretion after reionization in halos with circular velocity v_c <~ 35 km/s can reproduce the observed satellite counts for -15 < M_V < 0, with F ~ 10^{-3}. Successful models also require strong suppression of star formation BEFORE reionization in halos with v_c <~ 10 km/s; models without pre-reionization suppression predict far too many satellites with -5 < M_V < 0. Our models also reproduce the observed stellar velocity dispersions ~ 5-10 km/s of the SDSS dwarfs given the observed sizes of their stellar distributions, and model satellites have M(<300 pc) ~ 10^7 M_sun as observed even though their present day total halo masses span more than two orders of magnitude. Our modeling shows that natural physical mechanisms acting within the CDM framework can quantitatively explain the properties of the MW satellite population as it is presently known, thus providing a convincing solution to the `missing satellite' problem.Comment: 18 pages, 14 figures, accepted to ApJ. Minor changes following referees repor

The pseudo-evolution of halo mass

A dark matter halo is commonly defined as a spherical overdensity of matter with respect to a reference density, such as the critical density or the mean matter density of the Universe. Such definitions can lead to a spurious pseudo-evolution of halo mass simply due to redshift evolution of the reference density, even if its physical density profile remains constant over time. We estimate the amount of such pseudo-evolution of mass between z=1 to 0 for halos identified in a large N-body simulation, and show that it accounts for almost the entire mass evolution of the majority of halos with M200 of about 1E12 solar masses and can be a significant fraction of the apparent mass growth even for cluster-sized halos. We estimate the magnitude of the pseudo-evolution assuming that halo density profiles remain static in physical coordinates, and show that this simple model predicts the pseudo-evolution of halos identified in numerical simulations to good accuracy, albeit with significant scatter. We discuss the impact of pseudo-evolution on the evolution of the halo mass function and show that the non-evolution of the low-mass end of the halo mass function is the result of a fortuitous cancellation between pseudo-evolution and the absorption of small halos into larger hosts. We also show that the evolution of the low mass end of the concentration-mass relation observed in simulations is almost entirely due to the pseudo-evolution of mass. Finally, we discuss the implications of our results for the interpretation of the evolution of various scaling relations between the observable properties of galaxies and galaxy clusters and their halo masses.Comment: 15 pages, 9 figures. Minor changes. Published Versio

Net neutrality discourses: comparing advocacy and regulatory arguments in the United States and the United Kingdom

Telecommunications policy issues rarely make news, much less mobilize thousands of people. Yet this has been occurring in the United States around efforts to introduce "Net neutrality" regulation. A similar grassroots mobilization has not developed in the United Kingdom or elsewhere in Europe. We develop a comparative analysis of U.S. and UK Net neutrality debates with an eye toward identifying the arguments for and against regulation, how those arguments differ between the countries, and what the implications of those differences are for the Internet. Drawing on mass media, advocacy, and regulatory discourses, we find that local regulatory precedents as well as cultural factors contribute to both agenda setting and framing of Net neutrality. The differences between national discourses provide a way to understand both the structural differences between regulatory cultures and the substantive differences between policy interpretations, both of which must be reconciled for the Internet to continue to thrive as a global medium

Net neutrality discourses: comparing advocacy and regulatory arguments in the United States and the United Kingdom

Telecommunications policy issues rarely make news, much less mobilize thousands of people. Yet this has been occurring in the United States around efforts to introduce "Net neutrality" regulation. A similar grassroots mobilization has not developed in the United Kingdom or elsewhere in Europe. We develop a comparative analysis of U.S. and UK Net neutrality debates with an eye toward identifying the arguments for and against regulation, how those arguments differ between the countries, and what the implications of those differences are for the Internet. Drawing on mass media, advocacy, and regulatory discourses, we find that local regulatory precedents as well as cultural factors contribute to both agenda setting and framing of Net neutrality. The differences between national discourses provide a way to understand both the structural differences between regulatory cultures and the substantive differences between policy interpretations, both of which must be reconciled for the Internet to continue to thrive as a global medium

COPII-dependent export of cystic fibrosis transmembrane conductance regulator from the ER uses a di-acidic exit code

Cystic fibrosis (CF) is a childhood hereditary disease in which the most common mutant form of the CF transmembrane conductance regulator (CFTR) ΔF508 fails to exit the endoplasmic reticulum (ER). Export of wild-type CFTR from the ER requires the coat complex II (COPII) machinery, as it is sensitive to Sar1 mutants that disrupt normal coat assembly and disassembly. In contrast, COPII is not used to deliver CFTR to ER-associated degradation. We find that exit of wild-type CFTR from the ER is blocked by mutation of a consensus di-acidic ER exit motif present in the first nucleotide binding domain. Mutation of the code disrupts interaction with the COPII coat selection complex Sec23/Sec24. We propose that the di-acidic exit code plays a key role in linking CFTR to the COPII coat machinery and is the primary defect responsible for CF in ΔF508-expressing patients