The effect of macrophage polarization on the expression of the oxytocin signalling system in enteric neurons

Background The aim of the current study was to investigate the effect of macrophage polarization on the expression of oxytocin (OT) and the oxytocin receptor (OTR) in enteric neurons. Methods In this study, we used a classic colitis model and D-mannose model to observe the correlation between macrophage polarization and OT signalling system. In order to further demonstrate the effect of macrophages, we examined the expression of OT signalling system after depletion of macrophages. Results The data showed that, in vitro, following polarization of macrophages to the M1 type by LPS, the macrophage supernatant contained proinflammatory cytokines (IL-1β, IL-6 and TNF-α) that inhibited the expression of OT and OTR in cultured enteric neurons; following macrophage polarization to the M2 type by IL4, the macrophage supernatant contained anti-inflammatory cytokines (TGF-β) that promoted the expression of OT and OTR in cultured enteric neurons. Furthermore, M1 macrophages decreased the expression of the OT signalling system mainly through STAT3/NF-κB pathways in cultured enteric neurons; M2 macrophages increased the expression of the OT signalling system mainly through activation of Smad2/3 and inhibition of the expression of Peg3 in cultured enteric neurons. In a colitis model, we demonstrated that macrophages were polarized to the M1 type during the inflammatory phase, with significant decreased in the expression of OT and OTR. When macrophages were polarized to the M2 type during the recovery phase, OT and OTR expression increased significantly. In addition, we found that D-mannose increased the expression of OT and OTR through polarization of macrophages to the M2 type. Conclusions This is the first study to demonstrate that macrophage polarization differentially regulates the expression of OT and OTR in enteric neurons.

Auto-Regulation of Transcription and Translation: Oscillations, Excitability and Intermittency

Several members of the Hes/Her family, conserved targets of the Notch signalling pathway, encode transcriptional repressors that dimerise, bind DNA and self-repress. Such autoinhibition of transcription can yield homeostasis and, in the presence of delays that account for processes such as transcription, splicing and transport, oscillations. Whilst previous models of autoinhibition of transcription have tended to treat processes such as translation as being unregulated (and hence linear), here we develop and explore a mathematical model that considers autoinhibition of transcription together with nonlinear regulation of translation. It is demonstrated that such a model can yield, in the absence of delays, nonlinear dynamical behaviours such as excitability, homeostasis, oscillations and intermittency. These results indicate that regulation of translation as well as transcription allows for a much richer range of behaviours than is possible with autoregulation of transcription alone. A number of experiments are suggested that would that allow for the signature of autoregulation of translation as well as transcription to be experimentally detected in a Notch signalling system.

TRAIN HEADWAY OPTIMISATION USING VIRTUAL BLOCKS

Although the implementation of a new Automatic Train Protection (ATP) system increases the safety level, it also exerts some impact on the blocking time in block sections, and consequently, on the headway between trains. At the same time, ATP systems introduce a train positioning system based on odometry calculation and reporting back to the trackside system. This paper describes the concept of using virtual blocks based on train position reporting in the ATP system for purposes of non-occupancy determination. Virtual blocks can be used to reduce headways on railway lines without increasing the number of trackside signalling devices. Preliminary capacity assessment was performed to calculate the average headway depending on the signalling system with reference to a case study.

High-Speed Railway

Union Internationale des Chemins (UIC) defines the high-speed railway (HSR) as a high-speed railway system that contains the infrastructure and the rolling stock. The infrastructure can be newly built dedicated lines enabled for trains to travel with speed above 250 km/h or upgraded conventional lines with a speed up to 200 or even 220 km/h. HSR requires specially built trains with increased power to weight ratio and must have an in-cab signalling system as traditional signalling systems are incapable of above 200 km/h.

Reliability and Inspection Modelling of Railway Signalling Systems

The railway is one of the most prominent models of transportation across the globe and it carries a large number of people, thus requiring high reliability, maintainability and safety. The reliability of railways mostly depends on an effective signalling system, making it one of the critical parts of railway operation. A signalling system is part of a large array of systems with interconnected components and subcomponents. Therefore, there is a need to make the signalling system more reliable and optimised with enhanced fault detection. Proper inspection and maintenance are required to make the signalling system reliable and safe. In this study, different inspection modelling techniques are applied to find the reliability of the signalling system. The signalling system has been divided into subsystems (signal unit, track unit, point-and-point machine) considering their importance and their effects on the failure rate of the entire signalling system. Inspection modelling of each subsystem has been conducted to provide the basis for the entire signalling system. A case study has been investigated to validate the model developed in one of the busiest tracks in eastern India. The obtained data thus are used to analyse the inspection pattern of signalling subsystems. Special attention to maintenance for inspection activities and logistics support has been taken into consideration, which is required to improve the reliability and maintainability of signalling subsystems and systems to make the railway signalling system sustainable in the long run.

Ubiquitylation of MLKL at lysine 219 positively regulates necroptosis-induced tissue injury and pathogen clearance

Necroptosis is a lytic, inflammatory form of cell death that not only contributes to pathogen clearance but can also lead to disease pathogenesis. Necroptosis is triggered by RIPK3-mediated phosphorylation of MLKL, which is thought to initiate MLKL oligomerisation, membrane translocation and membrane rupture, although the precise mechanism is incompletely understood. Here, we show that K63-linked ubiquitin chains are attached to MLKL during necroptosis and that ubiquitylation of MLKL at K219 significantly contributes to the cytotoxic potential of phosphorylated MLKL. The K219R MLKL mutation protects animals from necroptosis-induced skin damage and renders cells resistant to pathogen-induced necroptosis. Mechanistically, we show that ubiquitylation of MLKL at K219 is required for higher-order assembly of MLKL at membranes, facilitating its rupture and necroptosis. We demonstrate that K219 ubiquitylation licenses MLKL activity to induce lytic cell death, suggesting that necroptotic clearance of pathogens as well as MLKL-dependent pathologies are influenced by the ubiquitin-signalling system.

Influence of the Purinergic Signalling System on the Properties of Human Blood Cells at Ageing

Adenosine triphosphate (ATP) molecules and nucleotide derivatives contribute to a wide range of cellular reactions through the activation of A2 and P2 purinergic receptors located on the cell surface. Almost any type of cells expresses such receptors, including red blood cells and white blood cells. The study of purinergic transmission of signals mediating calcium mobilization, actin polymerization, chemotaxis, release of mediators, tissue oxygenation, cell maturation, cytotoxicity, cell death and cell–cell interactions in dynamics at different stages of ontogenesis is an important issue in biology and medicine today. This paper aimed to explore the biophysical properties of blood cells during the activation of the purinergic signalling system in middle-aged people and older adults. To activate the elements of the purinergic signalling system, an in vitro model of mechanical stress was used. Blood samples were analysed using the methods of atomic force microscopy, namely, force spectroscopy and the Kelvin probe. When the purinergic signalling system is activated, an increase in ATP blood concentration is identified in the blood of both middle-aged people and older adults. In the blood of older adults, a smaller amount of ATP was recorded compared with the blood of middle-aged people, which can be due to changes in the expression of purinoreceptors on the surface of red blood cells at ageing. Erythrocytes and granulocytes in older adults are characterized by increased surface stiffness and potential upon activation of the purinergic signalling system, compared with cells of middle-aged people. In response to mechanical stress, lymphocyte membrane stiffness in older adults increases more significantly than in middle-aged people. Thus, the results indicate an important role of the ATP molecule and its derivatives in the regulation of functioning of blood cells through binding to receptors of the P2 family. Research on the changes in the biophysical properties of red blood cells and white blood cells at activation of the purinergic signalling system will allow us to identify new effects of purine compounds on intercellular interaction during ageing.

Small Signals: Comprehending the Australian Microlithic as Public Signalling

Signalling is a critical capacity in modern human cultures but it has often been difficult to identify and understand on lithic artefacts from pre-literate contexts. Often archaeologists have minimized the signalling role of lithic tools by arguing for strong form-function relationships that constrained signalling or else imposed ethnographic information on the archaeological patterns with the assumption they assist in defining the signalling carried out in prehistory. In this paper I present a case study for which it can be shown that function does not correlate with form and that the technology fell out of use 1000–1500 years ago. This means that neither presumptions of continuity in social practice nor reference to tool use provide strong explanations for the size, shape standardization and regional differentiation of Australian microliths. Sender-receiver signalling theory is harnessed to motivate a new synthesis of these microliths, and I demonstrate that not only were these artefacts probably key objects used in public signalling but also that sender-receiver frameworks enable us to infer details about the operation of the signalling system.