Subcellular information processing in the olfactory system

The nervous system is tasked with the challenge of processing a variety of sensory stimuli from the environment with limited coding space and energy consumption. Recent findings challenge the traditional view of the neuron as the elementary functional unit of the nervous system, in which dendrites mainly serve as input sites, and action potential propagation through axons generates output. Instead, individual neurites have emerged as the single functional unit capable of computing inputs and generating outputs locally. Despite recent advances, the link between the mechanisms that facilitate local computations and their behavioural relevance remains unclear. I addressed this problem in Drosophila Melanogaster. The anatomical organisation of the mushroom body, a brain region associated with learning, has a compartmentalised architecture that forms the basis for local computations. My project studied subcellular signalling in the mushroom body and its role in memory formation, with emphasis on the non-spiking APL neuron that is involved in sparse odour coding and memory formation, to determine if it operates locally. To investigate this, I addressed the following points. 1. I investigated the nature of activity spread in the APL neuron. I found that input to the APL neuron evokes activity that attenuates as it propagates, supporting local computations. 2. I characterised the spatial nature of inhibition from the APL neuron onto mushroom body neurons. I found that the inhibition had a strong local effect that diminished with distance. 3. I sought to determine if there are spatial differences in the APL neuron’s response to electric shock, and if plasticity in the APL neuron is similarly spatially distinct. I found that electric shock responses are spatially distinct, but my data on plasticity was inconclusive. 4. I investigated the effects of local muscarine signalling on Kenyon cell odour responses. I found that muscarine signalling has spatially distinct effects

Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data.

BACKGROUND: Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection. METHODS: We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling. FINDINGS: We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each day's delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18-1·28]; p<0·0001 for the increasing HR with each day's delay). INTERPRETATION: We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection. FUNDING: F Hoffmann-La Roche