On signalling over through-silicon via (TSV) interconnects in 3-D integrated circuits.

This paper discusses signal integrity (SI) issues and signalling techniques for Through Silicon Via (TSV) interconnects in 3-D Integrated Circuits (ICs). Field-solver extracted parasitics of TSVs have been employed in Spice simulations to investigate the effect of each parasitic component on performance metrics such as delay and crosstalk and identify a reduced-order electrical model that captures all relevant effects. We show that in dense TSV structures voltage-mode (VM) signalling does not lend itself to achieving high data-rates, and that current-mode (CM) signalling is more effective for high throughput signalling as well as jitter reduction. Data rates, energy consumption and coupled noise for the different signalling modes are extracted

FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours

A methodological approach to BISDN signalling performance

Sophisticated signalling protocols are required to properly handle the complex multimedia, multiparty services supported by the forthcoming BISDN. The implementation feasibility of these protocols should be evaluated during their design phase, so that possible performance bottlenecks are identified and removed. In this paper we present a methodology for evaluating the performance of BISDN signalling systems under design. New performance parameters are introduced and their network-dependent values are extracted through a message flow model which has the capability to describe the impact of call and bearer control separation on the signalling performance. Signalling protocols are modelled through a modular decomposition of the seven OSI layers including the service user to three submodels. The workload model is user descriptive in the sense that it does not approximate the direct input traffic required for evaluating the performance of a layer protocol; instead, through a multi-level approach, it describes the actual implications of user signalling activity for the general signalling traffic. The signalling protocol model is derived from the global functional model of the signalling protocols and information flows using a network of queues incorporating synchronization and dependency functions. The same queueing approach is followed for the signalling transfer network which is used to define processing speed and signalling bandwidth requirements and to identify possible performance bottlenecks stemming from the realization of the related protocols

An evolutionary advantage for extravagant honesty

A game-theoretic model of handicap signalling over a pair of signalling channels is introduced in order to determine when one channel has an evolutionary advantage over the other. The stability conditions for honest handicap signalling are presented for a single channel and are shown to conform with the results of prior handicap signalling models. Evolutionary simulations are then used to show that, for a two-channel system in which honest signalling is possible on both channels, the channel featuring larger advertisements at equilibrium is favoured by evolution. This result helps to address a significant tension in the handicap principle literature. While the original theory was motivated by the prevalence of extravagant natural signalling, contemporary models have demonstrated that it is the cost associated with deception that stabilises honesty, and that the honest signals exhibited at equilibrium need not be extravagant at all. The current model suggests that while extravagant and wasteful signals are not required to ensure a signalling system's evolutionary stability, extravagant signalling systems may enjoy an advantage in terms of evolutionary attainability

Mobility Prediction for Handover Management in Cellular Networks with Control/Data Separation

In research community, a new radio access network architecture with a logical separation between control plane (CP) and data plane (DP) has been proposed for future cellular systems. It aims to overcome limitations of the conventional architecture by providing high data rate services under the umbrella of a coverage layer in a dual connection mode. This configuration could provide significant savings in signalling overhead. In particular, mobility robustness with minimal handover (HO) signalling is considered as one of the most promising benefits of this architecture. However, the DP mobility remains an issue that needs to be investigated. We consider predictive DP HO management as a solution that could minimise the out-of-band signalling related to the HO procedure. Thus we propose a mobility prediction scheme based on Markov Chains. The developed model predicts the user's trajectory in terms of a HO sequence in order to minimise the interruption time and the associated signalling when the HO is triggered. Depending on the prediction accuracy, numerical results show that the predictive HO management strategy could significantly reduce the signalling cost as compared with the conventional non-predictive mechanism

Oncogenic K-Ras suppresses IP₃-dependent Ca²⁺ release through remodeling of IP₃Rs isoform composition and ER luminal Ca²⁺ levels in colorectal cancer cell lines

The GTPase Ras is a molecular switch engaged downstream of G-protein coupled receptors and receptor tyrosine inases that controls multiple cell fate-determining signalling athways. Ras signalling is frequently deregulated in cancer underlying associated changes in cell phenotype. Although Ca2+ signalling pathways control some overlapping functions with Ras, and altered Ca2+ signalling pathways are emerging as important players in oncogenic transformation, how Ca2+ signalling is remodelled during transformation and whether it has a causal role remains unclear. We have investigated Ca2+ signalling in two human colorectal cancer cell lines and their isogenic derivatives in which the mutated K-Ras allele (G13D) has been deleted by homologous recombination. We show that agonist-induced Ca2+ release from intracellular stores is enhanced by loss of K-RasG13D through an increase in the ER store content and a modification of IP3R subtype abundance. Consistently, uptake of Ca2+ into mitochondria and sensitivity to apoptosis was enhanced as a result of KRasG13D loss. These results suggest that suppression of Ca2+ signalling is a common response to naturally occurring levels of K-RasG13D that contributes to a survival advantage during oncogenic transformation

Ubiquitylation in immune disorders and cancer: from molecular mechanisms to therapeutic implications

Conjugation of ubiquitin to proteins (ubiquitylation) has emerged to be one of the most crucial post-translational modifications controlling virtually all cellular processes. What was once regarded as a mere signal for protein degradation has turned out to be a major regulator of molecular signalling networks. Deregulation of ubiquitin signalling is closely associated with various human pathologies. Here, we summarize the current knowledge of ubiquitin signalling in immune deficiencies and cancer as well as the available therapeutic strategies targeting the ubiquitin system in combating these pathogenic conditions

Phosphoproteomics identifies a bimodal EPHA2 receptor switch that promotes embryonic stem cell differentiation

Embryonic Stem Cell (ESC) differentiation requires complex cell signalling network dynamics, although the key molecular events remain poorly understood. Here, we use phosphoproteomics to identify an FGF4-mediated phosphorylation switch centred upon the key Ephrin receptor EPHA2 in differentiating ESCs. We show that EPHA2 maintains pluripotency and restrains commitment by antagonising ERK1/2 signalling. Upon ESC differentiation, FGF4 utilises a bimodal strategy to disable EPHA2, which is accompanied by transcriptional induction of EFN ligands. Mechanistically, FGF4-ERK1/2-RSK signalling inhibits EPHA2 via Ser/Thr phosphorylation, whilst FGF4-ERK1/2 disrupts a core pluripotency transcriptional circuit required for Epha2 gene expression. This system also operates in mouse and human embryos, where EPHA receptors are enriched in pluripotent cells whilst surrounding lineage-specified trophectoderm expresses EFNA ligands. Our data provide insight into function and regulation of EPH-EFN signalling in ESCs, and suggest that segregated EPH-EFN expression coordinates cell fate with compartmentalisation during early embryonic development

Intra-tumour signalling entropy determines clinical outcome in breast and lung cancer.

The cancer stem cell hypothesis, that a small population of tumour cells are responsible for tumorigenesis and cancer progression, is becoming widely accepted and recent evidence has suggested a prognostic and predictive role for such cells. Intra-tumour heterogeneity, the diversity of the cancer cell population within the tumour of an individual patient, is related to cancer stem cells and is also considered a potential prognostic indicator in oncology. The measurement of cancer stem cell abundance and intra-tumour heterogeneity in a clinically relevant manner however, currently presents a challenge. Here we propose signalling entropy, a measure of signalling pathway promiscuity derived from a sample's genome-wide gene expression profile, as an estimate of the stemness of a tumour sample. By considering over 500 mixtures of diverse cellular expression profiles, we reveal that signalling entropy also associates with intra-tumour heterogeneity. By analysing 3668 breast cancer and 1692 lung adenocarcinoma samples, we further demonstrate that signalling entropy correlates negatively with survival, outperforming leading clinical gene expression based prognostic tools. Signalling entropy is found to be a general prognostic measure, valid in different breast cancer clinical subgroups, as well as within stage I lung adenocarcinoma. We find that its prognostic power is driven by genes involved in cancer stem cells and treatment resistance. In summary, by approximating both stemness and intra-tumour heterogeneity, signalling entropy provides a powerful prognostic measure across different epithelial cancers