Measuring and modelling responses of Australian grasses to drought

Global climate models predict more frequent and intense drought events in the future. Grassland ecosystems are highly sensitive to changes in water availability and ecologically and economically important, so there is a pressing need to assess grassland response to drought. Drought responses are partially determined by the physiological mechanisms (e.g. stomatal closure, hydraulic impairment and leaf senescence) of component species and the timing and intensity of drought events. Thus, detailed understanding of these mechanisms is essential to parameterize mechanistic models that predict drought responses of grasslands. The primary objective of this thesis was to quantify the physiological traits regulating these mechanisms and utilize them to parameterize a model of grass response to drought. The aim of the first data chapter (Chapter 2) was to explore the key physiological traits that respond to drought. In the second data chapter (Chapter 3), I assessed the utility of easily measurable morphological (soft) traits as surrogates for the more difficult to measure physiological (hard) traits in grasses. In the third data chapter (Chapter 4), I evaluate four different formulations of a coupled photosynthesis - stomatal conductance model presented by Tuzet et al. (2003) for their capacity to predict drought responses of C3 grasses. In summary, my PhD research provides insight into the physiological mechanisms regulating grass response to drought, and subsequently provides a basis for modelling drought responses of grasses. The low variability in physiological thresholds among grass species indicate that these mechanisms have not adapted strongly to climate of origin. This result dictates the need for the future studies on alternative mechanisms of drought adaptation in grasses. In addition, my data show that grasses exhibit simultaneous progression of leaf senescence with stomatal closure and hydraulic impairment under drought. This result suggests that substantial improvements in modelling drought responses of grasses could be achieved by incorporating a drought response of leaf senescence in mechanistic models. Accordingly, the leaf senescence data presented here provide a basis for modelling leaf browning responses of grasses under drought

A quantitative analysis of complexity of human pathogen-specific CD4 T cell responses in healthy M. tuberculosis infected South Africans

Author Summary: Human pathogen-specific immune responses are tremendously complex and the techniques to study them ever expanding. There is an urgent need for a quantitative analysis and better understanding of pathogen-specific immune responses. Mycobacterium tuberculosis (Mtb) is one of the leading causes of mortality due to an infectious agent worldwide. Here, we were able to quantify the Mtb-specific response in healthy individuals with Mtb infection from South Africa. The response is highly diverse and 66 epitopes are required to capture 80% of the total reactivity. Our study also show that the majority of the identified epitopes are restricted by multiple HLA alleles. Thus, technical advances are required to capture and characterize the complete pathogen-specific response. This study demonstrates further that the approach combining identified epitopes into "megapools" allows capturing a large fraction of the total reactivity. This suggests that this technique is generally applicable to the characterization of immunity to other complex pathogens. Together, our data provide for the first time a quantitative analysis of the complex pathogen-specific T cell response and provide a new understanding of human infections in a natural infection setting

The impact of prime-boost interval on antibody responses in HIV vaccination

The HIV pandemic has been a global health emergency for more than 30 years with an annual reoccurrence of 2 million new HIV-infections. Implementation of existing prevention measures has proven challenging, highlighting the need for an efficacious HIV vaccine. However, to date the only HIV vaccine trial to demonstrate even modest efficacy was the RV144 study. The results of this trial identified several key features, such as suggesting correlates of protection, selection of the vaccine-delivery mode, design of the immunogens and optimisation of the immunisation regimen, all are potentially imperative for effective vaccine development. Optimisation of immunisation schedules is critical for shaping the profile of vaccine- induced immune responses, the primary focus of research in this thesis. The overall aim of the thesis was to evaluate the effect of alternately timed booster regimens on both humoral and cellular immune responses to the candidate HIV-1 Env protein CN54gp140, adjuvanted with GLA-AF. For this purpose, study participants received a common 3-dose intramuscular priming series followed by a final booster at either 6 or 12 months. The longitudinal tracking of immune responses revealed that the two homologous prime- boost regimens safely and effectively induced CN54gp140-specific responses in systemic and mucosal compartments. Levels of vaccine-induced IgG-subclass antibodies correlated significantly with the engagement of Fc-receptors and both vaccine-regimens were associated with identical patterns in titre and functional antibody response profiles. Additional depth was added to the characterisation of CN54gp140 vaccine regimens through the evaluation of Env- specific monoclonal antibody responses. In summary, the combined data revealed significant similarities in response magnitude and antibody profiles associated with both immunisation schedules. The findings strongly suggest that the 6-month regimen can be adopted for the rapid induction of immune responses against CN54gp140 without affecting response magnitude, antibody diversity or functionality adversely.Open Acces

Multiple threat responses in zooplankton - from communities to individuals

Most organisms on Earth live a life where they are exposed to multiple and variable threats. In order to maximise survival they need to be able to perceive and respond to these threats. Two common threats that crustacean zooplankton are faced with are predation and ultraviolet radiation (UVR). To cope with these threats zooplankton use different strategies such as diel vertical migration and the accumulation of photoprotective compounds. In this thesis I study the threat responses of zooplankton when exposed to predation and UVR. I explore both inter- and intraspecific differences in the response to these threat situations. In addition to field data I also developed a new technique for tracking zooplankton using fluorescent nanoparticles, which I use to track the individual responses of zooplankton. I investigate if accumulation of photoprotective pigmentation may affect the spatial distribution of species in nature and how individual size may affect the migratory behaviour of zooplankton. In addition I also explore how previous exposure to threats affect the behavioural responses and if some of the observed behavioural variance could be explained by consistent individual differences in behaviour. In summary, I show that even closely related species may show large differences in their response to UVR. Intraspecific differences in pigmentation could not be related to the spatial distribution of either Daphnia or calanoid copepods; however, both Daphnia and copepods were found to perform size structured migration. I also demonstrate that previous experiences of a threat can affect how the organism responds. Some evidence for consistent individual differences in the behavioural response of Daphnia to UVR is presented, suggesting that individual based studies could add further to our knowledge about behavioural responses in zooplankton. Given the variability both with respect to inter- and intraspecific differences in UVR response we need to keep these differences in mind when postulating new, more comprehensive theories explaining the behaviour of zooplankton exposed to everyday threats

Efficient coding of natural scenes improves neural system identification

Neural system identification aims at learning the response function of neurons to arbitrary stimuli using experimentally recorded data, but typically does not leverage normative principles such as efficient coding of natural environments. Visual systems, however, have evolved to efficiently process input from the natural environment. Here, we present a normative network regularization for system identification models by incorporating, as a regularizer, the efficient coding hypothesis, which states that neural response properties of sensory representations are strongly shaped by the need to preserve most of the stimulus information with limited resources. Using this approach, we explored if a system identification model can be improved by sharing its convolutional filters with those of an autoencoder which aims to efficiently encode natural stimuli. To this end, we built a hybrid model to predict the responses of retinal neurons to noise stimuli. This approach did not only yield a higher performance than the “stand-alone” system identification model, it also produced more biologically-plausible filters. We found these results to be consistent for retinal responses to different stimuli and across model architectures. Moreover, our normatively regularized model performed particularly well in predicting responses of direction-of-motion sensitive retinal neurons. In summary, our results support the hypothesis that efficiently encoding environmental inputs can improve system identification models of early visual processing

Improving T cell-induced response to subunit vaccines:opportunities for a proteomic systems approach

Prophylactic vaccines are an effective strategy to prevent development of many infectious diseases. With new and re-emerging infections posing increasing risks to food stocks and the health of the population in general, there is a need to improve the rationale of vaccine development. One key challenge lies in development of an effective T cell-induced response to subunit vaccines at specific sites and in different populations. Objectives: In this review, we consider how a proteomic systems-based approach can be used to identify putative novel vaccine targets, may be adopted to characterise subunit vaccines and adjuvants fully. Key findings: Despite the extensive potential for proteomics to aid our understanding of subunit vaccine nature, little work has been reported on identifying MHC 1-binding peptides for subunit vaccines generating T cell responses in the literature to date. Summary: In combination with predictive and structural biology approaches to mapping antigen presentation, proteomics offers a powerful and as yet un-tapped addition to the armoury of vaccine discovery to predict T-cell subset responses and improve vaccine design strategies

Comparison of the Immune Responses Induced by Chimeric Alphavirus-Vectored and Formalin-Inactivated Alum-Precipitated Measles Vaccines in Mice

A variety of vaccine platforms are under study for development of new vaccines for measles. Problems with past measles vaccines are incompletely understood and underscore the need to understand the types of immune responses induced by different types of vaccines. Detailed immune response evaluation is most easily performed in mice. Although mice are not susceptible to infection with wild type or vaccine strains of measles virus, they can be used for comparative evaluation of the immune responses to measles vaccines of other types. In this study we compared the immune responses in mice to a new protective alphavirus replicon particle vaccine expressing the measles virus hemagglutinin (VEE/SIN-H) with a non-protective formalin-inactivated, alum-precipitated measles vaccine (FI-MV). MV-specific IgG levels were similar, but VEE/SIN-H antibody was high avidity IgG2a with neutralizing activity while FI-MV antibody was low-avidity IgG1 without neutralizing activity. FI-MV antibody was primarily against the nucleoprotein with no priming to H. Germinal centers appeared, peaked and resolved later for FI-MV. Lymph node MV antibody-secreting cells were more numerous after FI-MV than VEE/SIN-H, but were similar in the bone marrow. VEE/SIN-H-induced T cells produced IFN-γ and IL-4 both spontaneously ex vivo and after stimulation, while FI-MV-induced T cells produced IL-4 only after stimulation. In summary, VEE/SIN-H induced a balanced T cell response and high avidity neutralizing IgG2a while FI-MV induced a type 2 T cell response, abundant plasmablasts, late germinal centers and low avidity non-neutralizing IgG1 against the nucleoprotein

Persistent Bacterial Bronchitis: time to venture beyond the Umbrella

Chronic cough in children is common and frequently mismanaged. In the past, cough was diagnosed as asthma and inappropriate asthma therapies prescribed and esca- lated. It has been realized that persistent bacterial bronchitis (PBB) is a common cause of wet cough and responds to oral antibiotics. The initial definition comprised a history of chronic wet cough, positive bronchoalveolar (BAL) cultures for a respiratory pathogen and response to a 2-week course of oral amoxicillin–clavulanic acid. This is now termed PBB-micro; PBB-clinical eliminates the need for BAL. PBB-extended is PBB-micro or PBB-clinical but resolution necessitating 4 weeks of antibiotics; and recurrent PBB is > 3 attacks of PBB-micro or-clinical/year. However, the airway has only a limited range of responses to chronic inflammation and infection, and neutrophilic airway disease is seen in many other conditions, such as cystic fibrosis and primary ciliary dyskinesia, both chronic suppurative lung disease endotypes, whose recognition has led to huge scientific and clinical advances. There is an urgent need to extend endotyping into PBB, especially PBB-recurrent. We need to move from associative studies and, in particular, deploy sophisticated modern –omics technologies and systems biology, rather as has been done in the context of asthma in U-BIOPRED. In summary, the use of the term PBB has done signal service in pointing us away from prescribing asthma therapies to children with infected airways, but we now need to move beyond a simple description to teasing out underlying endotypes