This work deals with the control of the human immune system. A standard immune system model is modified by introducing control signals corresponding to drug cocktail and immune suppressor treatments. The ultimate objective is to use these control signals to 'cure' a chronically-ill patient. Control is challenging for this system due to nonlinearities and time delays. In fact, it is shown that fundamental aspects of the system dynamics are lost when the system is linearised; hence, control approaches involving linearisation are fruitless. Feedback linearisation and some optimal control methods are also investigated and shown to be infeasible. However, it is shown that, for certain parameter values and initial conditions related to the virus and patient, a specific open-loop control scheme using only the drug cocktail achieves the objective. It is also proven that, unfortunately, this control scheme fails for other parameter values and initial conditions. A two-stage open-loop controller that uses both control inputs is then proposed. It is shown in simulation that the two-stage controller works over a larger set of parameters and initial conditions than the single-stage controller, but a rigorous analysis of the two-stage controller remains elusive.

Canada is the fourth largest producer of farmed salmon in the world, with Atlantic salmon being the major species cultivated. Paradoxically British Columbia (BC), which borders the Pacific Ocean, is the major producer province where Atlantic salmon was introduced in the mid-80’s. Escaped salmon may constitute a threat to natural populations of Pacific salmon as they compete for the same resources such as food and spawning territory. A potential solution to the aquaculture industry would be to further develop the aquaculture of native species in the region. The work presented here used semi-natural spawning channels to evaluate the effects of breeding strategies and early-rearing environments on the immune performance of Chinook salmon. Breeding strategy was tested analyzing artificial hatchery practices versus semi-natural propagation in spawning channels. Early-rearing environmental assessment contrasted indoor plastic hatchery tanks with outdoor gravelled-bottom spawning channels. A disease challenge involving over 1400 fish showed interaction effects between breeding strategy and rearing environment. Fish artificially mated presented a disease susceptibility influenced by the rearing environment. The contrary occurred in the offspring of self-breeding brood stock in the spawning channels, as no differences were observed in their susceptibility to the disease regardless of rearing environment. Monitoring of anti-Vibrio anguillarum antibodies during the disease challenge and a follow up of the survivors in sea net pens further confirmed the interaction between breeding strategy and rearing environment. Gene expression in pre- and post-infected artificially propagated fish showed differential gene expression when analyzed with a 695-gene cDNA microarray for Chinook salmon. Genotyping of major histocompatibility (MH) class II β1 alleles showed a tendency of a higher heterozygosity in survivors as expected, as well as a general tendency of a higher heterozygosity in semi-naturally propagated fish. The latter is likely a direct consequence of MH-linked mate choice, which was recently described in Chinook salmon (Neff et al., 2008). To further characterize the mating system of Chinook salmon in the spawning channels, brood stock were genotyped at 12 microsatellite loci. Females and males were found to mate randomly with regards to genetic pairwise relatedness, but they tended to mate with fish of similar condition as revealed by their pairwise differences in Fulton’s condition factor. This work demonstrated that genotype-by-environment interactions can modify the disease resistance of Chinook salmon. More importantly, these effects were seen after just one round of semi-natural spawning of domesticated hatchery fish, suggesting that further studies on spawning channels may highlight other hidden benefits. Therefore, breeding strategy and early-rearing environment should be considered when propagating cultured stocks. The use of more natural propagation methods such as spawning channels could improve the immune performance of Chinook salmon and help to expand the aquaculture of this native species in BC.

Fishes in the superorder Ostariophysi, including fathead minnows (Pimephales promelas), possess specialized epidermal club cells that contain an alarm substance. Damage to these cells, as would occur during a predator attack, causes the release of the alarm substance and can indicate the presence of actively foraging predators to nearby conspecifics. For nearly 70 years, research involving epidermal club cells has focused on the alarm substance and the role it plays in predator/prey interactions. However, recent studies have indicated that there may be a connection between epidermal club cells and the fish immune system. Fish increase investment in epidermal club cells upon exposure to skin penetrating pathogens and parasites. In this study I tested for differences in epidermal club cell investment by fathead minnows exposed to the immunosuppressive effects of the glucocorticoid hormone cortisol. In experiment 1, fathead minnows were exposed to either a single intraperitoneal injection of corn oil or no injection at all. The purpose of this experiment was to determine whether corn oil, the vehicle for cortisol injections in later experiments, had an effect on epidermal club cell density. The treatments had no effect on epidermal club cell size, cell area, or epidermal thickness. In experiment 2, skin extract was prepared from the skin of corn oil injected and non injected fathead minnows as in experiment 1 to determine whether corn oil had an effect on the epidermal club cell alarm substance concentration. The treatments showed no significant differences in observed anti-predator behaviour, including change in shelter use, dashing and freezing. In experiment 3, fathead minnows were exposed to either a single intraperitoneal injection of cortisol or corn oil. The purpose of this experiment was to determine whether cortisol, a known immunosuppressant, had an effect on epidermal club cell investment. Fathead minnows exposed to a single cortisol injection had significantly reduced respiratory burst activity of kidney phagocytes indicating that there was suppression of the innate immune system. Furthermore, cortisol treated fathead minnows showed significantly lower numbers of epidermal club cells. The treatments had no effect on individual epidermal club cell area, epidermal thickness and serum cortisol levels after 12 days. The results from this experiment suggest that pharmacological cortisol injections in fathead minnows have a suppressive effect on the fish innate immune system. Furthermore, the findings that cortisol induced immunosuppression also influences epidermal club cell investment provides support for the hypothesis that epidermal club cells may function as part of the fish immune system.

The correct and timely delivery of immune cells is critical for protection against foreign antigen. In order for cells to access most organs, there are requirements that must be met to facilitate exit from the blood into extravasculature. The initial requirement is selectin-selectin ligand interactions that mediate tethering and rolling to allow shear resistance. For proper selectin-selectin ligand interaction, glycoproteins must be modified by fucosyltransferases –IV and –VII, which adds fucose to an acceptor substrate to form the sialyl-LewisX moiety. Using fucosyltransferase –IV and –VII double knockout (FtDKO) mice, we made several novel observations. Our first observation showed increased numbers of naïve T cells in non-lymphoid organs. To support this observation, we blocked chemokine-mediated entry into lymph nodes (LNs) with pertussis toxin and L-selectin mediated entry with anti-CD62L antibody in WT mice. We also treated WT mice with the S1P1 agonist, FTY720, to retain lymphocytes in LNs. Our results suggested that when access to LN is perturbed, lymphocytes accumulate in non-lymphoid organs. Our second observation showed an enrichment of effector/memory T cells in FtDKO LNs. To determine if effector/memory CD8 T cells were retained in LNs, we transferred naïve and memory CD8 T cells into WT mice then treated the recipient mice with anti-CD62L. We found that LN exit rates of naïve and memory CD8 T cells were similar, but slowed as T cell density decreased. To understand if memory CD8 T cells were using selectin ligand independent mechanisms, we transferred naïve and memory CD8 T cells into WT or FtDKO mice. We found reduced numbers of memory CD8 T cells in LNs, however, their frequency was increased. We explored this result by transferring CFSE labeled memory CD8 T cells. We found that memory CD8 T cells divide more in FtDKO mice compared to WT. These experiments suggested that selectin ligand deficiencies cause increased frequency of effector/memory T cells in LNs due to low density and increased emptiness induced proliferation. Taken together, these findings reveal how selectin ligand deficiencies contribute to T cell accumulation in non-lymphoid organs and elucidate mechanisms of retention in LNs.

Thesis (M.S.)--Mississippi State University. Department of Computer Science. / Title from title screen. Includes bibliographical references.

Thesis (Ph. D.)-- State University of New York at Binghamton, Department of Biological Sciences, 2009.

published_or_final_version / Industrial and Manufacturing Systems Engineering / Doctoral / Doctor of Philosophy

For the successful deployment of task-achieving multi-robot systems (MRS), the interactions must be coordinated among the robots within the MRS and between the robots and the task environment. There have been a number of impressive experimentally demonstrated coordinated MRS. However it is still of a premature stage for real world applications. This dissertation presents an MRS control scheme using Artificial Immune Systems (AIS). This methodology is firmly grounded in the biological sciences and provides robust performance for the intertwined entities involved in any task-achieving MRS. Based on its formal foundation, it provides a platform to characterize interesting relationships and dependencies among MRS task requirements, individual robot control, capabilities, and the resulting task performance. The work presented in this dissertation is a first of its kind wherein the principles of AIS have been used to model and organize the group behavior of the MRS. This has been presented in the form of a novel algorithm. In addition to the above, generic environments for computer simulation and real experiment have been realized to demonstrate the working of an MRS. These could potentially be used as a test bed to implement other algorithms onto the MRS. The experiment in this research is a bomb disposal task which involves a team of three heterogeneous robots with different sensors and actuators. And the algorithm has been tested practically through computer simulations.

Οι ανοσολογικές διαταραχές στην οξεία θρομβοπενική πορφύρα (ΙΘΠ) της παιδικής ηλικίας εξακολουθούν να αποτελούν αντικείμενο μελέτης. Η έκφραση των Th1/Th2 κυτταροκινών έχει μελετηθεί σε αυτοάνοσα νοσήματα και φαίνεται ότι παίζει ανοσορυθμιστικό ρόλο. Έτσι, θεωρήθηκε σκόπιμη η μελέτη της έκφρασης Th1/Th2 κυτταροκινών καθώς και των επιπέδων του TGF-β1 στο πλάσμα σε 18 παιδιά (μέση ηλικία 6,4 χρόνια) με οξεία ΙΘΠ πριν και 24 ώρες μετά τη χορήγηση IVIG, καθώς και μετά από 0,5-5 χρόνια. Οι ασθενείς αυτοί παρουσίαζαν μειωμένο αριθμό CD4 κυττάρων και ανεστραμμένη αναλογία CD4/CD8. Μελετήθηκε η έκφραση των αποπτωτικών γονιδίων Fas και Bcl-2 και παρατηρήθηκε μειωμένη έκφραση του γονιδίου Fas στους ασθενείς, και φυσιολογική έκφραση του Bcl-2. Η θεραπεία με IVIG δε φάνηκε να επηρεάζει αυτές τις παραμέτρους. 12 από τα 18 παιδιά παρουσίαζαν χαμηλή έκφραση Th0/Th1 κυτταροκινών, με ταυτόχρονη έκφραση IL-10, ή δεν εξέφραζαν καμία κυτταροκίνη in vivo. 24 ώρες μετά τη χορήγηση IVIG, 5/12 παιδιά δεν εξέφραζαν καμμία κυτταροκίνη ενώ τα υπόλοιπα έδωσαν είτε ένα Th2, είτε ένα Th0/Th1 πρότυπο. Μελέτες που έγιναν κάποια χρόνια αργότερα έδειξαν ότι αυτά τα 12 παιδιά δεν παρουσίασαν δεύτερο επεισόδιο και in vivo δεν εξέφραζαν καμμία κυτταροκίνη ή μόνο IL-4. Σε 4/18 παιδιά παρατηρήθηκε ένα Th1 ή Th0/Th1 πρότυπο έκφρασης κυτταροκινών και έκφραση IL-10, το οποίο διατηρήθηκε και μετά τη θεραπεία με IVIG. 0,5-5 χρόνια αργότερα παρατηρήθηκε έκφραση Th1 κυτταροκινών και IL-10 και στα 4 παιδιά, τα οποία ανέπτυξαν μία υποτροπιάζουσα μορφή ΙΘΠ με σπάνια επεισόδια επαγόμενα από ιογενείς λοιμώξεις. 2/18 παιδιά παρουσίασαν κατά την εμφάνιση της νόσου ένα καθαρό Th1 πρότυπο, που χαρακτηριζόταν από αυξημένη έκφραση IFN-γ και το οποίο διατηρήθηκε τόσο μετά τη χορήγηση IVIG, όσο και αργότερα και σ’ αυτά η νόσος χαρακτηρίστηκε σαν χρόνια IΘΠ. Τα επίπεδα του TGF-β1 στο πλάσμα των ασθενών ήταν χαμηλά όταν ή νόσος ήταν σε έξαρση και αυξάνονταν όταν ή νόσος ήταν σε ύφεση. Γενικά, φαίνεται ότι μια σταθερή κατάσταση ύφεσης της νόσου σχετίζεται με απουσία έκφρασης κυτταροκινών ή με Τh2 πρότυπο. Έκφραση των μεταγραφικών παραγόντων AP-1, NFAT και NFκΒ υπήρχε στα Τ κύτταρα των ασθενών κατά την εμφάνιση της νόσου και όχι όταν η νόσος ήταν σε ύφεση, ενώ ο NFAT-S απουσίαζε. / Childhood ITP resolves usually after the rst episode, although it may recur, and in 10-20% of cases develops into a chronic disorder. Evidence of the immunoregulatory role of Th1/Th2 responses in autoimmune diseases, prompted us to perform a prospective study of Th1/Th2 gene expression proles and TGF-β plasma levels in 18 children (median age 6.4 years) with acute ITP, before and after IVIG infusion, and during a follow- up period (0.5-5 years). The patients had a decreased CD4 cell population and an inverted CD4/CD8 ratio. RT-PCR of their Fas and Bcl-2 genes revealed increased Fas activity but normal expression of Bcl-2. IVIG therapy had no effect on these parameters. 12 of 18 patients had either low Th0/Th1+IL-10 or no in vivo cytokine gene expression (0). 24h after IVIG infusion this pattern became 0 or Th2 or remained low Th0/Th1. During follow-up these patients did not relapse and maintained 0 or Th2 pattern without IL-10. Of the remaining 6 patients, 4 presented with a Th1 or Th0/Th1 pattern +IL-10 that persisted after IVIG treatment (though IFN-γ expression diminished) and stabilized to Th1+IL-10 at follow-up, which was marked by infrequent episodes of ITP. Two patients presenting with a strict Th1 pattern characterized by high expression of IFN-γ which remained unchanged after IVIG and at follow-up, can be characterized as chronic ITP. TGF-β plasma levels were low in patients with active disease and increased in remission. Overall, acute ITP presents with Th1, Th0/Th1 or 0 in vivo cytokine gene expression. Stable remission is associated with a 0 or Th2 pattern. A 0 or Th2 pattern after IVIG gave the best prognosis, whereas sustained high expression of IFN-γ and refractoriness to IVIG were the main indicators of poor prognosis. The transcription factors AP-1, NFAT and NFκΒ were studied in 2 patients in acute phase and in remission. They were found to be constitutive in the patients’ ex-vivo and stimulated T cells, but absent from the patients’ ex-vivo T cells in remission, while the NFAT transcriptional silencer was missing.

Σκοπός της παρούσας μελέτης ήταν να αξιολογηθεί το αγγειομετατρεπτικό ένζυμο στον ορό των ασθενών με πνευμονία, ως διαγνωστικός ή/και προγνωστικός δείκτης της νόσου και γενικά να μελετηθούν οι διάφοροι προγνωστικοί παράγοντες στις λοιμώξεις του κατώτερου αναπνευστικού συστήματος. / Objective: The aim of this study was to determine prognostic factors of outcome in patients with lower respiratory tract infections (LRTIs). LRTIs are an heterogeneous group of disorders, including acute bronchitis, pneumonia, superinfection of chronic bronchitis and flu. The recent publications of several prognostic factors of outcome address specific conditions such as pneumonia or bronchitis, while general practitioners cannot usually differentiate between these conditions in current practice. Methodology: A total of 616 patients with LRTIs were retrospectively reviewed with regard to epidemiological, clinical, laboratory and radiographic data. The prognostic analysis included an univariate as well as a multivariate approach, in order to identify parameters associated with death. Results: The parameters found to be significantly different between survivors and non survivors in the univariate analysis, were respiratory rate (p<0,01), oxygen partial pressure (PaO2) (p<0,001), heart rate (p<0,0003), systolic and diastolic blood pressure (p<0,047 and (p<0,022, respectively), platelet count (p<0,045), urea (p<0,002), creatinine Objective: The aim of this study was to determine prognostic factors of outcome in patients with lower respiratory tract infections (LRTIs). LRTIs are an heterogeneous group of disorders, including acute bronchitis, pneumonia, superinfection of chronic bronchitis and flu. The recent publications of several prognostic factors of outcome address specific conditions such as pneumonia or bronchitis, while general practitioners cannot usually differentiate between these conditions in current practice. Methodology: A total of 616 patients with LRTIs were retrospectively reviewed with regard to epidemiological, clinical, laboratory and radiographic data. The prognostic analysis included an univariate as well as a multivariate approach, in order to identify parameters associated with death. Results: The parameters found to be significantly different between survivors and non survivors in the univariate analysis, were respiratory rate (p<0,01), oxygen partial pressure (PaO2) (p<0,001), heart rate (p<0,0003), systolic and diastolic blood pressure (p<0,047 and (p<0,022, respectively), platelet count (p<0,045), urea (p<0,002), creatinine (p<0,002), previous admission in the hospital the last year (p<0,033), and cavitations in chest radiograph (p<0,047). In multivariate analysis, the only statistically significant risk factors were PaO2 (odds ratio (OR) =0,8574; 95% confidence interval (CI) 0,7499-0,9802 in non survivors compared to survivors) and heart rate (OR=1,063; 95% CI 1,0052-1,1241 in non survivors compared to survivors). Conclusions: LRTIs remain a widespread problem and have a significant impact on primary healthcare resources. The great variability seen in rates of hospital admission and lengths of stay in part reflects uncertainty among physicians in assessing the severity of the illness. According to our data, PaO2 and heart rate, were most closely associated with death in patients with LRTIs. These predictor variables are all explicitly defined and can be readily assessed at the time of patient presentation.