Doctor of Philosophy

dissertationBehavior is a complex and poorly understood result of nervous system function. How do molecules, cell, and circuits function in response to sensory input to achieve a behavioral response? This remains a fundamental question in the field of neurobiology. My thesis work addressed this question by undertaking a functional, genetic and electrophysiological analysis of a defined neuronal circuit in the nematode Caenorhabditis elegans. The C. elegans nervous system functions to allow animals to sense and navigate a wide variety of gradients. Worms use thermotactic behavior to maintain a favorable internal temperature, a fundamental component of worm behavior and survival. Chemotactic behavior is used to sense or avoid various stimuli. We describe the role of glutamate receptors in these circuits and provide insight into the molecular control of circuit function and behavior. The thermotaxis circuit is a well-defined circuit that directs worm movement in response to previous temperature experiences. One neuronal pair, RIA, functions as the major integrating and decision-making neuron within the circuit. Specific chemotactic behavior shares common circuitry with the thermotaxis circuit; including RIA. Understanding how RIA functions at the molecular level up to the level of circuit communication is vital to determining how these circuits control behavior. We show the characterization of two classes of glutamate receptors, kainate and AMPA, within RIA and the fundamental differences found at the levels of localization, channel kinetics and behavior during gradient taxis behaviors. Within RIA, the AMPA receptor GLR-1 is expressed at high levels and mediates the majority of glutamate-gated current. Alternatively, kainate receptors; composed of GLR-3 and GLR-6 subunits are expressed exclusively in RIA, show limited expression, and contribute a fraction of the glutamate-gated current. However despite these differences, glr-1 mutants show only subtle thermotaxis and chemotactic defects while glr-3, glr-6 mutants are severely impaired. AMPA and kainate receptors also localize to independent synapses in RIA. We show input from upstream neurons common to both circuits signal primarily through kainate receptors at specific synaptic inputs. We took advantage of this unique opportunity to study a highly conserved family of receptors within a single neuron and the behaviors that they regulate

Bacterial Interference in Human and Canine Resident Cutaneous Microflora

This study represented an attempt to learn more about the phenomenon of cooperative bacterial interference. The accomplishments of this work are the following: 1. Bacteria from the various regions of the skin of man and dog were isolated and identified. 2. The following assays were developed to test bacterial interference: a. Modified Crowe technique b. Spot technique 1. Nutritional spot technique 2. Combined spot technique c. Membrane filter technique 1. Overlay membrane filter technique 2. Double spot membrane filter technique d. Concentrated Broth technique 1. Plate scrapping technique Data has been obtained from the above assays which support the hypothesis that the members of the resident canine cutaneous microflora do cooperate in preventing skin infection. The prevention is implicated, by this study, as being the result of cooperative antibioticproduction by the cutaneous microflora. The fact that cooperation could not be demonstrated using the human microflora is probably a function of the assays used rather than the phenomenon of cooperative bacterial interference. The only real way to measure cooperative bacterial interference is to quantitate the mg of antibiotic produced by combined cultures of various test strains

Altun Bey'in kanlı düğünü

Nezihe Hazm'ın İkdam'da tefrika edilen Altun Beyin Kanlı Düğünü adlı roman

Identifying Prognostic Factors for Well-Differentiated Metastatic Pancreatic Neuroendocrine Tumours: A Retrospective International Multicentre Cohort Study

Pancreatic neuroendocrine tumours (pNETs) represent rare neoplasms of all NETs often presenting without functional activity. Many sporadic non-functioning pNET patients are already metastatic at the time of diagnosis, and the therapeutic approach to such patients is mostly palliative. In this international, multicentre, retrospective cohort study, we assessed the prognostic value of a set of anthropometric, clinical, biochemical, radiological and pathological parameters at baseline and the impact of the therapeutic strategies on the survival of patients with sporadic grade 1/2, stage IV, non-functioning pNETs. Three hundred and twelve consecutive patients diagnosed between 1993 and 2010 were included. The median overall survival (OS) was 6.6 years and survival at 5 and 10 years was 62 and 34% respectively. On univariate analysis, Eastern Cooperative Oncology Group (ECOG) status > 2, grade 2, bilobar hepatic metastases, synchronous metastases, and high chromogranin A, alkalinephosphatase and lactic-dehydrogenase were associated with a significant reduction of OS. Palliative/curative surgery and loco-regional hepatic interventions were significant factors improving OS. On multivariate analysis, ECOG status >= 2, synchronous metastases, Ki-67 >= 10%, and high alkalinephosphatase correlated significantly with an increased risk of death. Both palliative/curative surgery and loco-regional hepatic interventions had a positive impact on OS. Although most parameters did not prove to be independent OS predictors at multivariate analysis, they showed a tendency towards that. Future prospective studies including larger patient populations may give greater clarity. We believe the integration of these parameters has the potential to provide a reliable prognostic score for the stratification of patients with sporadic well-differentiated metastatic non-functioning pNETs

(68)Ga-DOTATOC PET and gene expression profile in patients with neuroendocrine carcinomas:strong correlation between PET tracer uptake and gene expression of somatostatin receptor subtype 2

Somatostatin receptor expression on both protein and gene expression level was compared with in vivo (68)Ga-DOTATOC PET/CT in patients with neuroendocrine carcinomas (NEC). Twenty-one patients with verified NEC who underwent a (68)Ga-DOTATOC PET/CT between November 2012 and May 2014, were retrospectively included. By real-time polymerase chain reaction, we quantitatively determined the gene expression of several genes and compared with (68)Ga-DOTATOC PET uptake. By immunohistochemistry we qualitatively studied the expression of assorted proteins in NEC. The median age at diagnosis was 68 years (range 41-84) years. All patients had WHO performance status 0-1. Median Ki67 index was 50% (range 20-100%). Gene expression of somatostatin receptor subtype (SSTR) 2 and Ki67 were both positively correlated to the (68)Ga-DOTATOC uptake (r=0.89; p<0.0001 and r=0.5; p=0.021, respectively). Furthermore, SSTR2 and SSTR5 gene expression were strongly and positively correlated (r=0.57; p=0.006). This study as the first verifies a positive and close correlation of (68)Ga-DOTATOC uptake and gene expression of SSTR2 in NEC. SSTR2 gene expression has a stronger correlation to (68)Ga-DOTATOC uptake than SSTR5. In addition, the results indicate that the gene expression levels of SSTR2 and SSTR5 at large follow one another

Timber gridshells: beyond the drawing board

In March 2011, a week-long workshop that invited participation from all architecture and architectural technology students at Sheffield Hallam University, UK was organised with the objective of enhancing students’ thinking and experience by construction thinking. It was aimed at creating a sense of realness to realise a design project collectively. Timber was set as the material of exploration. The students had to make use of bending to design and create a timber gridshell structure. This made use of a quality traditionally felt to be a structural weakness of the material. To do this, students form-found non-mathematically and non-digitally using paper gridmats. This paper describes the aims, activity and outcome of the timber gridshell workshop as a way of preparing architects and technologists of the future and introducing the challenges of architectural design in terms of economics and construction process, aesthetics, effective communication and structural intuition by working with a given material – all important aspects in achieving effective architecture

Reliability of Automated Biochemical Identification of Burkholderia pseudomallei Is Regionally Dependent

Misidentifications of Burkholderia pseudomallei as Burkholderia cepacia by Vitek 2 have occurred. Multidimensional scaling ordination of biochemical profiles of 217 Malaysian and Australian B. pseudomallei isolates found clustering of misidentified B. pseudomallei isolates from Malaysian Borneo. Specificity of B. pseudomallei identification in Vitek 2 and potentially other automated identification systems is regionally dependent