A critical look at power law modelling of the Internet

This paper takes a critical look at the usefulness of power law models of the Internet. The twin focuses of the paper are Internet traffic and topology generation. The aim of the paper is twofold. Firstly it summarises the state of the art in power law modelling particularly giving attention to existing open research questions. Secondly it provides insight into the failings of such models and where progress needs to be made for power law research to feed through to actual improvements in network performance.Comment: To appear Computer Communication

Robust Parameter Estimation for Hybrid Dynamical Systems

We consider the problem of estimating a vector of unknown constant parameters for a class of hybrid dynamical systems -- that is, systems whose state variables exhibit both continuous (flow) and discrete (jump) evolution. Using a hybrid systems framework, we propose a hybrid estimation algorithm that can operate during both flows and jumps that, under a notion of hybrid persistence of excitation, guarantees convergence of the parameter estimate to the true value. Furthermore, we show that the parameter estimate is input-to-state stable with respect to a class of hybrid disturbances. Simulation results including a spacecraft application show the merits of our proposed approach

Strategies for handling uncertainty in tactical distribution planning - an empirical study

International audienc

A Metaheuristic for Tactical Inventory Planning in Closed-Loop Supply Chains

International audienc

Model and Combinatorial Optimization Methods for Tactical Planning in Closed-Loop Supply Chains

International audienc

Tactical Supply Chain Distribution Planning In The Telecommunications Service Industry

Supply chains are ubiquitous across industries and a considerable e ort has been invested in supply chain management techniques over the last two decades. In equipment-intensive service industries, it often involves repair operations. In this context, tactical inventory planning is concerned with optimally planning supplies and repairs based on demand forecasts and in face of con icting business objectives. It is based on a case study in the telecommunications sector where large quantities and varieties of spare parts are required for service maintenance and repair tasks at customer premises or company exchanges. Speci cally, we consider a multi-echelon spare parts supply chain and tackle the problem of determining an optimal stock distribution plan given a demand forecast. We propose a mixed integer programming and a metaheuristic approach to this problem. The model is open to a variety of network topologies, site functions and transfer policies. It also accommodates multiple objectives by the means of a weighted cost function. We report experiments on pseudo-random instances designed to evaluate plan quality and impact of cost weightings. In particular, we show how appropriate weightings allow to emulate common planning strategies (e.g., just-in-time replenishment, minimal repair). We also assess plan quality and system performance against di erent classes of pseudo-random instances featuring different volume and distribution of stock and demand

The leucine-rich repeat kinase LRRK2/Park8 controls regulated exocytosis in neurons and endocrine cells of the pancreas

Endocrine cells of the pancreas share many physiological features with neurons, although they have different embryological origins. Regulated membrane fusion resulting in hormone exocytosis in endocrine cells is controlled by the same core SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) fusion machinery that mediates neurotransmitter release at synapses. The leucine-rich repeat kinase 2 (LRRK2), a protein expressed in neurons and associated with inherited Parkinson\u2019s disease, has been recently shown to interact with specific synaptic proteins and influence synaptic transmission. Given the functional similarities between neurons and endocrine cells of the pancreas, here we first verified LRRK2 expression in islet of Langerhans, and then we investigated its possible involvement in hormone release. By means of RT-PCR and western blotting experiments, we detected LRRK2 expression in beta and alpha cell lines and in human islets of Langerhans. Using the pH-sensitive dye acridine orange as a tool to monitor exocytosis/endocytosis and elisa assays in the presence and the absence of specific LRRK2 inhibitors, we demonstrated LRRK2 involvement in the control of vesicles trafficking and hormone release in both alpha and beta cells. Our data for the first time identified LRRK2 as a novel component of the secretory machinery of endocrine cells of the pancreas and further highlight the similarity between neurons and endocrine cells

A Combinatorial Optimisation Approach For Closed-Loop Supply Chains Inventory Planning With Deterministic Demands

Supply chains in equipment-intensive service industries often involve repair operations. In this context, tactical inventory planning is concerned with optimally planning supplies and repairs based on demand forecasts and in the face of conflicting business objectives. This paper considers closed-loop supply chains and proposes a mixed-integer programming model and a metaheuristic approach to this problem. The model is open to a variety of network topologies, site functions and transfer policies. It also accommodates multiple objectives by the means of a weighted cost function. We report experiments on pseudo-random instances designed to evaluate plan quality and impact of cost weightings. In particular, we show how appropriate weightings allow to implement common planning strategies (e.g., just-in-time replenishment, minimal repair

The LRRK2 G2385R variant is a partial loss-of-function mutation that affects synaptic vesicle trafficking through altered protein interactions.

Mutations in the Leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial Parkinson's disease (PD). LRRK2 protein contains several functional domains, including protein-protein interaction domains at its N- and C-termini. In this study, we analyzed the functional features attributed to LRRK2 by its N- and C-terminal domains. We combined TIRF microscopy and synaptopHluorin assay to visualize synaptic vesicle trafficking. We found that N- and C-terminal domains have opposite impact on synaptic vesicle dynamics. Biochemical analysis demonstrated that different proteins are bound at the two extremities, namely \u3b23-Cav2.1 at N-terminus part and \u3b2-Actin and Synapsin I at C-terminus domain. A sequence variant (G2385R) harboured within the C-terminal WD40 domain increases the risk for PD. Complementary biochemical and imaging approaches revealed that the G2385R variant alters strength and quality of LRRK2 interactions and increases fusion of synaptic vesicles. Our data suggest that the G2385R variant behaves like a loss-of-function mutation that mimics activity-driven events. Impaired scaffolding capabilities of mutant LRRK2 resulting in perturbed vesicular trafficking may arise as a common pathophysiological denominator through which different LRRK2 pathological mutations cause diseas

PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor

Aims PCSK9 loss of function genetic variants are associated with lower low-density lipoprotein cholesterol but also with higher plasma glucose levels and increased risk of Type 2 diabetes mellitus. Here, we investigated the molecular mechanisms underlying this association. Methods and results Pcsk9 KO, WT, Pcsk9/Ldlr double KO (DKO), Ldlr KO, albumin AlbCre+/Pcsk9LoxP/LoxP (liver-selective Pcsk9 knock-out mice), and AlbCre-/Pcsk9LoxP/LoxP mice were used. GTT, ITT, insulin and C-peptide plasma levels, pancreas morphology, and cholesterol accumulation in pancreatic islets were studied in the different animal models. Glucose clearance was significantly impaired in Pcsk9 KO mice fed with a standard or a high-fat diet for 20\u2009weeks compared with WT animals; insulin sensitivity, however, was not affected. A detailed analysis of pancreas morphology of Pcsk9 KO mice vs. controls revealed larger islets with increased accumulation of cholesteryl esters, paralleled by increased insulin intracellular levels and decreased plasma insulin, and C-peptide levels. This phenotype was completely reverted in Pcsk9/Ldlr DKO mice implying the low-density lipoprotein receptor (LDLR) as the proprotein convertase subtilisin/kexin Type 9 (PCSK9) target responsible for the phenotype observed. Further studies in albumin AlbCre+/Pcsk9LoxP/LoxP mice, which lack detectable circulating PCSK9, also showed a complete recovery of the phenotype, thus indicating that circulating, liver-derived PCSK9, the principal target of monoclonal antibodies, does not impact beta-cell function and insulin secretion. Conclusion PCSK9 critically controls LDLR expression in pancreas perhaps contributing to the maintenance of a proper physiological balance to limit cholesterol overload in beta cells. This effect is independent of circulating PCSK9 and is probably related to locally produced PCSK9