A loss-of-function screen reveals SNX5 and SNX6 as potential components of the mammalian retromer

The mammalian retromer is a multimeric protein complex involved in mediating endosome-to-trans-Golgi-network retrograde transport of the cation-independent mannose-6-phosphate receptor. The retromer is composed of two subcomplexes, one containing SNX1 and forming a membrane-bound coat, the other comprising VPS26, VPS29 and VPS35 and being cargo-selective. In yeast, an additional sorting nexin--Vps17p--is a component of the membrane bound coat. It remains unclear whether the mammalian retromer requires a functional equivalent of Vps17p. Here, we have used an RNAi loss-of-function screen to examine whether any of the other 30 mammalian sorting nexins are required for retromer-mediated endosome-to-trans-Golgi-network retrieval of the cation-independent mannose-6-phosphate receptor. Using this screen, we identified two proteins, SNX5 and SNX6, that, when suppressed, induced a phenotype similar to that observed upon suppression of known retromer components. Whereas SNX5 and SNX6 colocalised with SNX1 on early endosomes, in immunoprecipitation experiments only SNX6 appeared to exist in a complex with SNX1. Interestingly, suppression of SNX5 and/or SNX6 resulted in a significant loss of SNX1, an effect that seemed to result from post-translational regulation of the SNX1 level. Such data suggest that SNX1 and SNX6 exist in a stable, endosomally associated complex that is required for retromer-mediated retrieval of the cation-independent mannose-6-phosphate receptor. SNX5 and SNX6 may therefore constitute functional equivalents of Vps17p in mammals.

Learning and change in interorganizational networks:the case for network learning and network change

The ALBA 2002 Call for Papers asks the question ‘How do organizational learning and knowledge management contribute to organizational innovation and change?’. Intuitively, we would argue, the answer should be relatively straightforward as links between learning and change, and knowledge management and innovation, have long been commonly assumed to exist. On the basis of this assumption, theories of learning tend to focus ‘within organizations’, and assume a transfer of learning from individual to organization which in turn leads to change. However, empirically, we find these links are more difficult to articulate. Organizations exist in complex embedded economic, political, social and institutional systems, hence organizational change (or innovation) may be influenced by learning in this wider context. Based on our research in this wider interorganizational setting, we first make the case for the notion of network learning that we then explore to develop our appreciation of change in interorganizational networks, and how it may be facilitated. The paper begins with a brief review of lite rature on learning in the organizational and interorganizational context which locates our stance on organizational learning versus the learning organization, and social, distributed versus technical, centred views of organizational learning and knowledge. Developing from the view that organizational learning is “a normal, if problematic, process in every organization” (Easterby-Smith, 1997: 1109), we introduce the notion of network learning: learning by a group of organizations as a group. We argue this is also a normal, if problematic, process in organizational relationships (as distinct from interorganizational learning), which has particular implications for network change. Part two of the paper develops our analysis, drawing on empirical data from two studies of learning. The first study addresses the issue of learning to collaborate between industrial customers and suppliers, leading to the case for network learning. The second, larger scale study goes on to develop this theme, examining learning around several major change issues in a healthcare service provider network. The learning processes and outcomes around the introduction of a particularly controversial and expensive technology are described, providing a rich and contrasting case with the first study. In part three, we then discuss the implications of this work for change, and for facilitating change. Conclusions from the first study identify potential interventions designed to facilitate individual and organizational learning within the customer organization to develop individual and organizational ‘capacity to collaborate’. Translated to the network example, we observe that network change entails learning at all levels – network, organization, group and individual. However, presenting findings in terms of interventions is less meaningful in an interorganizational network setting given: the differences in authority structures; the less formalised nature of the network setting; and the importance of evaluating performance at the network rather than organizational level. Academics challenge both the idea of managing change and of managing networks. Nevertheless practitioners are faced with the issue of understanding and in fluencing change in the network setting. Thus we conclude that a network learning perspective is an important development in our understanding of organizational learning, capability and change, locating this in the wider context in which organizations are embedded. This in turn helps to develop our appreciation of facilitating change in interorganizational networks, both in terms of change issues (such as introducing a new technology), and change orientation and capability.

Network density and R&D spillovers

This paper models how the structure and function of a network of firms affects their aggregate innovativeness. Each firm has the potential to innovate, either from in-house R&D or from innovation spillovers from neighboring firms. The nature of innovation spillovers depends upon network density, the commonality of knowledge between firms, and the learning capability of firms. Innovation spillovers are modelled in detail using ideas from organizational theory. Two main results emerge: (i) the marginal effect on innovativeness of spillover intensity is non-monotonic, and (ii) network density can affect innovativeness but only when there are heterogeneous firms.

Design and analysis of distributed utility maximization algorithm for multihop wireless network with inaccurate feedback

Distributed network utility maximization (NUM) is receiving increasing interests for cross-layer optimization problems in multihop wireless networks. Traditional distributed NUM algorithms rely heavily on feedback information between different network elements, such as traffic sources and routers. Because of the distinct features of multihop wireless networks such as time-varying channels and dynamic network topology, the feedback information is usually inaccurate, which represents as a major obstacle for distributed NUM application to wireless networks. The questions to be answered include if distributed NUM algorithm can converge with inaccurate feedback and how to design effective distributed NUM algorithm for wireless networks. In this paper, we first use the infinitesimal perturbation analysis technique to provide an unbiased gradient estimation on the aggregate rate of traffic sources at the routers based on locally available information. On the basis of that, we propose a stochastic approximation algorithm to solve the distributed NUM problem with inaccurate feedback. We then prove that the proposed algorithm can converge to the optimum solution of distributed NUM with perfect feedback under certain conditions. The proposed algorithm is applied to the joint rate and media access control problem for wireless networks. Numerical results demonstrate the convergence of the proposed algorithm. © 2013 John Wiley & Sons, Ltd.

Function interval arithmetic

We propose an arithmetic of function intervals as a basis for convenient rigorous numerical computation. Function intervals can be used as mathematical objects in their own right or as enclosures of functions over the reals. We present two areas of application of function interval arithmetic and associated software that implements the arithmetic: (1) Validated ordinary differential equation solving using the AERN library and within the Acumen hybrid system modeling tool. (2) Numerical theorem proving using the PolyPaver prover. © 2014 Springer-Verlag.

The application of a long period grating array for respiratory function monitoring

In this paper, multiplexed sensor network capable of monitoring the shape changes of the torso for respiratory function monitoring is developed. As a demonstration, LPGs written into refractive index insensitive, progressive three layered fibre are embedded into supporting material is then placed on a resuscitation training manikin simulating respiration. A derivative spectroscopy interrogation technique is implemented and the bend sensitivity of the LPGs is used to reconstruct the shape of the manikin's torso. © 2003 IEEE.

Neuronal network dynamics during epileptogenesis in the medial temporal lobe

Epilepsy is one of the most common neurological disorders, a large fraction of which is resistant to pharmacotherapy. In this light, understanding the mechanisms of epilepsy and its intractable forms in particular could create new targets for pharmacotherapeutic intervention. The current project explores the dynamic changes in neuronal network function in the chronic temporal lobe epilepsy (TLE) in rat and human brain in vitro. I focused on the process of establishment of epilepsy (epileptogenesis) in the temporal lobe. Rhythmic behaviour of the hippocampal neuronal networks in healthy animals was explored using spontaneous oscillations in the gamma frequency band (SγO). The use of an improved brain slice preparation technique resulted in the natural occurence (in the absence of pharmacological stimulation) of rhythmic activity, which was then pharmacologically characterised and compared to other models of gamma oscillations (KA- and CCh-induced oscillations) using local field potential recording technique. The results showed that SγO differed from pharmacologically driven models, suggesting higher physiological relevance of SγO. Network activity was also explored in the medial entorhinal cortex (mEC), where spontaneous slow wave oscillations (SWO) were detected. To investigate the course of chronic TLE establishment, a refined Li-pilocarpine-based model of epilepsy (RISE) was developed. The model significantly reduced animal mortality and demonstrated reduced intensity, yet high morbidy with almost 70% mean success rate of developing spontaneous recurrent seizures. We used SγO to characterize changes in the hippocampal neuronal networks throughout the epileptogenesis. The results showed that the network remained largely intact, demonstrating the subtle nature of the RISE model. Despite this, a reduction in network activity was detected during the so-called latent (no seizure) period, which was hypothesized to occur due to network fragmentation and an abnormal function of kainate receptors (KAr). We therefore explored the function of KAr by challenging SγO with kainic acid (KA). The results demonstrated a remarkable decrease in KAr response during the latent period, suggesting KAr dysfunction or altered expression, which will be further investigated using a variety of electrophysiological and immunocytochemical methods. The entorhinal cortex, together with the hippocampus, is known to play an important role in the TLE. Considering this, we investigated neuronal network function of the mEC during epileptogenesis using SWO. The results demonstrated a striking difference in AMPAr function, with possible receptor upregulation or abnormal composition in the early development of epilepsy. Alterations in receptor function inevitably lead to changes in the network function, which may play an important role in the development of epilepsy. Preliminary investigations were made using slices of human brain tissue taken following surgery for intratctable epilepsy. Initial results showed that oscillogenesis could be induced in human brain slices and that such network activity was pharmacologically similar to that observed in rodent brain. Overall, our findings suggest that excitatory glutamatergic transmission is heavily involved in the process of epileptogenesis. Together with other types of receptors, KAr and AMPAr contribute to epilepsy establishment and may be the key to uncovering its mechanism.

Progmosis:evaluating risky individual behavior during epidemics using mobile network data

The possibility to analyze, quantify and forecast epidemic outbreaks is fundamental when devising effective disease containment strategies. Policy makers are faced with the intricate task of drafting realistically implementable policies that strike a balance between risk management and cost. Two major techniques policy makers have at their disposal are: epidemic modeling and contact tracing. Models are used to forecast the evolution of the epidemic both globally and regionally, while contact tracing is used to reconstruct the chain of people who have been potentially infected, so that they can be tested, isolated and treated immediately. However, both techniques might provide limited information, especially during an already advanced crisis when the need for action is urgent. In this paper we propose an alternative approach that goes beyond epidemic modeling and contact tracing, and leverages behavioral data generated by mobile carrier networks to evaluate contagion risk on a per-user basis. The individual risk represents the loss incurred by not isolating or treating a specific person, both in terms of how likely it is for this person to spread the disease as well as how many secondary infections it will cause. To this aim, we develop a model, named Progmosis, which quantifies this risk based on movement and regional aggregated statistics about infection rates. We develop and release an open-source tool that calculates this risk based on cellular network events. We simulate a realistic epidemic scenarios, based on an Ebola virus outbreak; we find that gradually restricting the mobility of a subset of individuals reduces the number of infected people after 30 days by 24%.

Numerical analysis of artificial neural network and volterra-based nonlinear equalizers for coherent optical OFDM

One major drawback of coherent optical orthogonal frequency-division multiplexing (CO-OFDM) that hitherto remains unsolved is its vulnerability to nonlinear fiber effects due to its high peak-to-average power ratio. Several digital signal processing techniques have been investigated for the compensation of fiber nonlinearities, e.g., digital back-propagation, nonlinear pre- and post-compensation and nonlinear equalizers (NLEs) based on the inverse Volterra-series transfer function (IVSTF). Alternatively, nonlinearities can be mitigated using nonlinear decision classifiers such as artificial neural networks (ANNs) based on a multilayer perceptron. In this paper, ANN-NLE is presented for a 16QAM CO-OFDM system. The capability of the proposed approach to compensate the fiber nonlinearities is numerically demonstrated for up to 100-Gb/s and over 1000km and compared to the benchmark IVSTF-NLE. Results show that in terms of Q-factor, for 100-Gb/s at 1000km of transmission, ANN-NLE outperforms linear equalization and IVSTF-NLE by 3.2dB and 1dB, respectively.

Artificial neural network nonlinear equalizer for coherent optical OFDM

We propose a novel low-complexity artificial neural network (ANN)-based nonlinear equalizer (NLE) for coherent optical orthogonal frequency-division multiplexing (CO-OFDM) and compare it with the recent inverse Volterra-series transfer function (IVSTF)-based NLE over up to 1000 km of uncompensated links. Demonstration of ANN-NLE at 80-Gb/s CO-OFDM using 16-quadrature amplitude modulation reveals a Q-factor improvement after 1000-km transmission of 3 and 1 dB with respect to the linear equalization and IVSTF-NLE, respectively.

Experimental comparison of artificial neural network and volterra based nonlinear equalization for CO-OFDM

A novel artificial neural network (ANN)-based nonlinear equalizer (NLE) of low complexity is demonstrated for 40-Gb/s CO-OFDM at 2000 km, revealing ∼1.5 dB enhancement in Q-factor compared to inverse Volterra-series transfer function based NLE.