Aspects of learning within networks of spiking neurons

Spiking neural networks have, in recent years, become a popular tool for investigating the properties and computational performance of large massively connected networks of neurons. Equally as interesting is the investigation of the potential computational power of individual spiking neurons. An overview is provided of current and relevant research into the Liquid Sate Machine, biologically inspired artificial STDP learning mechanisms and the investigation of aspects of the computational power of artificial, recurrent networks of spiking neurons. First, it is shown that, using simple structures of spiking Leaky Integrate and Fire (LIF) neurons, a network n(P), can be built to perform any program P that can be performed by a general parallel programming language. Next, a form of STDP learning with normalisation is developed, referred to as STDP + N learning. The effects of applying this STDP + N learning within recurrently connected networks of neurons is then investigated. It is shown experimentally that, in very specific circumstances Anti-Hebbian and Hebbian STDP learning may be considered to be approximately equivalent processes. A metric is then developed that can be used to measure the distance between any two spike trains. The metric is then used, along with the STDP + N learning, in an experiment to examine the capacity of a single spiking neuron that receives multiple input spike trains, to simultaneously learn many temporally precise Input/Output spike train associations. The STDP +N learning is further modified for use in recurrent networks of spiking neurons, to give the STDP + NType2 learning methodology. An experiment is devised which demonstrates that the Type 2 method of applying learning to the synapses of a recurrent network — effectively a randomly shifting locality of learning — can enable the network to learn firing patterns that the typical application of learning is unable to learn. The resulting networks could, in theory, be used to create to simple structures discussed in the first chapter of original work.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

An Algorithm for Finding Candidate Synaptic Sites in Computer Generated Networks of Neurons with Realistic Morphologies

Neurons make synaptic connections at locations where axons and dendrites are sufficiently close in space. Typically the required proximity is based on the dimensions of dendritic spines and axonal boutons. Based on this principle one can search those locations in networks formed by reconstructed neurons or computer generated neurons. Candidate synapses are then located where axons and dendrites are within a given criterion distance from each other. Both experimentally reconstructed and model generated neurons are usually represented morphologically by piecewise-linear structures (line pieces or cylinders). Proximity tests are then performed on all pairs of line pieces from both axonal and dendritic branches. Applying just a test on the distance between line pieces may result in local clusters of synaptic sites when more than one pair of nearby line pieces from axonal and dendritic branches is sufficient close, and may introduce a dependency on the length scale of the individual line pieces. The present paper describes a new algorithm for defining locations of candidate synapses which is based on the crossing requirement of a line piece pair, while the length of the orthogonal distance between the line pieces is subjected to the distance criterion for testing 3D proximity

Open urethroplasty versus endoscopic urethrotomy - clarifying the management of men with recurrent urethral stricture (the OPEN trial) : study protocol for a randomised controlled trial

Peer reviewedPublisher PD

Development of the esterase PestE for amide bond synthesis under aqueous conditions: Enzyme cascades for converting waste PET into tamibarotene.

A growing number of hydrolase enzymes show promiscuous acyltransferase activity, even under aqueous conditions. Here we report, for the first time, the ability of Pyrobaculum calidifontis VA1 esterase (PestE) to catalyse the formation of a wide range of amides in buffer, where the acyl donor forms a significant structural component in the amide product. The reactions occur under mild conditions and can achieve conversions up to 97% in 6 h for formation of N-benzylfuranamide as the model reaction. We demonstrate PestE's potential in enzyme cascades to make amides from waste PET plastic and the conversion of the terephthalic acid product to tamibarotene, a drug with activity against acute leukemia. Rational mutagenesis led to identification of PestE variants F33L_F289A and F33L. F33L_F289A increased conversion of N-benzylfuranamide by 1.2-fold, and F33L gave a 4-fold increase in conversion to tamibarotene

Development of the esterase PestE for amide bond synthesis under aqueous conditions: Enzyme cascades for converting waste PET into tamibarotene.

A growing number of hydrolase enzymes show promiscuous acyltransferase activity, even under aqueous conditions. Here we report, for the first time, the ability of Pyrobaculum calidifontis VA1 esterase (PestE) to catalyse the formation of a wide range of amides in buffer, where the acyl donor forms a significant structural component in the amide product. The reactions occur under mild conditions and can achieve conversions up to 97% in 6 h for formation of N‐benzylfuranamide as the model reaction. We demonstrate PestE’s potential in enzyme cascades to make amides from waste PET plastic and the conversion of the terephthalic acid product to tamibarotene, a drug with activity against acute leukemia. Rational mutagenesis led to identification of PestE variants F33L_F289A and F33L. F33L_F289A increased conversion of N‐benzylfuranamide by 1.2‐fold, and F33L gave a 4‐fold increase in conversion to tamibarotene.</jats:p

Transcriptional analysis of the response of \u3ci\u3eC. elegans\u3c/i\u3e to ethanol exposure

Ethanol-induced transcriptional changes underlie important physiological responses to ethanol that are likely to contribute to the addictive properties of the drug. We examined the transcriptional responses of Caenorhabditis elegans across a timecourse of ethanol exposure, between 30 min and 8 h, to determine what genes and genetic pathways are regulated in response to ethanol in this model. We found that short exposures to ethanol (up to 2 h) induced expression of metabolic enzymes involved in metabolizing ethanol and retinol, while longer exposure (8 h) had much more profound effects on the transcriptome. Several genes that are known to be involved in the physiological response to ethanol, including direct ethanol targets, were regulated at 8 h of exposure. This longer exposure to ethanol also resulted in the regulation of genes involved in cilia function, which is consistent with an important role for the effects of ethanol on cilia in the deleterious effects of chronic ethanol consumption in humans. Finally, we found that food deprivation for an 8-h period induced gene expression changes that were somewhat ameliorated by the presence of ethanol, supporting previous observations that worms can use ethanol as a calorie source

Tetherin antagonism by SARS-CoV-2 ORF3a and spike protein enhances virus release

The antiviral restriction factor, tetherin, blocks the release of several different families of enveloped viruses, including the Coronaviridae. Tetherin is an interferon‐induced protein that forms parallel homodimers between the host cell and viral particles, linking viruses to the surface of infected cells and inhibiting their release. We demonstrate that SARS‐CoV‐2 infection causes tetherin downregulation and that tetherin depletion from cells enhances SARS‐CoV‐2 viral titres. We investigate the potential viral proteins involved in abrogating tetherin function and find that SARS‐CoV‐2 ORF3a reduces tetherin localisation within biosynthetic organelles where Coronaviruses bud, and increases tetherin localisation to late endocytic organelles via reduced retrograde recycling. We also find that expression of Spike protein causes a reduction in cellular tetherin levels. Our results confirm that tetherin acts as a host restriction factor for SARS‐CoV‐2 and highlight the multiple distinct mechanisms by which SARS‐CoV‐2 subverts tetherin function

Paucity and discordance of neutralising antibody responses to SARS-CoV-2 VOCs in vaccinated immunodeficient patients and health-care workers in the UK.

As of June, 2021, the UK population is only partly vaccinated against COVID-19, with many people having received just one vaccination dose (either BNT162b2 [Pfizer–BioNTech]) or ChAdOx1 nCoV-19 [AZD1222; Oxford–AstraZeneca]). Tracking the spread of SARS-CoV-2 Variants of Concern (VOCs) remains important for understanding the levels of vaccine-induced immunity and for identifying the emergence of vaccine escape variants. The immune correlates of protection to SARS-CoV-2 and COVID-19 established in phase 3 clinical trials following two doses of vaccine was the titre of neutralising antibodies (NAbs) to SARS-CoV-2 in study groups, before the VOCs emerged.1 Vaccination programmes are leading to promising reductions in disease severity and mortality in vaccinated populations. However, the combined situation of ongoing transmission within communities, including in some vaccine recipients, alongside newly arising VOCs, continues to pose a serious threat to public health and the efficacy of these vaccines. As of Jan 11, 2021, in the UK, the interval between the first and second dose of vaccination was extended to 12 weeks. This extension achieved the aim of maximising population coverage by immunising the greatest possible number of individuals to prevent disease and hospital admissions. Encouragingly, a growing number of studies have reported a marked reduction in the number of individuals with moderate-to-severe clinical symptoms and a substantial decline in the number of hospitalised patients with COVID-19 in the UK, underscoring the success of this strategy