The generation of phase differences and frequency changes in a network model of inferior olive subthreshold oscillations

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedicationIt is commonly accepted that the Inferior Olive (IO) provides a timing signal to the cerebellum. Stable subthreshold oscillations in the IO can facilitate accurate timing by phase-locking spikes to the peaks of the oscillation. Several theoretical models accounting for the synchronized subthreshold oscillations have been proposed, however, two experimental observations remain an enigma. The first is the observation of frequent alterations in the frequency of the oscillations. The second is the observation of constant phase differences between simultaneously recorded neurons. In order to account for these two observations we constructed a canonical network model based on anatomical and physiological data from the IO. The constructed network is characterized by clustering of neurons with similar conductance densities, and by electrical coupling between neurons. Neurons inside a cluster are densely connected with weak strengths, while neurons belonging to different clusters are sparsely connected with stronger connections. We found that this type of network can robustly display stable subthreshold oscillations. The overall frequency of the network changes with the strength of the inter-cluster connections, and phase differences occur between neurons of different clusters. Moreover, the phase differences provide a mechanistic explanation for the experimentally observed propagating waves of activity in the IO. We conclude that the architecture of the network of electrically coupled neurons in combination with modulation of the inter-cluster coupling strengths can account for the experimentally observed frequency changes and the phase differences.Peer reviewedFinal Published versio

Inspired or foolhardy: sensemaking, confidence and entrepreneurs' decision-making.

The purpose of this paper is to investigate the role of confidence in how both new and experienced entrepreneurs interpret and make sense of their business environment to inform decision-making. We illustrate our conceptual arguments with descriptive results from a large-scale (n = 6289) survey on entrepreneurs' perception of business performance and their decisions taken at a time of uncertainty in an economic downturn. Quantitative findings are stratified along experiential lines to explore heterogeneity in entrepreneurial decision-making and directly inform our conceptual arguments, while qualitative data from open questions are used to explain the role of confidence. Newer entrepreneurs are found to be more optimistic in the face of environmental risk, which impacts on their decision-making and innovative capabilities. However, the more experienced entrepreneurs warily maintain margin and restructure to adapt to environmental changes. Instead of looking directly at the confidence of individuals, we show how confidence impacts sensemaking, and ultimately, decision-making. These insights inform research on the behaviour of novice and experienced entrepreneurs in relation to innovative business activities. Specifically, blanket assumptions on the role of confidence may be misplaced as its impact changes with experience to alter how entrepreneurs make sense of their environment

Structure-Function Relationship of Analogues of PTH(1-11) Containing a Combination of Aib and (\u3b1Me)Val.

The N-terminal 1-34 fragment of paratyroid hormone (PTH) is fully active in vitro and in vivo and it can reproduce all biological responses characteristic of the native intact PTH. Recently, helicity-enhancing substitutions in PTH(1-11) and PTH(1-14) have yielded potent analogues. To further investigate the role of a-helicity on biological potency and of substitutions enhancing bioactivity, in the present work we synthesised and conformationally and biologically characterised PTH(1-11) analogues containing sterically hindered and helix-promoting Ca-tetrasubstituted amino acids, such as a-amino isobutyric acid (Aib), a-methyl Valine (aMeVal) and amino cyclopentane carboxylic acid (Ac5c). CD and NMR experiments and molecular dynamics calculations demonstrate that the substitution with Ca-tetrasubstituted amino acids led to the enhancement of the helical conformation. In TFE/water solutions, analogue VII, used as reference, adopts a stable a-helical segment spanning the sequence from Ile5 to His9. Analogues I - VI show a higher preference for the helical structure which comprises the sequence 2-9

Structure-function relationship of analogues of PTH (1-11) containing a combination of C-alpha-tetrasubstituited amino acids

The N-terminal 1-34 fragment of paratyroid hormone (PTH) is fully active in vitro and in vivo and it can reproduce all biological responses characteristic of the native intact PTH. Recently, helicity-enhancing substitutions in PTH(1-11) and PTH(1-14) have yielded potent analogues. To further investigate the role of a-helicity on biological potency, in the present work we synthesised and conformationally and biologically characterised seven PTH(1-11) analogues containing sterically hindered and helix-promoting Ca-tetrasubstituted amino acids, such as a-amino isobutyric acid (Aib), a-methyl Valine (aMeVal) and amino cyclopentane carboxylic acid (Ac5c). CD and NMR experiments and molecular dynamics calculations demonstrate that the substitution with Ca-tetrasubstituted amino acids led to the enhancement of the helical conformation. In TFE/water solutions, analogue VII, used as reference, adopts a stable a-helical segment spanning the sequence from Ile5 to His9. Analogues I - VI show a higher preference for the helical structure which comprises the sequence 2-9