My dissertation focuses on the articulation of the concepts of precarity —i.e., temporary, affective, creative, immaterial and insecure labor—and community in an overheating system. My site of inquiry is homelessness broadly, but more specifically the labor of panhandling and the identity of “the panhandler.” I recognize that primary theorizations of precarity have located it as a problem of labor and economy. Others have looked at it from the sociological domain. My work looks at precarity as diffuse across social, political, and communal systems, but primarily as an effect of the problem of overheating as it manifests at varying levels of scale. Narrowing the global vision of such instability and insecurity to a local landscape—to streets, corners, traffic, the people who occupy infrastructural liminal zones and whose lives are precariously bound to the forces of speed and heat—reveals the critical nature of elemental metaphors. That is to say, if we might accept the thesis that we are in an epoch in which speed and time subsumes space and place, and if speed is another way of talking about heat, about intensities, then communication in the over-sped, overheated system is in dire straights. Precarity, I argue, is not causally linked to the breakdown in economy or the breakdown in affiliative bonds or networks—it does not precede or presage these shutdowns. Rather it is the shutdown. Precarity may now be viewed as the management and organization of social, political, affective, and communal bonds around economic and affiliative insecurities. I use ethnographic data from institutional meetings, and conversations with the key stakeholders at varying levels of scale, as well as textual analyses of local policies, news coverage, and public responses to those texts in order to understand how precarious communicative conditions affect the structuration of community and politics.

Neuromodulation of the immune system has been described to be influenced by hemispheric lateralisation (HL), the stable tendency to relatively utilise one hemisphere or its functions over another. To date there has not been a systematic review of research in this phenomenon conducted, and only one study has examined the effects of HL on the progression of a disease – Human Immunodeficiency Virus (HIV). That research was conducted on a small sample with little control for confounders. The present work sought to compile a systematic review of literature concerning HL and immunity in humans, using effect size analysis. Further, the present work also describes an empirical advancement of this earlier HIV study with stricter control over confounds in a larger sample. The findings corroborated the theory of asymmetrical immune influence by HL via the systematic review showing clear, relatively consistent and strong relationships between left-HL and immunopotentiation. The empirical prospective study extended current knowledge of this relationship in HIV to identify a moderator – HAART treatment. Specifically, left-HL predicted better immunity in HIV-1 patients independent of confounders, with further findings of the same pattern in untreated patients, but not in HAART-treated patients. Further observations were made between HL and HIV-relevant behaviours, again adding to current knowledge. The finding of left-HL being associated with fewer sexual partners in Europeans presents new information of relevance to public health. The combined findings of the present work suggest that left-HL has predictive value in illness (HIV-1) and in general immunity. The present work adds to the existing knowledge new information concerning a moderating factor of the HLimmunity relationship in HIV, and behavioural implications of HL which impact upon HIV disease. Potential explanations for moderation, proposals for neurobiological mechanisms and direction towards future, more rigourous study in the field, both in HIV and immunity, are discussed.

The mammalian immune system has evolved a complex and diverse set of mechanisms to detect and respond to pathogens by recognizing conserved molecular structures and inducing protective immune responses. While many of these mechanisms are capable of sensing diverse molecular structures, a large fraction of pathogen sensors recognize nucleic acids. Pathogen-derived nucleic acids trigger nucleic acid sensors that typically induce anti-viral or anti-microbial immunity, however host-derived nucleic acids may also activate these sensors and lead to increased risk of inflammatory or autoimmune disease. Animal models and humans lacking key DNA nucleases, such as Trex1/Dnase3, accumulate intracellular DNA and develop progressive autoimmunity marked by increased Type-I Interferon (IFN) expression and inflammatory signatures. Double-stranded DNA (dsDNA) is a potent inducer of the Type-I IFN response. Many of the sensors and signaling components that drive the IFN signature following simulation with transfected dsDNA (also called 'Interferon Stimulatory DNA' or 'ISD') remain unknown. We set out to identify novel components of the ISD pathway by developing a large-scale loss-of-function genetic perturbation screen of 1003 candidate genes. We interrogated multiple human and murine primary and immortalized cells, tested several Type-I IFN reporters, and considered multiple loss-of-function strategies before proceeding with an RNAi screen whereby mouse embryonic fibroblasts were stimulated with ISD and Type-IFN pathway activation was assessed by measuring Cxcl10 protein by ELISA. Candidate genes for testing in the RNAi screen were curated from quantitative proteomic screens, IFN-beta and ISD stimulated mRNA expression profiles, and a selection of domain-based proteins including helicases, cytoplasmically located DNA- binding proteins and a set of potential negative regulators including phosphatases, deubiquitinases and known signaling proteins. We identified a number of novel ISD pathway components including Abcf1, Ptpn1 and Hells. We validated hits through siRNA-resistant cDNA rescue, chemical inhibition or targeted knockout. Additionally, we evaluated protein-protein interactions of our strongest validated hits to develop a network model of the ISD pathway. In addition to the identification of novel ISD pathway components, our enriched screening data set may provide a useful resource of candidate genes involved in the response to cytosolic DNA.

This study sought to examine the physiological correlates of migratory flight performance the North American migratory grasshopper Melanoplus sanguinipes Fabricius (Orthoptera: Acrididae) with a focus on mechanisms of resource allocation, the dynamics of hemolymph proteins, their interface with immune function, and the mechanism of flight-enhanced oogenesis. The performance of long duration flights has been shown previously to be of reproductive benefit to females who make them. Examination of possible mechanisms of resource compensation for the costs of flight showed no significant increase in either feeding, mating or digestion in females who performed long duration flight. A comparison of two populations of M. sanguinipes from Arizona and Colorado showed significant variation in body size, diapause regulation as well as internal and external morphology. The two populations did not differ in taxonomic characters or in short sequences of genomic and mitochondrial DNA. The follicle cell epithelium of ovaries from M. sanguinipes was examined for its relationship to juvenile hormone III (JH III). JH III induces patency in vitro in intercellular spaces of M. sanguinipes follicular epithelium as well as the characteristic apical endocytosis at the follicle cell oocyte interface. Exogenous JH III treatment of females on day 7 in lieu of flight reduced the threshold for induction of patency to 10-7 M JH III from 10-5 M JH III. These results indicate that JH III can act as a prime to the pump of oogenesis. An HPLC/LC-MS peptidomic survey of the hemolymph of M. sanguinipes following flight performance showed the presence of and changes in serine protease inhibitors. These peptides regulate numerous protease cascades involved in reproduction and immunity which suggested that flight might have a more broad impact than previously thought. Males who performed these flights showed a higher probability of surviving a bacterial challenge. The duration of flight performance was positively correlated in males with increases in titers of the hemolymph lipoproteins apolipophorin I and hexemerin. The exchangeable apolipophorin III showed no variation in correlation with flight. Females were not affected by flight performance in terms of hemolymph protein titers or the probability of surviving a bacterial challenge. These results suggest that the lipid transport system plays an important role in the immune response of this insect. / text

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The last decade has been witness to a number of seminal discoveries in the field of innate immunity. The discovery that microbial molecules and endogenous danger signals can be detected by germ-line encoded receptors has changed the way we study the immune system. Indeed, the characterization of Toll in Drosophila as a sensor of microbial products in 1997 then led to the discovery of a family of Toll Like Receptors (TLRs) in mammals. TLRs are critical for the induction of inflammatory responses and the generation of a successful adaptive immune response. The array of ligands that these transmembrane proteins recognized mediates defense against bacteria, viruses, fungus and parasites, as well as, possibly, cancerous cells. In addition to this membrane-bound family of recognition proteins, two families of pattern recognition receptors have been recently shown to respond to microbial and chemical ligands within the cytosol. These represent the Nod Like Receptors (NLRs) and RIGI-like helicase receptor (RLH) families. Nod1 and Nod2 are members of the NLR family of proteins, which are responsible for the recognition of components derived from the bacterial cell wall, more precisely, moieties of peptidoglycan. As such, Nod1 and Nod2 are implicated in the recognition and the defense against bacterial pathogens. Importantly, the genes encoding these two proteins have also been linked to the etiology of several inflammatory disorders such as Crohn’s disease and asthma. In this thesis, we show that recognition of Nod1 and Nod2 ligands generates a rapid and transient inflammatory response in vivo. When co-injected with a model protein, Nod1 and Nod2 ligands exhibit adjuvant properties that lead to the generation of an antigen-specific Th2 type adaptive immune response. Surprisingly, recognition of the Nod1 ligand in non-hematopoietic cells is critical for the generation of this immune response. In contrast, TLRs classically tip the balance towards a Th1 response and interestingly, co-injection of TLR and Nod ligands synergize to generate a more potent immune response characterized by the generation of Th1, Th2 and Th17 T cell respones. To study the role of Nod1 and Nod2 in the context of a bacterial infection in vivo, we used an intestinal mouse pathogen, Salmonella enterica serovar Typhimurium. We were able to show that Nod1-deficient mice, but not Nod2-deficient mice, are more susceptible to the strain of this bacterium, which enters the host through the active pickup in the intestinal lumen by underlying myeloid cells. This sampling mechanism is mediated by a subset of dendritic cells that populate the intestinal lamina propria. Accordingly, the defect seen in Nod1-deficient mice localizes to the mucosal barrier where these dendritic cells appear to have an impaired response towards the bacteria. Taken together, these results increase our knowledge on the general role of Nod1 and Nod2 in immunity and might generate new avenues of research and potential therapeutic targets.

Pseudomonas syringae delivers a plethora of effector proteins into host cells to sabotage host immune responses and physiology to favor infection. We have previously shown that P. syringae pv. tomato DC3000 effector HopF2 suppresses Arabidopsis innate immunity triggered by multiple pathogen-associated molecular patterns (PAMP) at the plasma membrane. We show here that HopF2 possesses distinct mechanisms in the suppression of two branches of PAMP-activated MAP kinase cascades. In contrast to blocking MKK5 in MEKK1-MKK4/5-MPK3/6 cascade, HopF2 targets additional component(s) upstream of MEKK1 in MEKK1-MKK1/2-MPK4 cascade and plasma membrane-localized receptor-like cytoplasmic kinase BIK1 and its homologs. We further show that HopF2 directly targets BAK1, a plasma membrane-localized receptor-like kinase involved in multiple PAMP signaling. The interaction between BAK1 and HopF2 or two additional P. syringae effectors AvrPto and AvrPtoB, was confirmed in vivo and in vitro. Consistent with BAK1 as a physiological target of HopF2, the lethality of overexpression of HopF2 in wild-type Arabidopsis transgenic plants was largely alleviated in bak1 mutant plants. Identification of BAK1 as an additional HopF2 virulence target not only explains HopF2 suppression of multiple PAMP signaling at the plasma membrane, but also supports the notion that pathogen virulence effectors have multiple targets in host cells.