MALT1 activity controls Kaposi's sarcoma-associated herpesvirus latency and growth of primary effusion lymphoma

The identification of cancer-specific enzymatic activities that can be therapeutically targeted is key to the development of suitable anti-cancer drugs. Primary effusion lymphoma (PEL) is a rare and incurable malignancy that can occur in immunodeficient patients as a consequence of latent infection of B-cells with Kaposi's sarcoma-associated herpesvirus, KSHV (also known as human herpesvirus-8, HHV8). Malignant growth of KSHV-infected B cells requires the constitutive activity of the transcription factor NF-KB, which controls expression of viral genes required for maintenance of viral latency and suppression of the viral lytic program. Here we identify the protease mucosa-associated lymphoid tissue transformation protein 1 (MALTI), a key driver of NF-KB activation in lymphocytes, as an essential component in KSHV-dependent NF-KB activation and growth of latently infected PEL cell lines. Inhibition of the MALTI protease activity induced a switch from the latent to the lytic stage of viral infection, and led to reduced growth and survival of PEL cell lines in vitro and in a xenograft model. These results demonstrate a key role for the proteolytic activity of MALTI in PEL, and provide a rationale for the pharmacological targeting of MALTI in PEL therapy. -- L'identification d'activités enzymatiques propre au cancer est clé dans le développement des nouvaux médicaments anti-cancer. Le lymphome primitif des séreuses est un lymphome rare et incurable qui peut se developer chez les patients immunodéficients. Il est la conséquence d'une infection latente des cellules B, dûe à l'herpes virus 8, plus connu comme herpes virus associé au sarcome de Kaposi (KSHV). La croissance maligne des cellules B infecteés par KSHV requière l'activité constitutive du facteur de transcription NF-KB qui contrôle l'expression des genes viraux requis pour la maintenance latente et la suppression du programme de lyse du virus. Avec cette étude, nous avons identifié la protease MALTI comme un composant essentiel dans l'activation de NF-KB dans les cellules B du lymphome primitif des séreuses. L'inhibition de l'activité de la protéase MALTI induit un virement de la phase latente à la phase lytique du KSHV et conduit à une reduction de la viabilité des cellules tumorales in vitro et dans un modèle de xénogreffe. Ces résultats démontrent un rôle clé pour l'activité protéolytique de MALTI dans le développement du lymphome primitif des séreuses et soutiennent l'idée que MALTI pourrait être une cible pharmacologique dans la thérapie de cette forme rare du lymphome.

Neuronal activity controls the antagonistic between PGC-1α and SMRT in regulating antioxidant defences

Transcriptional coactivators and corepressors often have multiple targets and can have opposing actions on transcription and downstream physiological events. The coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α is under-expressed in Huntington's disease and is a regulator of antioxidant defenses and mitochondrial biogenesis. We show that in primary cortical neurons, expression of PGC-1α strongly promotes resistance to excitotoxic and oxidative stress in a cell autonomous manner, whereas knockdown increases sensitivity. In contrast, the transcriptional corepressor silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) specifically antagonizes PGC-1α-mediated antioxidant effects. The antagonistic balance between PGC-1α and SMRT is upset in favor of PGC-1α by synaptic activity. Synaptic activity triggers nuclear export of SMRT reliant on multiple regions of the protein. Concommitantly, synaptic activity post-translationally enhances the transactivating potential of PGC-1α in a p38-dependent manner, as well as upregulating cyclic-AMP response element binding protein-dependent PGC-1α transcription. Activity-dependent targeting of PGC-1α results in enhanced gene expression mediated by the thyroid hormone receptor, a prototypical transcription factor coactivated by PGC-1α and repressed by SMRT. As a consequence of these events, SMRT is unable to antagonize PGC-1α-mediated resistance to oxidative stress in synaptically active neurons. Thus, PGC-1α and SMRT are antagonistic regulators of neuronal vulnerability to oxidative stress. Further, this coactivatorcorepressor antagonism is regulated by the activity status of the cell, with implications for neuronal viability.

Managing the Front End of Innovation in a Networked Company Environment - Combining Strategy, Processes and Systems of Innovation

The objective of the thesis is to enhance the understanding about the management of the front end phases of the innovation process in a networked environment. The thesis approaches the front end of innovation from three perspectives, including the strategy, processes and systems of innovation. The purpose of the use of different perspectives in the thesis is that of providing an extensive systemic view of the front end, and uncovering the complex nature of innovation management. The context of the research is the networked operating environment of firms. The unit of analysis is the firm itself or its innovation processes, which means that this research approaches the innovation networks from the point of view of a firm. The strategy perspective of the thesis emphasises the importance of purposeful innovation management, the innovation strategy of firms. The role of innovation processes is critical in carrying out innovation strategies in practice, supporting the development of organizational routines for innovation, and driving the strategic renewal of companies. The primary focus of the thesis from systems perspective is on idea management systems, which are defined as a part of innovation management systems, and defined for this thesis as any working combination of methodology and tools (manual or IT-supported) that enhance the management of innovations within their early phases. The main contribution of the thesis are the managerial frameworks developed for managing the front end of innovation, which purposefully “wire” the front end of innovation into the strategy and business processes of a firm. The thesis contributes to modern innovation management by connecting the internal and external collaboration networks as foundational elements for successful management of the early phases of innovation processes in a dynamic environment. The innovation capability of a firm is largely defined by its ability to rely on and make use of internal and external collaboration already during the front end activities, which by definition include opportunity identification and analysis, idea generation, profileration and selection, and concept definition. More specifically, coordination of the interfaces between these activities, and between the internal and external innovation environments of a firm is emphasised. The role of information systems, in particular idea management systems, is to support and delineate the innovation-oriented behaviour and interaction of individuals and organizations during front end activities. The findings and frameworks developed in the thesis can be used by companies for purposeful promotion of their front end processes. The thesis provides a systemic strategy framework for managing the front end of innovation – not as a separate process, but as an elemental bundle ofactivities that is closely linked to the overall innovation process and strategy of a firm in a distributed environment. The theoretical contribution of the thesis relies on the advancement of the open innovation paradigm in the strategic context of a firm within its internal and external innovation environments. This thesis applies the constructive research approach and case study methodology to provide theoretically significant results, which are also practically beneficial.

Improved understanding of drought controls on seasonal variation in Mediterranean forest canopy CO2 and water fluxes through combined in situ measurements and ecosystem modelling

Water stress is a defining characteristic of Mediterranean ecosystems, and is likely to become more severe in the coming decades. Simulation models are key tools for making predictions, but our current understanding of how soil moisture controls ecosystem functioning is not sufficient to adequately constrain parameterisations. Canopy-scale flux data from four forest ecosystems with Mediterranean-type climates were used in order to analyse the physiological controls on carbon and water flues through the year. Significant non-stomatal limitations on photosynthesis were detected, along with lesser changes in the conductance-assimilation relationship. New model parameterisations were derived and implemented in two contrasting modelling approaches. The effectiveness of two models, one a dynamic global vegetation model ('ORCHIDEE'), and the other a forest growth model particularly developed for Mediterranean simulations ('GOTILWA+'), was assessed and modelled canopy responses to seasonal changes in soil moisture were analysed in comparison with in situ flux measurements. In contrast to commonly held assumptions, we find that changing the ratio of conductance to assimilation under natural, seasonally-developing, soil moisture stress is not sufficient to reproduce forest canopy CO2 and water fluxes. However, accurate predictions of both CO2 and water fluxes under all soil moisture levels encountered in the field are obtained if photosynthetic capacity is assumed to vary with soil moisture. This new parameterisation has important consequences for simulated responses of carbon and water fluxes to seasonal soil moisture stress, and should greatly improve our ability to anticipate future impacts of climate changes on the functioning of ecosystems in Mediterranean-type climates.

Exploration and Design of Power-Efficient Networked Many-Core Systems

Multiprocessing is a promising solution to meet the requirements of near future applications. To get full benefit from parallel processing, a manycore system needs efficient, on-chip communication architecture. Networkon- Chip (NoC) is a general purpose communication concept that offers highthroughput, reduced power consumption, and keeps complexity in check by a regular composition of basic building blocks. This thesis presents power efficient communication approaches for networked many-core systems. We address a range of issues being important for designing power-efficient manycore systems at two different levels: the network-level and the router-level. From the network-level point of view, exploiting state-of-the-art concepts such as Globally Asynchronous Locally Synchronous (GALS), Voltage/ Frequency Island (VFI), and 3D Networks-on-Chip approaches may be a solution to the excessive power consumption demanded by today’s and future many-core systems. To this end, a low-cost 3D NoC architecture, based on high-speed GALS-based vertical channels, is proposed to mitigate high peak temperatures, power densities, and area footprints of vertical interconnects in 3D ICs. To further exploit the beneficial feature of a negligible inter-layer distance of 3D ICs, we propose a novel hybridization scheme for inter-layer communication. In addition, an efficient adaptive routing algorithm is presented which enables congestion-aware and reliable communication for the hybridized NoC architecture. An integrated monitoring and management platform on top of this architecture is also developed in order to implement more scalable power optimization techniques. From the router-level perspective, four design styles for implementing power-efficient reconfigurable interfaces in VFI-based NoC systems are proposed. To enhance the utilization of virtual channel buffers and to manage their power consumption, a partial virtual channel sharing method for NoC routers is devised and implemented. Extensive experiments with synthetic and real benchmarks show significant power savings and mitigated hotspots with similar performance compared to latest NoC architectures. The thesis concludes that careful codesigned elements from different network levels enable considerable power savings for many-core systems.

Adaptive Routing Approaches for Networked Many-Core Systems

Through advances in technology, System-on-Chip design is moving towards integrating tens to hundreds of intellectual property blocks into a single chip. In such a many-core system, on-chip communication becomes a performance bottleneck for high performance designs. Network-on-Chip (NoC) has emerged as a viable solution for the communication challenges in highly complex chips. The NoC architecture paradigm, based on a modular packet-switched mechanism, can address many of the on-chip communication challenges such as wiring complexity, communication latency, and bandwidth. Furthermore, the combined benefits of 3D IC and NoC schemes provide the possibility of designing a high performance system in a limited chip area. The major advantages of 3D NoCs are the considerable reductions in average latency and power consumption. There are several factors degrading the performance of NoCs. In this thesis, we investigate three main performance-limiting factors: network congestion, faults, and the lack of efficient multicast support. We address these issues by the means of routing algorithms. Congestion of data packets may lead to increased network latency and power consumption. Thus, we propose three different approaches for alleviating such congestion in the network. The first approach is based on measuring the congestion information in different regions of the network, distributing the information over the network, and utilizing this information when making a routing decision. The second approach employs a learning method to dynamically find the less congested routes according to the underlying traffic. The third approach is based on a fuzzy-logic technique to perform better routing decisions when traffic information of different routes is available. Faults affect performance significantly, as then packets should take longer paths in order to be routed around the faults, which in turn increases congestion around the faulty regions. We propose four methods to tolerate faults at the link and switch level by using only the shortest paths as long as such path exists. The unique characteristic among these methods is the toleration of faults while also maintaining the performance of NoCs. To the best of our knowledge, these algorithms are the first approaches to bypassing faults prior to reaching them while avoiding unnecessary misrouting of packets. Current implementations of multicast communication result in a significant performance loss for unicast traffic. This is due to the fact that the routing rules of multicast packets limit the adaptivity of unicast packets. We present an approach in which both unicast and multicast packets can be efficiently routed within the network. While suggesting a more efficient multicast support, the proposed approach does not affect the performance of unicast routing at all. In addition, in order to reduce the overall path length of multicast packets, we present several partitioning methods along with their analytical models for latency measurement. This approach is discussed in the context of 3D mesh networks.

Reusable formal architectures for networked systems

Today's networked systems are becoming increasingly complex and diverse. The current simulation and runtime verification techniques do not provide support for developing such systems efficiently; moreover, the reliability of the simulated/verified systems is not thoroughly ensured. To address these challenges, the use of formal techniques to reason about network system development is growing, while at the same time, the mathematical background necessary for using formal techniques is a barrier for network designers to efficiently employ them. Thus, these techniques are not vastly used for developing networked systems. The objective of this thesis is to propose formal approaches for the development of reliable networked systems, by taking efficiency into account. With respect to reliability, we propose the architectural development of correct-by-construction networked system models. With respect to efficiency, we propose reusable network architectures as well as network development. At the core of our development methodology, we employ the abstraction and refinement techniques for the development and analysis of networked systems. We evaluate our proposal by employing the proposed architectures to a pervasive class of dynamic networks, i.e., wireless sensor network architectures as well as to a pervasive class of static networks, i.e., network-on-chip architectures. The ultimate goal of our research is to put forward the idea of building libraries of pre-proved rules for the efficient modelling, development, and analysis of networked systems. We take into account both qualitative and quantitative analysis of networks via varied formal tool support, using a theorem prover the Rodin platform and a statistical model checker the SMC-Uppaal.

Disconnect.Me. User Engagement and Facebook

In the beginning of its 10th year of existence Facebook has engaged and connected 1.2 billion monthly active users. This article-based dissertation Disconnect.Me – User Engagement and Facebook approaches this engagement from the opposite direction: disconnection. The research articles focus on social media specific phenomena including leaving Facebook, tactical media works such as Web 2.0 SuicideMachine, memorializing dead Facebook users and Facebook trolling. The media theoretical framework for this study is built around affect theory, software studies, biopolitics as well as different critical studies of new media. The argument is that disconnection is a necessary condition of social media connectivity and exploring social media through disconnection – as an empirical phenomenon, future potential and theoretical notion – helps us to understand how users are engaged with social media, its uses and subsequent business models. The results of the study indicate that engagement is a relation that precedes user participation, a notion often used to conceptualize social media. Furthermore, this engagement turns the focus from users’ actions towards the platform and how the platform actively controls users and their behavior. Facebook aims to engage new users and maintain the old ones by renewing its platform and user interface. User engagement with the platform is thus social but also technical and affective. When engaged, the user is positioned to algorithmic connectivity where machinc processes mine user data. This data is but sold also used to affect and engage other users. In the heart of this study is the notion that our networked engagements matter and disconnection can bring us to the current limits of network culture.

Corn yield response to weed and fall armyworm controls

The interference imposed the by weeds on corn decreases practically all vegetative characteristics. As consequence, the green ear and grain yield are also reduced. Losses due to the fall armyworm (Spodoptera frugiperda) attack can reduce corn grain yield up to 34%. In general, weed and insect control issues are addressed separately in research papers. Nevertheless, interaction between weeds and insects may exist. This study aimed to evaluate green ear and corn grain yield response to weed and fall armyworm control. A completely randomized block design with split-plots and five replicates was adopted. Corn cultivar AG 1051 was grown under weedy conditions or with control by hand hoeings performed at 20 and 40 days after planting. Fall armyworm control (applied to subplots) was performed with sprays of water (control), deltamethrin (5g active ingredient ha-1); neem oil, at 0.5% (diluted in water), and neem leaf extract at 5%. Each product was sprayed three times, at seven-day intervals, starting at the 7th day after planting, using 150 L ha-1 of the tank solution. Dry mass of the above-ground part, internode diameter, leaf length, leaf width, leaf area, green ear yield and grain yield of corn were reduced due to the lack of weed control. Fall armyworm control in the weeded plots did not influence green ear yield and grain yield, except green mass of marketable, husked ears, which was reduced when the caterpillar was not controlled. Without weed control, neem extracts and deltamethrin sprays provided highest yields of number and total weight of green ears with husks, number and weight of marketable ears with husks and number of marketable ears without husks. The best results for husked ear mass and for grain yield were obtained with neem extract and deltamethrin, respectively.

Thermal-Aware Networked Many-Core Systems

Advancements in IC processing technology has led to the innovation and growth happening in the consumer electronics sector and the evolution of the IT infrastructure supporting this exponential growth. One of the most difficult obstacles to this growth is the removal of large amount of heatgenerated by the processing and communicating nodes on the system. The scaling down of technology and the increase in power density is posing a direct and consequential effect on the rise in temperature. This has resulted in the increase in cooling budgets, and affects both the life-time reliability and performance of the system. Hence, reducing on-chip temperatures has become a major design concern for modern microprocessors. This dissertation addresses the thermal challenges at different levels for both 2D planer and 3D stacked systems. It proposes a self-timed thermal monitoring strategy based on the liberal use of on-chip thermal sensors. This makes use of noise variation tolerant and leakage current based thermal sensing for monitoring purposes. In order to study thermal management issues from early design stages, accurate thermal modeling and analysis at design time is essential. In this regard, spatial temperature profile of the global Cu nanowire for on-chip interconnects has been analyzed. It presents a 3D thermal model of a multicore system in order to investigate the effects of hotspots and the placement of silicon die layers, on the thermal performance of a modern ip-chip package. For a 3D stacked system, the primary design goal is to maximise the performance within the given power and thermal envelopes. Hence, a thermally efficient routing strategy for 3D NoC-Bus hybrid architectures has been proposed to mitigate on-chip temperatures by herding most of the switching activity to the die which is closer to heat sink. Finally, an exploration of various thermal-aware placement approaches for both the 2D and 3D stacked systems has been presented. Various thermal models have been developed and thermal control metrics have been extracted. An efficient thermal-aware application mapping algorithm for a 2D NoC has been presented. It has been shown that the proposed mapping algorithm reduces the effective area reeling under high temperatures when compared to the state of the art.

The response of social anxiety disorder patients to threat scenarios differs from that of healthy controls

The objective of the present study was to evaluate the response of social anxiety disorder (SAD) patients to threat scenarios. First-choice responses to 12 scenarios describing conspecific threatening situations and mean scores of defensive direction and defensive intensity dimensions were compared between 87 SAD patients free of medication and 87 matched healthy controls (HC). A significant gender difference in the first-choice responses was identified for seven scenarios among HCs but only for two scenarios among SAD patients. A significantly higher proportion of SAD patients chose "freezing" in response to "Bush" and "Noise" scenarios, whereas the most frequent response by HCs to these scenarios was "check out". SAD males chose "run away" and "yell" more often than healthy men in response to the scenarios "Park" and "Elevator", respectively. There was a positive correlation between the severity of symptoms and both defensive direction and defensive intensity dimensions. Factorial analysis confirmed the gradient of defensive reactions derived from animal studies. SAD patients chose more urgent defensive responses to threat scenarios, seeming to perceive them as more dangerous than HCs and tending to move away from the source of threat. This is consistent with the hypothesis that the physiopathology of anxiety disorders involves brain structures responsible for defensive behaviors.

Rethinking the economics of capital mobility and capital controls

This paper reexamines the issue of international financial capital mobility, which is today's economic orthodoxy. Discussion is often framed in terms of the impossible trinity. That framing distorts discussion by representing capital mobility as having equal significance with sovereign monetary policy and control over exchange rates. It also distorts discussion by ignoring possibilities for coordinated monetary policy and exchange rates, and for managed capital flows. The case for capital mobility rests on neo-classical economic efficiency arguments and neo-liberal political arguments. The case against capital mobility is based on Keynesian macroeconomic inefficiency arguments, neo-Walrasian market failure arguments, and neo-Marxian arguments regarding distortion of the social structure of accumulation. Close examination shows the case for capital mobility to be extremely flimsy, pointing to the ideological dimension behind today's policy orthodoxy.

Electrophysiological analysis of the sleep onset period : a comparison between subjects with long term insomnia complaints associated with mild traumatic brain injury and matched controls /

The purpose of the current undertaking was to study the electrophysiological properties of the sleep onset period (SOP) in order to gain understanding into the persistent sleep difficulties of those who complain of insomnia following mild traumatic brain injury (MTBI). While many believe that symptoms of post concussion syndrome (PCS) following MTBI resolve within 6 to 12 months, there are a number of people who complain of persistent sleep difficulty. Two models were proposed which hypothesize alternate electrophysiological presentations of the insomnia complaints of those sustaining a MTBI: 1) Analyses of standard polysomnography (PSG) sleep parameters were conducted in order to determine if the sleep difficulties of the MTBI population were similar to that of idiopathic insomniacs (i.e. greater proportion ofREM sleep, reduced delta sleep); 2) Power spectral analysis was conducted over the SOP to determine if the sleep onset signature of those with MTBI would be similar to psychophysiological insomniacs (characterized by increased cortical arousal). Finally, exploratory analyses examined whether the sleep difficulties associated with MTBI could be explained by increases in variability of the power spectral data. Data were collected from 9 individuals who had sustained a MTBI 6 months to 5 years earlier and reported sleep difficulties that had arisen within the month subsequent to injury and persisted to the present. The control group consisted of 9 individuals who had experienced neither sleep difficulties, nor MTBI. Previous to spending 3 consecutive uninterrupted nights in the sleep lab, subjects completed questionnaires regarding sleep difficulties, adaptive functioning, and personality.