Management and orchestration (MANO) of resources by virtual network functions (VNFs) represents one of the key challenges towards a fully virtualized network architecture as envisaged by 5G ...standards. Current threshold-based policies inefficiently over-provision network resources and under-utilize available hardware, incurring high cost for network operators, and consequently, the users. In this work, we present a MANO algorithm for VNFs allowing a central unit (CU) to learn to autonomously re-configure resources (processing power and storage), deploy new VNF instances, or offload them to the cloud, depending on the network conditions, available pool of resources, and the VNF requirements, with the goal of minimizing a cost function that takes into account the economical cost as well as latency and the quality-of-service (QoS) experienced by the users. First, we formulate the stochastic resource optimization problem as a parameterized action Markov decision process (PAMDP). Then, we propose a solution based on deep reinforcement learning (DRL). More precisely, we present a novel RL approach, called parameterized action twin (PAT) deterministic policy gradient, which leverages an actor-critic architecture to learn to provision resources to the VNFs in an online manner. Finally, we present numerical performance results, and map them to 5G key performance indicators (KPIs). To the best of our knowledge, this is the first work that considers DRL for MANO of VNFs' physical resources.
Today's mobile data traffic is dominated by content-oriented traffic. Caching popular contents at the network edge can alleviate network congestion and reduce content delivery latency. This paper ...provides a comprehensive and unified study of caching and delivery techniques in wireless radio access networks (RANs) with caches at all edge nodes (ENs) and user equipments (UEs). Three cache-aided RAN architectures are considered: RANs without fronthaul, with dedicated fronthaul, and with wireless fronthaul. It first reviews in a tutorial nature how caching facilitates interference management in these networks by enabling interference cancelation (IC), zero-forcing (ZF), and interference alignment (IA). Then, two new delivery schemes are presented. One is for RANs with dedicated fronthaul, which considers centralized cache placement at the ENs but both centralized and decentralized placement at the UEs. This scheme combines IA, ZF, and IC together with soft-transfer fronthauling. The other is for RANs with wireless fronthaul, which considers decentralized cache placement at all nodes. It leverages the broadcast nature of wireless fronthaul to fetch not only uncached but also cached contents to boost transmission cooperation among the ENs. The numerical results show that both schemes outperform existing results for a wide range of system parameters, thanks to the various caching gains obtained opportunistically.
The function of microtubules depends on their arrangement into highly ordered arrays. Spatio-temporal control over the formation of new microtubules and regulation of their properties are central to ...the organization of these arrays. The nucleation of new microtubules requires γ-tubulin, an essential protein that assembles into multi-subunit complexes and is found in all eukaryotic organisms. However, the way in which γ-tubulin complexes are regulated and how this affects nucleation and, potentially, microtubule behavior, is poorly understood. γ-tubulin has been found in complexes of various sizes but several lines of evidence suggest that only large, ring-shaped complexes function as efficient microtubule nucleators. Human γ-tubulin ring complexes (γTuRCs) are composed of γ-tubulin and the γ-tubulin complex components (GCPs) 2, 3, 4, 5 and 6, which are members of a conserved protein family. Recent work has identified additional unrelated γTuRC subunits, as well as a large number of more transient γTuRC interactors. In this Commentary, we discuss the regulation of γTuRC-dependent microtubule nucleation as a key mechanism of microtubule organization. Specifically, we focus on the regulatory roles of the γTuRC subunits and interactors and present an overview of other mechanisms that regulate γTuRC-dependent microtubule nucleation and organization.
A K T × K R cache-aided wireless interference network, in which both the transmitters and the receivers are equipped with cache memories is studied. Each user requests one file from a library of N ...popular files. The goal is to design the cache contents without the knowledge of the particular user demands, such that all possible demand combinations can be satisfied reliably over the interference channel. The achievable sum degrees-of-freedom (sDoF) and the normalized delivery time (NDT) are studied for centralized and decentralized network architectures, respectively. First, using a combination of interference alignment (IA), zero-forcing (ZF) and interference cancellation (IC) techniques, a novel caching and transmission scheme for centralized networks is introduced, and it is shown to improve the sDoF upon the state-of-the-art. Then, the NDT is studied when the content placement at the receiver caches is carried out in a decentralized manner. Our results indicate that, for this particular network architecture, caches located at the receiver side are more effective than those at the transmitter side in order to reduce the NDT.
We propose a novel formulation of the "effectiveness problem" in communications, put forth by Shannon and Weaver in their seminal work " The Mathematical Theory of Communication ", by considering ...multiple agents communicating over a noisy channel in order to achieve better coordination and cooperation in a multi-agent reinforcement learning (MARL) framework. Specifically, we consider a multi-agent partially observable Markov decision process (MA-POMDP), in which the agents, in addition to interacting with the environment, can also communicate with each other over a noisy communication channel. The noisy communication channel is considered explicitly as part of the dynamics of the environment, and the message each agent sends is part of the action that the agent can take. As a result, the agents learn not only to collaborate with each other but also to communicate "effectively" over a noisy channel. This framework generalizes both the traditional communication problem, where the main goal is to convey a message reliably over a noisy channel, and the "learning to communicate" framework that has received recent attention in the MARL literature, where the underlying communication channels are assumed to be error-free. We show via examples that the joint policy learned using the proposed framework is superior to that where the communication is considered separately from the underlying MA-POMDP. This is a very powerful framework, which has many real world applications, from autonomous vehicle planning to drone swarm control, and opens up the rich toolbox of deep reinforcement learning for the design of multi-user communication systems.
Mitotic Regulation by NEK Kinase Networks Fry, Andrew M; Bayliss, Richard; Roig, Joan
Frontiers in cell and developmental biology,
12/2017, Letnik:
5
Journal Article
Recenzirano
Odprti dostop
Genetic studies in yeast and
led to identification of cyclin-dependent kinases (CDKs), Polo-like kinases (PLKs) and Aurora kinases as essential regulators of mitosis. These enzymes have since been ...found in the majority of eukaryotes and their cell cycle-related functions characterized in great detail. However, genetic studies in another fungal species,
, identified a distinct family of protein kinases, the NEKs, that are also widely conserved and have key roles in the cell cycle, but which remain less well studied. Nevertheless, it is now clear that multiple NEK family members act in networks to regulate specific events of mitosis, including centrosome separation, spindle assembly and cytokinesis. Here, we describe our current understanding of how the NEK kinases contribute to these processes, particularly through targeted phosphorylation of proteins associated with the microtubule cytoskeleton. We also present the latest findings on molecular events that control the activation state of the NEKs and how these are revealing novel modes of enzymatic regulation relevant not only to other kinases but also to pathological mechanisms of disease.
To identify in vitro inhibitors of xanthine crystallization that have potential for inhibiting the formation of xanthine crystals in urine and preventing the development of the renal calculi in ...patients with xanthinuria.
The formation of xanthine crystals in synthetic urine and the effects of 10 potential crystallization inhibitors were assessed using a kinetic turbidimetric system with a photometer. The maximum concentration tested for each compound was: 20 mg/L for 3-methylxanthine (3-MX); 40 mg/L for 7-methylxanthine (7-MX), 1-methylxanthine (1-MX), theobromine (TB), theophylline, paraxanthine, and caffeine; 45 mg/L for 1-methyluric acid; 80 mg/L for 1,3-dimethyluric acid; and 200 mg/L for hypoxanthine. Scanning electron microscopy was used to examine the morphology of the crystals formed when inhibitory effects were observed.
Only 7-MX, 3-MX, and 1-MX significantly inhibited xanthine crystallization at the tested concentrations. Mixtures of inhibitors had an additive effect rather than a synergistic effect on crystallization.
Two of the inhibitors identified here-7-MX and 3-MX-are major metabolites of TB. In particular, after TB consumption, 20% is excreted in the urine as TB, 21.5% as 3-MX, and 36% as 7-MX. Thus, consumption of theobromine could protect patients with xanthinuria from the development of renal xanthine calculi. Clinical trials are necessary to demonstrate these effects in vivo.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Centrosomes 1, 2 play a central role during spindle assembly in most animal cells 3. In early mitosis, they organize two symmetrical microtubule arrays that upon separation define the two poles of ...the forming spindle. Centrosome separation is tightly regulated 4, 5, occurring through partially redundant mechanisms that rely on the action of microtubule-based dynein and kinesin motors and the actomyosin system 6. While centrosomes can separate in prophase or in prometaphase after nuclear envelope breakdown (NEBD), prophase centrosome separation optimizes spindle assembly and minimizes the occurrence of abnormal chromosome attachments that could end in aneuploidy 7, 8. Prophase centrosome separation relies on the activity of Eg5/KIF11, a mitotic kinesin 9 that accumulates around centrosomes in early mitosis under the control of CDK1 and the Nek9/Nek6/7 kinase module 10–17. Here, we show that Eg5 localization and centrosome separation in prophase depend on the nuclear microtubule-associated protein TPX2 18, a pool of which localizes to the centrosomes before NEBD. This localization involves RHAMM/HMMR 19 and the kinase Nek9 20, which phosphorylates TPX2 nuclear localization signal (NLS) preventing its interaction with importin and nuclear import. The pool of centrosomal TPX2 in prophase has a critical role for both microtubule aster organization and Eg5 localization, and thereby for centrosome separation. Our results uncover an unsuspected role for TPX2 before NEBD and define a novel regulatory mechanism for centrosome separation in prophase. They furthermore suggest NLS phosphorylation as a novel regulatory mechanism for spindle assembly factors controlled by the importin/Ran system.
Display omitted
•Eg5 localization and centrosome separation in prophase depend on TPX2•Eg5Ser1033 phosphorylation downstream of Nek9 controls Eg5 binding to TPX2•TPX2 localizes to the centrosomes before NEBD in a RHAMM- and Nek9-dependent manner•Nek9 phosphorylation of TPX2 NLS prevents importin interaction and nuclear import
Eibes et al. find that Eg5 localization and centrosome separation in prophase depend on TPX2. Nek9 controls Eg5 binding to TPX2 and, through phosphorylation of its NLS, TPX2 centrosomal localization. NLS phosphorylation is suggested to be a novel regulatory mechanism for spindle assembly factors controlled by the importin/Ran system.
The activity of dynein is regulated by a number of adaptors that mediate its interaction with dynactin, effectively activating the motor complex while also connecting it to different cargos. The ...regulation of adaptors is consequently central to dynein physiology but remains largely unexplored. We now describe that one of the best-known dynein adaptors, BICD2, is effectively activated through phosphorylation. In G2, phosphorylation of BICD2 by CDK1 promotes its interaction with PLK1. In turn, PLK1 phosphorylation of a single residue in the N-terminus of BICD2 results in a structural change that facilitates the interaction with dynein and dynactin, allowing the formation of active motor complexes. Moreover, modified BICD2 preferentially interacts with the nucleoporin RanBP2 once RanBP2 has been phosphorylated by CDK1. BICD2 phosphorylation is central for dynein recruitment to the nuclear envelope, centrosome tethering to the nucleus and centrosome separation in the G2 and M phases of the cell cycle. This work reveals adaptor activation through phosphorylation as crucial for the spatiotemporal regulation of dynein activity.
Organization of microtubules into ordered arrays is best understood in mitotic systems, but remains poorly characterized in postmitotic cells such as neurons. By analyzing the cycling cell ...microtubule cytoskeleton proteome through expression profiling and targeted RNAi screening for candidates with roles in neurons, we have identified the mitotic kinase NEK7. We show that NEK7 regulates dendrite morphogenesis in vitro and in vivo. NEK7 kinase activity is required for dendrite growth and branching, as well as spine formation and morphology. NEK7 regulates these processes in part through phosphorylation of the kinesin Eg5/KIF11, promoting its accumulation on microtubules in distal dendrites. Here, Eg5 limits retrograde microtubule polymerization, which is inhibitory to dendrite growth and branching. Eg5 exerts this effect through microtubule stabilization, independent of its motor activity. This work establishes NEK7 as a general regulator of the microtubule cytoskeleton, controlling essential processes in both mitotic cells and postmitotic neurons.
PDF
