The absence of invariant Natural Killer T cells (iNKT cells) in mice infected with Influenza A virus (flu) has previously been shown to augment the expansion of Myeloid-derived suppressor cells (MDSCs), a bone marrow derived population that powerfully suppress the development of viral and tumor immune responses. Moreover, iNKT cell adoptive transfer into flu-infected mice has been shown to abolish the expansion and flu-induced suppressive activity of the MDSCs in a CD1d- and CD40-dependent manner. However, the mechanisms by which this relatively small subset of T cells influence myelopoiesis and MDSC differentiation remain largely unknown. In this manuscript we firstly better define the MDSCs found in flu-infection as IL-10-secreting neutrophils that can suppress T cell proliferation. We then go further to show that the flu-induced ability to suppress T cells is acquired as early as the level of the Granulocyte-Macrophage Progenitors (GMPs) in the bone marrow and that iNKT cells can not only abrogate the suppressive activity of the IL-10-secreting neutrophils in the periphery but also that of the GMPs by a direct CD1d-dependent GCSF-mediated crosstalk. MDSC expansion has previously been shown to be associated with the expression of the myeloid-related protein S100A9, and the mechanism of action of granulocytic-MDSCs shown to be ARG1-dependent. We built upon both these findings to show that iNKT cells influence the expansion and function of the MDSCs in part by regulating S100A9 and ARG1 expression. Following this we then showed for the first time that the acute phase protein Serum Amyloid A (SAA), shown to increase during flu-infection, has a dual reciprocal role: having the ability to up-regulate S100A9 and ARG1 in myeloid cells and differentiate IL-10-secreting suppressive neutrophils, while simultaneously facilitating the ability of the MDSCs to crosstalk with iNKT cells in a CD1d-dependent GCSF-mediated manner to abrogate the SAA-induced suppressive activity. All together the data highlights the complexity of the immune response and the role iNKT cells play in influencing the differentiation of MDSCs during demand-driven myelopoiesis. More importantly however, it further affirms that research into harnessing the immunomodulatory capacity of iNKT cells remains an exciting prospect in bolstering future vaccination strategies and should continue to be pursued.

The use of antibiotic growth promoters has been limited all around the world because of the concerns about antibiotic resistant bacteria and the presence of antibiotic residues in poultry products. Yeast-derived products are rich sources of ß1,3-1,6-glucan, mannan polysaccharides, and nucleotides and are considered as possible antibiotic alternatives due to their potential intestinal health benefits, growth promotion, and immune system stimulation. The objectives of the current research were: (1) to the evaluate effect of yeast products derived from yeast Saccharomyces cerevisiae on growth performance, gut histomorphology, and innate immune response of broiler chickens; (2) to investigate the effect of yeast products, including distillers dried grains with solubles (DDGS), on innate and antibody-mediated immune response following immunization with different antigens; and (3) to examine the effect of yeast-derived products and DDGS on growth performance, incidence of necrotic enteritis (NE), and local innate immunity in broiler chickens challenged with Clostridium perfringens. Overall, supplementation of diets with yeast products did not affect growth performance of broilers. However, the diets containing yeast cell walls (YCW) and nucleotides increased the villus height in the jejunum and enhanced the number of goblet cells in the ileum. Inclusion of diets with yeast products did not activate the innate immune response of birds under non-pathogen challenge conditions. However, the diet containing YCW activated Th2 cell-mediated immune response in birds immunized with sheep red blood cells and bovine serum albumin. Furthermore, supplementation of diets with YCW and DDGS in birds challenged with Escherichia coli lipopolysaccharide, activated the systemic innate immune response. Regarding antibody-mediated immune response, when compared to the control, serum antibody titer and specific antibody response against different antigens were not affected by dietary treatments. In the C. perfringens challenge study, growth performance, NE lesions and C. perfringens counts in the intestine were not affected by yeast-derived products. However, diets containing YCW and nucleotides stimulated the local innate immune response of birds by upregulation of cytokines and receptors involved in innate immunity. Such findings suggest that the immune-adjuvant like properties of YCW and nucleotides activate the innate immunity of broiler chickens following immunization or challenge with different antigens. / October 2015

This thesis presents a series of results obtained in [13, 18, 19, 23{25, 87]. In [19], we prove a Darboux theorem for derived schemes with symplectic forms of degree k < 0, in the sense of [142]. We use this to show that the classical scheme X = t₀(X) has the structure of an algebraic d-critical locus, in the sense of Joyce [87]. Then, if (X, s) is an oriented d-critical locus, we prove in [18] that there is a natural perverse sheaf P·_X,s on X, and in [25], we construct a natural motive MF_X,s, in a certain quotient ring M^μ_X of the μ-equivariant motivic Grothendieck ring M^μ_X, and used in Kontsevich and Soibelman's theory of motivic Donaldson-Thomas invariants [102]. In [13], we obtain similar results for k-shifted symplectic derived Artin stacks. We apply this theory to categorifying Donaldson-Thomas invariants of Calabi-Yau 3-folds, and to categorifying Lagrangian intersections in a complex symplectic manifold using perverse sheaves, and to prove the existence of natural motives on moduli schemes of coherent sheaves on a Calabi-Yau 3-fold equipped with 'orientation data', as required in Kontsevich and Soibelman's motivic Donaldson-Thomas theory [102], and on intersections L??M of oriented Lagrangians L,M in an algebraic symplectic manifold (S,ω). In [23] we show that if (S,ω) is a complex symplectic manifold, and L,M are complex Lagrangians in S, then the intersection X= L??M, as a complex analytic subspace of S, extends naturally to a complex analytic d-critical locus (X, s) in the sense of Joyce [87]. If the canonical bundles K_L,K_M have square roots K^1/2_L, K^1/2_M then (X, s) is oriented, and we provide a direct construction of a perverse sheaf P·_L,M on X, which coincides with the one constructed in [18]. In [24] we have a more in depth investigation in generalized Donaldson-Thomas invariants DT^α(τ) defined by Joyce and Song [85]. We propose a new algebraic method to extend the theory to algebraically closed fields <b>K</b> of characteristic zero, rather than <b>K = C</b>, and we conjecture the extension of generalized Donaldson-Thomas theory to compactly supported coherent sheaves on noncompact quasi-projective Calabi-Yau 3-folds, and to complexes of coherent sheaves on Calabi-Yau 3-folds.

HINTERGRUND: Der brain-derived neurotrophic factor (BDNF) reguliert die synaptische Plastizität und spielt somit eine wichtige Rolle in der Gedächtnisbildung und -erhaltung. Deswegen gibt es eingehende Untersuchungen dieses neurotrophischen Faktors in Bezug auf Demenzerkrankungen, vor allem der Alzheimer Demenz. In dieser Studie wurde nach einem Zusammenhang zwischen BDNF Blutplasmawerten und der Alzheimer Demenz in einer longitudinalen Kohortenstudie, der Vienna-Transdanube-Aging(VITA)-Studie gesucht. METHODEN: Die VITA-Studie ist eine kommunale Kohortenstudie aller 75jährigen Einwohner einer geographischen Region Wiens. Es wurden die BDNF Plasmawerte der Basisuntersuchung und der ersten Folgeuntersuchung 30 Monate später als mögliche Biomarker für die Alzheimer Demenz untersucht. Assoziationen zwischen BDNF Plasmawerten und anderen epidemiologischen Eckdaten wurden ebenfalls analysiert. ERGEBNISSE: Wir konnten keine Assoziation zwischen BDNF Plasmawerten und der Entwicklung oder einer bereits bestehenden Alzheimer Demenz finden. Geschlecht, Body-Maß-Index und Depression stellten sich als Komorbiditäts-Faktoren von Demenz-erkrankungen dar. SCHLUSSFOLGERUNG: BDNF Plasmawerte sind diesen Ergebnissen nach kein so viel versprechender molekularer Marker für Alzheimer Demenz wie erhofft. BDNF wird jedoch weiterhin in vielen interessanten Studienprotokollen untersucht, da es sowohl im Blutserum als auch im Hirngewebe nachgewiesen werden kann und somit viele diagnostische und therapeutische Ansätze inspiriert. / BACKGROUND: Brain-derived neurotrophic factor (BDNF) regulates the plasticity of synapses and plays an important role in developing and sustaining memory. Therefore it is intensely researched with regard to dementia, especially Alzheimer’s disease. In this study, we searched for a relationship between BDNF plasma levels and Alzheimer’s disease in a longitudinal cohort, the Vienna-Transdanube-Aging (VITA)-study. METHODS: The VITA is a prospective community-based cohort study of all 75 years old inhabitants of a geographical region of Vienna. We have investigated the BDNF plasma levels of the baseline and the first follow-up 30 months later as a possible biomarker for Alzheimer’s disease. Associations between BDNF plasma levels and other epidemiologic data were also analyzed. RESULTS: We found no association between BDNF plasma levels and the development or existence of Alzheimer’s disease. Gender, body-mass-index and depression were shown to be co-morbid to dementia. CONCLUSION: According to these results, BDNF plasma levels are not as promising as a molecular marker for Alzheimer’s disease as hoped for. BDNF, though, is still subject to many interesting study protocols, as it can be detected also in blood serum and brain tissue and therefore invites many diagnostic and therapeutic scenarios.

Thesis advisor: Barbara E. Wolfe / Background: Anorexia nervosa (AN) is a serious mental illness with physical and emotional consequences. Currently, there are limited effective treatments available to address this devastating condition. One possible biomarker implicated in this condition is brain derived neurotrophic factor (BDNF), a member of the neuron growth family. Pre-clinical studies indicate administration of BDNF is associated with decreased food intake and weight loss. Serum BDNF levels also have been shown to be reduced in AN compared to healthy controls (HC). In studies of selective serotonin reuptake inhibitors (SSRI's), blood levels of BDNF have been shown to increase following SSRI administration. This study sought to examine the possible relationship between peripheral BDNF levels and influence of an SSRI, and augmentation with 5-hydroxytryptophan (5-HTP) in persons with AN and HC's. Methods: This study examined previously collected samples from an investigation assessing the influence of SSRI administration and augmentation with 5-HTP on serotonin function in AN. The original study utilized a randomized double-blind placebo-controlled design. AN (n=16) and HC (n=49) subjects were randomized to 1 of 3 treatment conditions (fluoxetine, fluoxetine plus 5-HTP, and placebo) for 7 days of drug administration. Blood samples were collected following an overnight fast and stored at -70°C prior to batch analysis (ELISA). Results: Plasma BDNF levels in AN subjects (59.7 (SD 43.3) pg/ml) were not significantly (p=0.24) different from HC's (76.2 (SD 49.0) pg/ml). There were no significant differences between SSRI, SSRI plus 5-HTP, and placebo treatment groups within or between AN and HC groups. Conclusions: Although BDNF levels in AN subjects were lower than HC, the difference was not statistically significant. After 7 days of SSRI, SSRI plus 5-HTP, or placebo, there were no differences in BDNF levels between or within groups. The possibility exists that 7 days is not long enough to see an expressed effect of SSRI's on BDNF. Future studies would benefit from longer duration of SSRI's, assessing potential covariates (e.g. BMI, depression), and a larger sample. / Thesis (PhD) — Boston College, 2013. / Submitted to: Boston College. Connell School of Nursing. / Discipline: Nursing.

Olfactory Granule cells (GCs) are a population of inhibitory interneurons responsible for maintaining normal olfactory bulb (OB) function and circuitry. Through dendrodendritic synapses with the OBs projection neurons, the GCs regulate information sent to the olfactory cortices. Throughout adulthood, GCs continue to integrate into the OB and contribute to olfactory circuitry. However, only ~50% will integrate and survive longterm. Factors aiding in the survival and morphological development of these neurons are still being explored. The neurotrophin brain-derived neurotrophic factor (BDNF) aids in the survival and dendritic spine maturation/maintenance in several populations of CNS neurons. Investigators show that increasing BDNF in the adult-rodent SVZ stimulates proliferation and increases numbers of new OB GCs. However, attempts to replicate these experiments failed to find that BDNF affects proliferation or survival of adult-born granule cells (abGCs). BDNFs regulation of dendritic spines in the CNS is well characterized. In the OB, absence of BDNF’s receptor on abGCs hinders normal spine development and demonstrates a role for BDNF /TrkB signaling in abGCs development. In this study, we use transgenic mice over-expressing endogenous BDNF in the OB (TgBDNF) to determine how sustained increased in BDNF affect the morphology of olfactory GCs and the survival and development of abGCs. Using protein assays, we discovered that TgBDNF mice have higher BDNF protein levels in their OB. We employed a Golgi-cox staining technique to show that increased BDNF expression leads to an increase in dendritic spines, mainly the mature, headed-type spine on OB GCs. With cell birth-dating using 5-bromo-2’- deoxyuridine (BrdU), immunofluorescent cell markers, TUNEL staining and confocal microscopy, we demonstrate that over-expression of BDNF in the OB does not increase survival of abGCs or reduce cell death in the GC population. Using virally labeled abGCs, we concluded that abGCs in TgBDNF mice had similar integration patterns compared to wild-type (WT) mice, but maintained increases in apical headed-type spine density from 12 to 60 days PI. The evidence combined demonstrates that although increased BDNF does not promote cell survival, BDNF modifies GC morphology and abGC development through its regulation of dendritic spine development, maturation and maintenance in vivo. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

The present investigation examined observational learning during equivalence-based instruction using the PEAK Equivalence curriculum, across five children with disabilities. A multiple baseline across skills was used to evaluate observational learning across the participants, including directly observed relations, as well as derived symmetrical and transitive relations. Each skill contained 5 stimulus classes, where a subset of relations for a single class was trained for each participant. The remaining 4 class subsets were observed by each of the participants. For the derived relations, participants never observed peers contact reinforcement for correct responding nor did they themselves contact reinforcement for correct responding. After multiple sessions, results indicated increases in both observed directly trained relations, as well as emergent derived relations. Over the course of the sessions, the participants average correct answers increased from an average of 12% during baseline to100% at the end of the training phase and during a follow-up test probe. The results have implications for equivalence-based ABA instruction in schools and other settings where group-based instruction is common in application with individuals with disabilities.

The context of this thesis is derived categories in algebraic geometry and geo- metric quotients. Specifically, we prove the embedding of the derived category of a smooth curve of genus greater than one into the derived category of the moduli space of semistable pairs over the curve. We also describe closed cover conditions under which the composition of a pullback and a pushforward induces a fully faithful functor. To prove our main result, we give an exposition of how to think of general Geometric Invariant Theory quotients as quotients by the multiplicative group.

The tumour microenvironment consists of an immunosuppressive niche created by the complex interactions between cancer cells and surrounding stromal cells. A critical component of this environment are myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immature myeloid cells arrested at different stages of differentiation and expanded in response to a variety of tumour factors. MDSCs exert diverse effects in modulating the interactions between immune effector cells and malignant cells. An increased presence of MDSCs is associated with tumour progression, poorer outcomes, and decreased effectiveness of immunotherapeutic strategies. In this project, we sought to quantify and characterise MDSC populations in patients with Acute Myeloid Leukaemia (AML) and delineate the mechanisms underlying their expansion. We have demonstrated that immune suppressive MDSCs are expanded in the peripheral blood and bone marrow of patients with AML. Furthermore, AML cells secrete extra-cellular vesicles (EVs) that skew the tumour microenvironment from antigen-presentation to a tumour tolerogenic environment, through the expansion of MDSCs. We then demonstrated that MDSC expansion is dependent on tumour and EV expression of the oncoproteins MUC1 and c-Myc. Furthermore, we determined that MUC1 signalling promotes c-MYC expression in a microRNA (miRNA) dependent mechanism. This observation lead us to elucidate the critical role of MUC1 in suppressing microRNA-genesis in AML, via the down-regulation of the DICER protein, a key component of miRNA processing machinery. Finally, exploiting this critical pathway, we showed that MDSCs can be targeted by MUC1 inhibition or by the use of a novel hypomethylating agent SGI-110.

"February 2002." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (p. 171-209). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.