The nuclear receptor sub-family 4 group A (NR4A) family are early response genes that encode proteins that are activated in several tissues/cells in response to a variety of stressors. The NR4A family comprises NR4A1, NR4A2 and NR4A3 of which NR4A2 and NR4A3 are under researched and less understood, particularly in the context of immune cells. NR4A expression is associated with multiple diseases e.g. arthritis and atherosclerosis and the development of NR4A-targetting molecules as therapeutics is a current focus in this research field. Here, we use a combination of RNA-sequencing coupled with strategic bioinformatic analysis to investigate the down-stream effects of NR4A2 and NR4A3 in monocytes and dissect their common and distinct signalling roles. Our data reveals that NR4A2 and NR4A3 depletion has a robust and broad-reaching effect on transcription in both the unstimulated state and in the presence of LPS. Interestingly, many of the genes affected were present in both the unstimulated and stimulated states revealing a previously unappreciated role for the NR4As in unstimulated cells. Strategic clustering and bioinformatic analysis identified both distinct and common transcriptional roles for NR4A2 and NR4A3 in monocytes. NR4A2 notably was linked by both bioinformatic clustering analysis and transcription factor interactome analysis to pathways associated with antigen presentation and regulation of MHC genes. NR4A3 in contrast was more closely linked to pathways associated with viral response. Functional studies further support our data analysis pointing towards preferential/selective roles for NR4A2 in the regulation of antigen processing with common roles for NR4A2 and NR4A3 evident with respect to cell migration. Taken together this study provides novel mechanistic insights into the role of the enigmatic nuclear receptors NR4A2 and NR4A3 in monocytes.

Carbon dioxide (CO 2 ) is a fundamental physiological gas known to profoundly influence the behaviour and health of millions of species within the plant and animal kingdoms in particular. A recent Royal Society meeting on the topic of ‘Carbon dioxide detection in biological systems' was extremely revealing in terms of the multitude of roles that different levels of CO 2 play in influencing plants and animals alike. While outstanding research has been performed by leading researchers in the area of plant biology, neuronal sensing, cell signalling, gas transport, inflammation, lung function and clinical medicine, there is still much to be learned about CO 2 -dependent sensing and signalling. Notably, while several key signal transduction pathways and nodes of activity have been identified in plants and animals respectively, the precise wiring and sensitivity of these pathways to CO 2 remains to be fully elucidated. In this article, we will give an overview of the literature relating to CO 2 -dependent signal transduction in mammalian systems. We will highlight the main signal transduction hubs through which CO 2 -dependent signalling is elicited with a view to better understanding the complex physiological response to CO 2 in mammalian systems. The main topics of discussion in this article relate to how changes in CO 2 influence cellular function through modulation of signal transduction networks influenced by pH, mitochondrial function, adenylate cyclase, calcium, transcriptional regulators, the adenosine monophosphate-activated protein kinase pathway and direct CO 2 -dependent protein modifications. While each of these topics will be discussed independently, there is evidence of significant cross-talk between these signal transduction pathways as they respond to changes in CO 2 . In considering these core hubs of CO 2 -dependent signal transduction, we hope to delineate common elements and identify areas in which future research could be best directed.

Publication informationInformation System Frontiers, 11 (1) IrelandMobile computing is undoubtedly one of the predominant computer usage paradigms in operation today.The implications of what might be cautiously termed a usage paradigm shift have still not crystallised fully, either for society, or those envisaging a new raft of applications and services for mobile users. However, fundamental to the current and future success of mobile computing are mobile telecommunications networks. Such networks have been a success story in their own right in recent years, both as traditional voice carriers and, increasingly importantly, as a conduit of mobile data. The potential for new mobile data applications is immense, but, crucially, this potential is severely compromised by two factors inherent in mobile computing: limited bandwidth and computationally restricted devices. Hence, the academic and commercial interest in harnessing intelligent techniques as a means of mitigating these concerns, and ensuring the user experience is a satisfactory one. In this paper, the broad area of intelligence in telecommunications networks is examined, and issues relating to the deployment of intelligent technologies are explored. In particular, the potential of intelligent agents is identified as a viable mechanism for realising a full end-to-end deployment of intelligence throughout the network, including possibly the most crucial component: the end user's device. As an illustration of the viability of this approach, a brief description of a mobile blogging application is presented.

CO 2 , the primary gaseous product of respiration, is a major physiologic gas, the biology of which is poorly understood. Elevated CO 2 is a feature of the microenvironment in multiple inflammatory diseases that suppresses immune cell activity. However, little is known about the CO 2 -sensing mechanisms and downstream pathways involved. We found that elevated CO 2 correlates with reduced monocyte and macrophage migration in patients undergoing gastrointestinal surgery and that elevated CO 2 reduces migration in vitro. Mechanistically, CO 2 reduces autocrine inflammatory gene expression, thereby inhibiting macrophage activation in a manner dependent on decreased intracellular pH. Pharmacologic or genetic inhibition of carbonic anhydrases (CAs) uncouples a CO 2 -elicited intracellular pH response and attenuates CO 2 sensitivity in immune cells. Conversely, CRISPRdriven upregulation of the isoenzyme CA2 confers CO 2 sensitivity in nonimmune cells. Of interest, we found that patients with chronic lung diseases associated with elevated systemic CO 2 (hypercapnia) display a greater risk of developing anastomotic leakage following gastrointestinal surgery, indicating impaired wound healing. Furthermore, low intraoperative pH levels in these patients correlate with reduced intestinal macrophage infiltration. In conclusion, CO 2 is an immunomodulatory gas sensed by immune cells through a CA2-coupled change in intracellular pH.

CO2 is produced during aerobic respiration. Normally, levels of CO2 in the blood are tightly regulated but pCO2 can rise (hypercapnia, pCO2 > 45 mmHg) in patients with lung diseases, for example, chronic obstructive pulmonary disease (COPD). Hypercapnia is a risk factor in COPD but may be of benefit in the context of destructive inflammation. The effects of CO2 per se, on transcription, independent of pH change are poorly understood and warrant further investigation. Here we elucidate the influence of hypercapnia on monocytes and macrophages through integration of state‐of‐the‐art RNA‐sequencing, metabolic and metabolomic approaches. THP‐1 monocytes and interleukin 4–polarized primary murine macrophages were exposed to 5% CO2 versus 10% CO2 for up to 24 h in pH‐buffered conditions. In hypercapnia, we identified around 370 differentially expressed genes (DEGs) under basal and about 1889 DEGs under lipopolysaccharide‐stimulated conditions in monocytes. Transcripts relating to both mitochondrial and nuclear‐encoded gene expression were enhanced in hypercapnia in basal and lipopolysaccharide‐stimulated cells. Mitochondrial DNA content was not enhanced, but acylcarnitine species and genes associated with fatty acid metabolism were increased in hypercapnia. Primary macrophages exposed to hypercapnia also increased activation of genes associated with fatty acid metabolism and reduced activation of genes associated with glycolysis. Thus, hypercapnia elicits metabolic shifts in lipid metabolism in monocytes and macrophages under pH‐buffered conditions. These data indicate that CO2 is an important modulator of monocyte transcription that can influence immunometabolic signaling in immune cells in hypercapnia. These immunometabolic insights may be of benefit in the treatment of patients experiencing hypercapnia.