Growth factor, energy and nutrient sensing signalling pathways in metabolic ageing

The field of the biology of ageing has received increasing attention from a biomedical point of view over the past decades. The main reason has been the realisation that increases in human population life expectancy are accompanied by late onset diseases. Indeed, ageing is the most important risk factor for a number of neoplastic, neurodegenerative and metabolic pathologies. Advances in the knowledge of the genetics of ageing, mainly through research in model organisms, have implicated various cellular processes and the respective signalling pathways that regulate them in cellular and organismal ageing. Associated with ageing is a dysregulation of metabolic homeostasis usually manifested as age-related obesity, diminished insulin sensitivity and impaired glucose and lipid homeostasis. Metabolic deterioration contributes to the ageing phenotype and metabolic pathologies are thought to be one of the main factors limiting the potential for lifespan extension. Great efforts have been directed towards identifying pharmacological interventions with the potential to improve healthspan and a number of natural and synthetic compounds have shown promise in achieving beneficial metabolic effects

ASPIS: A Holistic and Practical Mechanism for Efficient MTC Support over Mobile Networks

Machine Type Communications (MTC) collectively refers to the exchange of data among devices that operate without human intervention. A significant number of such devices are currently served by cellular networks, and that number is expected to grow in the near future. However, cellular networks, including current fourth generation LTE networks, face several challenges when it comes to handling MTC traffic as they were primarily designed for Human Type Communications (HTC) which have very different traffic patterns. In this paper we focus on periodic MTC devices, such as sensors and meters, which cause significant signaling load and increased collisions over standard LTE networks. We propose ASPIS, a holistic mechanism designed to overcome these problems. ASPIS reduces the signaling load by partly preserving a device’s connection to the network in conjunction with a new Random Access process and efficient support for short message transmissions. In addition, it uses a proactive preamble split scheme to alleviate collisions. ASPIS is easy to implement without requiring hardware changes while at the same time maintains security and can be incrementally deployed alongside legacy devices/infrastructure. We showcase the practicality of ASPIS by implementing it on the OpenAirInterface platform. Further, we demonstrate its effectiveness through extensive evaluations via a combination of small-scale experimental evaluation and large-scale, realistic simulations

Short-Range Cooperation of Mobile Devices for Energy-Efficient Vertical Handovers

The availability of multiple collocated wireless networks using heterogeneous technologies and the multiaccess support of contemporary mobile devices have allowed wireless connectivity optimization, enabled through vertical handover (VHO) operations. However, this comes at high energy consumption on the mobile device due to the inherently expensive nature of some of the involved operations. This work proposes exploiting short-range cooperation among collocated mobile devices to improve the energy efficiency of vertical handover operations. The proactive exchange of handover-related information through low-energy short-range communication technologies, like Bluetooth, can help in eliminating expensive signaling steps when the need for a VHO arises. A model is developed for capturing the mean energy expenditure of such an optimized VHO scheme in terms of relevant factors by means of closed-form expressions. The descriptive power of the model is demonstrated by investigating various typical usage scenarios and is validated through simulations. It is shown that the proposed scheme has superior performance in several realistic usage scenarios considering important relevant factors, including network availability, the local density of mobile devices, and the range of the cooperation technology. Finally, the paper explores cost/benefit trade-offs associated with the short-range cooperation protocol. It is demonstrated that the protocol may be parametrized so that the trade-off becomes nearly optimized and the cost is maintained affordable for a wide range of operational scenarios

Caffeine Inhibits EGF-Stimulated Trophoblast Cell Motility through the Inhibition of mTORC2 and Akt.

Impaired trophoblast invasion is associated with pregnancy disorders such as early pregnancy loss and preeclampsia. There is evidence to suggest that the consumption of caffeine during pregnancy may increase the risk of pregnancy loss; however, little is known about the direct effect of caffeine on normal trophoblast biology. Our objectives were to examine the effect of caffeine on trophoblast migration and motility after stimulation with epidermal growth factor (EGF) and to investigate the intracellular signaling pathways involved in this process. Primary first-trimester extravillous trophoblasts (EVT) and the EVT-derived cell line SGHPL-4 were used to study the effect of caffeine on EGF-stimulated cellular motility using time-lapse microscopy. SGHPL-4 cells were further used to study the effect of caffeine and cAMP on EGF-stimulated invasion of fibrin gels. The influence of caffeine and cAMP on EGF-stimulated intracellular signaling pathways leading to the activation of Akt were investigated by Western blot analysis. Caffeine inhibits both EGF-stimulated primary EVT and SGHPL-4 cell motility. EGF stimulation activates phosphatidylinositol 3-kinase, and Akt and caffeine inhibit this activation. Although cAMP inhibits both motility and invasion, it does not inhibit the activation of Akt, indicating that the effects of caffeine seen in this study are independent of cAMP. Further investigation indicated a role for mammalian target of rapamycin complex 2 (mTORC2) as a target for the inhibitory effect of caffeine. In conclusion, we demonstrate that caffeine inhibits EGF-stimulated trophoblast invasion and motility in vitro and so could adversely influence trophoblast biology in vivo

Protein kinase activity of phosphoinositide 3-kinase regulates cytokine-dependent cell survival

Extent: 14 p.The dual specificity protein/lipid kinase, phosphoinositide 3-kinase (PI3K), promotes growth factor-mediated cell survival and is frequently deregulated in cancer. However, in contrast to canonical lipid-kinase functions, the role of PI3K protein kinase activity in regulating cell survival is unknown. We have employed a novel approach to purify and pharmacologically profile protein kinases from primary human acute myeloid leukemia (AML) cells that phosphorylate serine residues in the cytoplasmic portion of cytokine receptors to promote hemopoietic cell survival. We have isolated a kinase activity that is able to directly phosphorylate Ser585 in the cytoplasmic domain of the interleukin 3 (IL-3) and granulocyte macrophage colony stimulating factor (GM-CSF) receptors and shown it to be PI3K. Physiological concentrations of cytokine in the picomolar range were sufficient for activating the protein kinase activity of PI3K leading to Ser585 phosphorylation and hemopoietic cell survival but did not activate PI3K lipid kinase signaling or promote proliferation. Blockade of PI3K lipid signaling by expression of the pleckstrin homology of Akt1 had no significant impact on the ability of picomolar concentrations of cytokine to promote hemopoietic cell survival. Furthermore, inducible expression of a mutant form of PI3K that is defective in lipid kinase activity but retains protein kinase activity was able to promote Ser585 phosphorylation and hemopoietic cell survival in the absence of cytokine. Blockade of p110α by RNA interference or multiple independent PI3K inhibitors not only blocked Ser585 phosphorylation in cytokine-dependent cells and primary human AML blasts, but also resulted in a block in survival signaling and cell death. Our findings demonstrate a new role for the protein kinase activity of PI3K in phosphorylating the cytoplasmic tail of the GM-CSF and IL-3 receptors to selectively regulate cell survival highlighting the importance of targeting such pathways in cancer.Daniel Thomas, Jason A. Powell, Benjamin D. Green, Emma F. Barry, Yuefang Ma, Joanna Woodcock, Stephen Fitter, Andrew C.W. Zannettino, Stuart M. Pitson, Timothy P. Hughes, Angel F. Lopez, Peter R. Shepherd, Andrew H. Wei, Paul G. Ekert and Mark A. Guthridg

Towards a programmable and virtualized mobile radio access network architecture

Emerging 5G mobile networks are envisioned to become multi-service environments, enabling the dynamic deployment of services with a diverse set of performance requirements, accommodating the needs of mobile network operators, verticals and over-the-top service providers. The Radio Access Network (RAN) part of mobile networks is expected to play a very significant role towards this evolution. Unfortunately, such a vision cannot be efficiently supported by the conventional RAN architecture, which adopts a fixed and rigid design. For the network to evolve, flexibility in the creation, management and control of the RAN components is of paramount importance. The key elements that can allow us to attain this flexibility are the programmability and the virtualization of the network functions. While in the case of the mobile core, these issues have been extensively studied due to the advent of technologies like Software-Defined Networking (SDN) and Network Functions Virtualization (NFV) and the similarities that the core shares with other wired networks like data centers, research in the domain of the RAN is still in its infancy. The contributions made in this thesis significantly advance the state of the art in the domain of RAN programmability and virtualization in three dimensions. First, we design and implement a software-defined RAN (SD-RAN) platform called FlexRAN, that provides a flexible control plane designed with support for real-time RAN control applications, flexibility to realize various degrees of coordination among RAN infrastructure entities, and programmability to adapt control over time and easier evolution to the future following SDN/NFV principles. Second, we leverage the capabilities of the FlexRAN platform to design and implement Orion, which is a novel RAN slicing system that enables the dynamic on-the-fly virtualization of base stations, the flexible customization of slices to meet their respective service needs and which can be used in an end-to-end network slicing setting. Third, we focus on the use case of multi-tenancy in a neutral-host indoors small-cell environment, where we design Iris, a system that builds on the capabilities of FlexRAN and Orion and introduces a dynamic pricing mechanism for the efficient and flexible allocation of shared spectrum to the tenants. A number of additional use cases that highlight the benefits of the developed systems are also presented. The lessons learned through this research are summarized and a discussion is made on interesting topics for future work in this domain. The prototype systems presented in this thesis have been made publicly available and are being used by various research groups worldwide in the context of 5G research

Iris: Deep Reinforcement Learning Driven Shared Spectrum Access Architecture for Indoor Neutral-Host Small Cells

We consider indoor mobile access, a vital use case for current and future mobile networks. For this key use case, we outline a vision that combines a neutral-host based shared small-cell infrastructure with a common pool of spectrum for dynamic sharing as a way forward to proliferate indoor small-cell deployments and open up the mobile operator ecosystem. Towards this vision, we focus on the challenges pertaining to managing access to shared spectrum (e.g., 3.5GHz US CBRS spectrum). We propose Iris, a practical shared spectrum access architecture for indoor neutral-host small-cells. At the core of Iris is a deep reinforcement learning based dynamic pricing mechanism that efficiently mediates access to shared spectrum for diverse operators in a way that provides incentives for operators and the neutral-host alike. We then present the Iris system architecture that embeds this dynamic pricing mechanism alongside cloud-RAN and RAN slicing design principles in a practical neutral-host design tailored for the indoor small-cell environment. Using a prototype implementation of the Iris system, we present extensive experimental evaluation results that not only offer insight into the Iris dynamic pricing process and its superiority over alternative approaches but also demonstrate its deployment feasibility

Recent advances upper gastrointestinal lymphomas: molecular updates and diagnostic implications.

Approximately one-third of extranodal non-Hodgkin lymphomas involve the gastrointestinal (GI) tract, with the vast majority being diagnosed in the stomach, duodenum, or proximal small intestine. A few entities, especially diffuse large B-cell lymphoma and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, represent the majority of cases. In addition, there are diseases specific to or characteristic of the GI tract, and any type of systemic lymphoma can present in or disseminate to these organs. The recent advances in the genetic and molecular characterisation of lymphoid neoplasms have translated into notable changes in the classification of primary GI T-cell neoplasms and the recommended diagnostic approach to aggressive B-cell tumours. In many instances, diagnoses rely on morphology and immunophenotype, but there is an increasing need to incorporate molecular genetic markers. Moreover, it is also important to take into consideration the endoscopic and clinical presentations. This review gives an update on the most recent developments in the pathology and molecular pathology of upper GI lymphoproliferative diseases