A Large-Scale Model of Spatio-Temporal Patterns of Excitation and Inhibition Evoked by the Horizontal Network in Layer 2/3 of the Visual Cortex

Cortical processing of even the most elementary visual stimuli can result in the propagation of information over significant spatiotemporal scales. To fully understand the impact of such phenomena it is essential to consider the influence of both the neural circuitry beyond the immediate retinotopic location of the stimulus, including pre-cortical areas, and the temporal components of stimulus driven activity that may persist over significant periods. Two computational modelling studies have been performed to explore these phenomena and are reported in this thesis. I) The plexus of long and short range lateral connections is a prominent feature of the layer 2/3 microcircuit in primary visual cortex. Despite the scope for possible functionality, the interdependence of local and long range circuits is still unclear. Spatiotemporal patterns of activity appear to be shaped by the underlying connectivity architecture and strong inhibition. A modelling study has been conducted to capture population activity that has been observed in vitro using voltage sensitive dyes. The model demonstrates that the precise spatiotemporal spread of activity seen in the cortical slice results from long range connections that target specific orientation domains whilst distinct regions of suppressed activity are shown to arise from local isotropic axonal projections. Distal excitatory activity resulting from long range axons is shaped by local interneurons similarly targeted by such connections. It is shown that response latencies of distal excitation are strongly influenced by frequency dependent facilitation and low threshold characteristics of interneurons. Together, these results support hypotheses made following experimental observations in vitro and clearly illustrate the underlying mechanisms. However, predictions by the model suggest that in vivo conditions give rise to markedly different spatiotemporal activity. Furthermore, opposing data in the literature regarding inter-laminar connectivity give rise to profoundly different spatiotemporal patterns of activity in cortex. 2) The second computational modelling study considers simple moving stimuli. These stimuli are implicated in the 'motion streak' phenomenon whereby the movement of a visual feature can give rise to trajectory information that is not explicitly present. Published experimental data of an in vivo study in the cat has shown that a single small light square moving stimulus elicits activity in populations of neurons in primary visual cortex that are selective for orientations parallel to stimulus trajectory (Jancke 2000). In more recent, unpublished data, this work is extended to consider long term persistent cortical activity that is generated by similar stimuli. These data indicate that following initial cortical activation that appears to result directly from the stimulus, iso-orientation domains display persistent activity. Furthermore, initial activity is broadly tuned with respect to orientation whilst later activity is strongly selective for orientations that are parallel to the stimulus trajectory. Currently the generative processes involved have not been clearly defined. Hence the proposed thesis will contribute to a more complete understanding of the mechanisms responsible for such cortical representations of moving visual stimuli. More specifically this will be achieved by a large scale mean field model that will enable a thorough investigation of the anatomical and electrophysiological elements concerned with the observed spatiotemporal dynamic behaviour and will represent a significant region of cortex. In conjunction, an existing computational model of the retina will be integrated. In doing so this thesis will offer the notion that certain cortical representations are inextricably linked with earlier stages of the visual pathway. As such consideration of retinal processing is fundamental to the understanding cortical functions and failure to do so can only result in erroneous conclusions

Preliminary Measurement of Neutrino Oscillation Parameters By NuMI/MINOS and Calibration Studies for Improving this Measurement

This thesis explains the origins of neutrinos and their interactions, and the phenomenon of neutrino oscillations. Experiments for measuring neutrino oscillations are mentioned and the experiment investigated in this thesis, the ''Main Injector Neutrino Oscillation Search'', and its neutrino beam, the Fermi National Accelerator Laboratory's ''Neutrinos At The Main Injector'', are described. MINOS is a long baseline (735 km) neutrino oscillation experiment with a near and a far detector, intended to make precision measurements of the atmospheric sector neutrino oscillation parameters. A measurement is made of the ''atmospheric'' neutrino oscillation parameters, {Delta}m{sub 23}{sup 2} and sin {sup 2}(2{theta}{sub 23}), using neutrinos from the NuMI beam. The results of this analysis are compared to measurements at MINOS using neutrinos from the atmosphere and with other experiments. A more detailed method of beam neutrino analysis is discussed, and the extra calibrations needed to perform that analysis properly are described, with special attention paid to two aspects of the calibration, which comprise the bulk of work for this thesis. The light injection calibration system uses LEDs to illuminate the detector readout and provides a normalization of the stability of the detector over time. The hardware and different modi operandi of the system are described. There is a description of installation and commissioning of the system at one of the MINOS detectors. The response normalization of each detector with cosmic ray muons is described. Special attention is paid to the explanation of necessary corrections that must be made to the muon sample in order for the sample to be used to calibrate each detector to the specified accuracy. The performance of the calibration is shown

Immunoglobulin Replacement Therapy During COVID-19 Pandemic: Practical and Psychological Impact in Patients with Antibody Deficiency

Purpose: The COVID-19 pandemic has impacted on how health services deliver care and the mental health of the population. Due to their clinical vulnerability, to reduce in-hospital attendances during the COVID-19 pandemic, modifications in immunoglobulin treatment regimens were made for patients with antibody deficiency. These patients were also likely to experience social isolation due to shielding measure that were advised. We aimed to investigate the impact of modifying immunoglobulin treatment regimen on infection and mental health burden during shielding restrictions.// Method: Patients on immunoglobulin replacement therapy (IGRT) responded to a standardised questionnaire examining self-reported infection frequency, anxiety (GAD-7), depression (PHQ-8), fatigue (FACIT), and quality of life during the pandemic. Infection frequency and immunoglobulin trough levels were compared to pre-pandemic levels.// Results: Patients who did not change treatment modality or those who received immunoglobulin replacement at home during the pandemic reported fewer infections. In patients who received less frequent hospital infusions, there was no significant increase in infections whilst immunoglobulin trough levels remained stable. There was no significant difference in anxiety, or depression scores between the treatment modality groups. Patients reported higher fatigue scores compared to the pre-COVID general population and in those discharged following hospitalisation for COVID.// Conclusion: Changing immunoglobulin treatment regimen did not negatively impact infection rates or psychological wellbeing. However, psychological welfare should be prioritised for this group particularly given uncertainties around COVID-19 vaccination responsiveness and continued social isolation for many

Nutritional significance of a winter-flowering succulent for opportunistic avian nectarivores

The winter-flowering succulent Aloe marlothii provides nectar for many opportunistic avian nectarivores in southern African savannas. We assessed the importance of A. marlothii nectar sugar for opportunistic nectarivores by analysing temporal changes in stable carbon isotope ratios (d13C) in the tissues of birds in Suikerbosrand Nature Reserve, South Africa. The blood of the 11 most common non-granivorous opportunistic nectarivores at our site was enriched in 13C by 3.4 ± 1.5& during the flowering period of A. marlothii, reflecting the enriched crassulacean acid metabolism (CAM) isotopic signature of nectar ()12.6 ± 0.5&). This relatively small contribution of A. marlothii nectar to assimilated carbon in whole blood contrasted with that of exhaled CO2 in African Red-eyed Bulbuls Pycnonotus nigricans and Cape White-eyes Zosterops capensis. In both these species, the d13C of breath samples was significantly enriched compared with blood and feathers, and closely resembled that of the nectar, revealing combustion of ingested nectar rather than assimilation. Although our analysis was complicated by the presence of C4 grasses, whose d13C values are similar to those of CAM photosynthesizers, when considered with previously published feeding observations our data reveal that opportunistic nectarivores feeding on A. marlothii nectar obtain a relatively small fraction of their assimilated carbon, but most of their metabolized carbon, from this seasonally available carbohydrate food resource. Because the d13C values of insects associated with C3 plants also became enriched during the flowering season, some insect-eating opportunistic nectarivores may have assimilated A. marlothii carbon indirectly from insects. This study highlights the importance of understanding isotopic routing when assessing the nutritional significance of specific dietary items to consumer communities.The National Research Foundation of South Africahttp://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1474-919X/ab201

A Novel Role for Wnt/Ca2+ Signaling in Actin Cytoskeleton Remodeling and Cell Motility in Prostate Cancer

Wnt signaling is a critical regulatory pathway in development and disease. Very little is known about the mechanisms of Wnt signaling in prostate cancer, a leading cause of death in men. A quantitative analysis of the expression of Wnt5A protein in human tissue arrays, containing 600 prostate tissue cores, showed >50% increase in malignant compared to benign cores (p<0.0001). In a matched pair of prostate cancer and normal cell line, expression of Wnt5A protein was also increased. Calcium waves were induced in prostate cells in response to Wnt5A with a 3 fold increase in Flou-4 intensity. The activity of Ca2+/calmodulin dependent protein kinase (CaMKII), a transducer of the non-canonical Wnt/Ca2+ signaling, increased by 8 fold in cancer cells; no change was observed in β-catenin expression, known to activate the canonical Wnt/β-catenin pathway. Mining of publicly available human prostate cancer oligoarray datasets revealed that the expression of numerous genes (e.g., CCND1, CD44) under the control of β-catenin transcription is down-regulated. Confocal and quantitative electron microscopy showed that specific inhibition of CaMKII in cancer cells causes remodeling of the actin cytoskeleton, irregular wound edges and loose intercellular architecture and a 6 and 8 fold increase in the frequency and length of filopodia, respectively. Conversely, untreated normal prostate cells showed an irregular wound edge and loose intercellular architecture; incubation of normal prostate cells with recombinant Wnt5A protein induced actin remodeling with a regular wound edge and increased wound healing capacity. Live cell imaging showed that a functional consequence of CaMKII inhibition was 80% decrease in wound healing capacity and reduced cell motility in cancer cells. We propose that non-canonical Wnt/Ca2+ signaling via CaMKII acts as a novel regulator of structural plasticity and cell motility in prostate cancer

Assessing the cost of global biodiversity and conservation knowledge

Knowledge products comprise assessments of authoritative information supported by stan-dards, governance, quality control, data, tools, and capacity building mechanisms. Considerable resources are dedicated to developing and maintaining knowledge productsfor biodiversity conservation, and they are widely used to inform policy and advise decisionmakers and practitioners. However, the financial cost of delivering this information is largelyundocumented. We evaluated the costs and funding sources for developing and maintain-ing four global biodiversity and conservation knowledge products: The IUCN Red List ofThreatened Species, the IUCN Red List of Ecosystems, Protected Planet, and the WorldDatabase of Key Biodiversity Areas. These are secondary data sets, built on primary datacollected by extensive networks of expert contributors worldwide. We estimate that US$160million (range: US$116–204 million), plus 293 person-years of volunteer time (range: 278–308 person-years) valued at US$14 million (range US$12–16 million), were invested inthese four knowledge products between 1979 and 2013. More than half of this financingwas provided through philanthropy, and nearly three-quarters was spent on personnelcosts. The estimated annual cost of maintaining data and platforms for three of these knowl-edge products (excluding the IUCN Red List of Ecosystems for which annual costs were notpossible to estimate for 2013) is US$6.5 million in total (range: US$6.2–6.7 million). We esti-mated that an additional US$114 million will be needed to reach pre-defined baselines ofdata coverage for all the four knowledge products, and that once achieved, annual mainte-nance costs will be approximately US$12 million. These costs are much lower than those tomaintain many other, similarly important, global knowledge products. Ensuring that biodi-versity and conservation knowledge products are sufficiently up to date, comprehensiveand accurate is fundamental to inform decision-making for biodiversity conservation andsustainable development. Thus, the development and implementation of plans for sustain-able long-term financing for them is critical

Commercial Immunoglobulin Products Contain Neutralizing Antibodies Against Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein

BACKGROUND: Patients with antibody deficiency respond poorly to COVID-19 vaccination and are at risk of severe or prolonged infection. They are given long-term immunoglobulin replacement therapy (IRT) prepared from healthy donor plasma to confer passive immunity against infection. Following widespread COVID-19 vaccination alongside natural exposure, we hypothesised that immunoglobulin preparations will now contain neutralising SARS-CoV-2 spike antibodies which confer protection against COVID-19 disease and may help to treat chronic infection. METHODS: We evaluated anti-SARS-CoV-2 spike antibody in a cohort of patients before and after immunoglobulin infusion. Neutralising capacity of patient samples and immunoglobulin products was assessed using in vitro pseudo-virus and live-virus neutralisation assays, the latter investigating multiple batches against current circulating omicron variants. We describe the clinical course of nine patients started on IRT during treatment of COVID-19. RESULTS: In 35 individuals with antibody deficiency established on IRT, median anti-spike antibody titre increased from 2123 to 10600 U/ml post-infusion, with corresponding increase in pseudo-virus neutralisation titres to levels comparable to healthy donors. Testing immunoglobulin products directly in the live-virus assay confirmed neutralisation, including of BQ1.1 and XBB variants, but with variation between immunoglobulin products and batches.Initiation of IRT alongside Remdesivir in patients with antibody deficiency and prolonged COVID-19 infection (median 189 days, maximum over 900 days with an ancestral viral strain) resulted in clearance of SARS-CoV-2 virus at a median of 20 days. CONCLUSIONS: Immunoglobulin preparations now contain neutralising anti-SARS-CoV-2 antibodies which are transmitted to patients and help to treat COVID-19 in individuals with failure of humoral immunity

A Bioelectrochemical Approach to Characterize Extracellular Electron Transfer by Synechocystis sp. PCC6803

Biophotovoltaic devices employ photosynthetic organisms at the anode of a microbial fuel cell to generate electrical power. Although a range of cyanobacteria and algae have been shown to generate photocurrent in devices of a multitude of architectures, mechanistic understanding of extracellular electron transfer by phototrophs remains minimal. Here we describe a mediatorless bioelectrochemical device to measure the electrogenic output of a planktonically grown cyanobacterium, Synechocystis sp. PCC6803. Light dependent production of current is measured, and its magnitude is shown to scale with microbial cell concentration and light intensity. Bioelectrochemical characterization of a Synechocystis mutant lacking Photosystem II demonstrates conclusively that production of the majority of photocurrent requires a functional water splitting aparatus and electrons are likely ultimately derived from water. This shows the potential of the device to rapidly and quantitatively characterize photocurrent production by genetically modified strains, an approach that can be used in future studies to delineate the mechanisms of cyanobacterial extracellular electron transport

Parrots Eat Nutritious Foods despite Toxins

Generalist herbivores are challenged not only by the low nitrogen and high indigestibility of their plant foods, but also by physical and chemical defenses of plants. This study investigated the foods of wild parrots in the Peruvian Amazon and asked whether these foods contain dietary components that are limiting for generalist herbivores (protein, lipids, minerals) and in what quantity; whether parrots chose foods based on nutrient content; and whether parrots avoid plants that are chemically defended.We made 224 field observations of free-ranging parrots of 17 species in 8 genera foraging on 102 species of trees in an undisturbed tropical rainforest, in two dry seasons (July-August 1992-1993) and one wet season (January-February1994). We performed laboratory analyses of parts of plants eaten and not eaten by parrots and brine shrimp assays of toxicity as a proxy for vertebrates. Parrots ate seeds, fruits, flowers, leaves, bark, and insect larvae, but up to 70% of their diet comprised seeds of many species of tropical trees, in various stages of ripeness. Plant parts eaten by parrots were rich in protein, lipid, and essential minerals, as well as potentially toxic chemicals. Seeds were higher than other plant materials in protein and lipid and lower in fiber. Large macaws of three species ate foods higher in protein and lipids and lower in fiber compared to plant parts available but not eaten. Macaws ate foods that were lower in phenolic compounds than foods they avoided. Nevertheless, foods eaten by macaws contained measurable levels of toxicity. Macaws did not appear to make dietary selections based on mineral content.Parrots represent a remarkable example of a generalist herbivore that consumes seeds destructively despite plant chemical defenses. With the ability to eat toxic foods, rainforest-dwelling parrots exploited a diversity of nutritious foods, even in the dry season when food was scarce for other frugivores and granivores