Novos sistemas terapêuticos para administração nasal de fármacos

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

A randomized solution to BGP divergence

The Border Gateway Protocol (BGP) is an interdomain routing protocol that allows each Autonomous System (AS) to define its own routing policies independently and use them to select the best routes. By means of policies, ASes are able to prevent some traffic from accessing their resources, or direct their traffic to a preferred route. However, this flexibility comes at the expense of a possibility of divergence behavior because of mutually conflicting policies. Since BGP is not guaranteed to converge even in the absence of network topology changes, it is not safe. In this paper, we propose a randomized approach to providing safety in BGP. The proposed algorithm dynamically detects policy conflicts, and tries to eliminate the conflict by changing the local preference of the paths involved. Both the detection and elimination of policy conflicts are performed locally, i.e. by using only local information. Randomization is introduced to prevent synchronous updates of the local preferences of the paths involved in the same conflict.

Load Profiling for Efficient Route Selection in Multi-Class Networks

High-speed networks, such as ATM networks, are expected to support diverse Quality of Service (QoS) constraints, including real-time QoS guarantees. Real-time QoS is required by many applications such as those that involve voice and video communication. To support such services, routing algorithms that allow applications to reserve the needed bandwidth over a Virtual Circuit (VC) have been proposed. Commonly, these bandwidth-reservation algorithms assign VCs to routes using the least-loaded concept, and thus result in balancing the load over the set of all candidate routes. In this paper, we show that for such reservation-based protocols|which allow for the exclusive use of a preset fraction of a resource's bandwidth for an extended period of time-load balancing is not desirable as it results in resource fragmentation, which adversely affects the likelihood of accepting new reservations. In particular, we show that load-balancing VC routing algorithms are not appropriate when the main objective of the routing protocol is to increase the probability of finding routes that satisfy incoming VC requests, as opposed to equalizing the bandwidth utilization along the various routes. We present an on-line VC routing scheme that is based on the concept of "load profiling", which allows a distribution of "available" bandwidth across a set of candidate routes to match the characteristics of incoming VC QoS requests. We show the effectiveness of our load-profiling approach when compared to traditional load-balancing and load-packing VC routing schemes.

Evaluation of a Load Profiling Approach to Routing Guaranteed Bandwidth Flows

To support the diverse Quality of Service (QoS) requirements of real-time (e.g. audio/video) applications in integrated services networks, several routing algorithms that allow for the reservation of the needed bandwidth over a Virtual Circuit (VC) established on one of several candidate routes have been proposed. Traditionally, such routing is done using the least-loaded concept, and thus results in balancing the load across the set of candidate routes. In a recent study, we have established the inadequacy of this load balancing practice and proposed the use of load profiling as an alternative. Load profiling techniques allow the distribution of "available" bandwidth across a set of candidate routes to match the characteristics of incoming VC QoS requests. In this paper we thoroughly characterize the performance of VC routing using load profiling and contrast it to routing using load balancing and load packing. We do so both analytically and via extensive simulations of multi-class traffic routing in Virtual Path (VP) based networks. Our findings confirm that for routing guaranteed bandwidth flows in VP networks, load balancing is not desirable as it results in VP bandwidth fragmentation, which adversely affects the likelihood of accepting new VC requests. This fragmentation is more pronounced when the granularity of VC requests is large. Typically, this occurs when a common VC is established to carry the aggregate traffic flow of many high-bandwidth real-time sources. For VP-based networks, our simulation results show that our load-profiling VC routing scheme performs better or as well as the traditional load-balancing VC routing in terms of revenue under both skewed and uniform workloads. Furthermore, load-profiling routing improves routing fairness by proactively increasing the chances of admitting high-bandwidth connections.

On the Stable Paths Problem and a Restricted Variant

Interdomain routing on the Internet is performed using route preference policies specified independently, and arbitrarily by each Autonomous System in the network. These policies are used in the border gateway protocol (BGP) by each AS when selecting next-hop choices for routes to each destination. Conflicts between policies used by different ASs can lead to routing instabilities that, potentially, cannot be resolved no matter how long BGP is run. The Stable Paths Problem (SPP) is an abstract graph theoretic model of the problem of selecting nexthop routes for a destination. A stable solution to the problem is a set of next-hop choices, one for each AS, that is compatible with the policies of each AS. In a stable solution each AS has selected its best next-hop given that the next-hop choices of all neighbors are fixed. BGP can be viewed as a distributed algorithm for solving SPP. In this report we consider the stable paths problem, as well as a family of restricted variants of the stable paths problem, which we call F stable paths problems. We show that two very simple variants of the stable paths problem are also NP-complete. In addition we show that for networks with a DAG topology, there is an efficient centralized algorithm to solve the stable paths problem, and that BGP always efficiently converges to a stable solution on such networks.

Forewarding in Mobile Opportunistic Networks

Recent advances in processor speeds, mobile communications and battery life have enabled computers to evolve from completely wired to completely mobile. In the most extreme case, all nodes are mobile and communication takes place at available opportunities – using both traditional communication infrastructure as well as the mobility of intermediate nodes. These are mobile opportunistic networks. Data communication in such networks is a difficult problem, because of the dynamic underlying topology, the scarcity of network resources and the lack of global information. Establishing end-to-end routes in such networks is usually not feasible. Instead a store-and-carry forwarding paradigm is better suited for such networks. This dissertation describes and analyzes algorithms for forwarding of messages in such networks. In order to design effective forwarding algorithms for mobile opportunistic networks, we start by first building an understanding of the set of all paths between nodes, which represent the available opportunities for any forwarding algorithm. Relying on real measurements, we enumerate paths between nodes and uncover what we refer to as the path explosion effect. The term path explosion refers to the fact that the number of paths between a randomly selected pair of nodes increases exponentially with time. We draw from the theory of epidemics to model and explain the path explosion effect. This is the first contribution of the thesis, and is a key observation that underlies subsequent results. Our second contribution is the study of forwarding algorithms. For this, we rely on trace driven simulations of different algorithms that span a range of design dimensions. We compare the performance (success rate and average delay) of these algorithms. We make the surprising observation that most algorithms we consider have roughly similar performance. We explain this result in light of the path explosion phenomenon. While the performance of most algorithms we studied was roughly the same, these algorithms differed in terms of cost. This prompted us to focus on designing algorithms with the explicit intent of reducing costs. For this, we cast the problem of forwarding as an optimal stopping problem. Our third main contribution is the design of strategies based on optimal stopping principles which we refer to as Delegation schemes. Our analysis shows that using a delegation scheme reduces cost over naive forwarding by a factor of O(√N), where N is the number of nodes in the network. We further validate this result on real traces, where the cost reduction observed is even greater. Our results so far include a key assumption, which is unbounded buffers on nodes. Next, we relax this assumption, so that the problem shifts to one of prioritization of messages for transmission and dropping. Our fourth contribution is the study of message prioritization schemes, combined with forwarding. Our main result is that one achieves higher performance by assigning higher priorities to young messages in the network. We again interpret this result in light of the path explosion effect.

Utility-Based Decision-Making in Wireless Sensor Networks

We consider challenges associated with application domains in which a large number of distributed, networked sensors must perform a sensing task repeatedly over time. For the tasks we consider, there are three significant challenges to address. First, nodes have resource constraints imposed by their finite power supply, which motivates computations that are energy-conserving. Second, for the applications we describe, the utility derived from a sensing task may vary depending on the placement and size of the set of nodes who participate, which often involves complex objective functions for nodes to target. Finally, nodes must attempt to realize these global objectives with only local information. We present a model for such applications, in which we define appropriate global objectives based on utility functions and specify a cost model for energy consumption. Then, for an important class of utility functions, we present distributed algorithms which attempt to maximize the utility derived from the sensor network over its lifetime. The algorithms and experimental results we present enable nodes to adaptively change their roles over time and use dynamic reconfiguration of routes to load balance energy consumption in the network.

On the Marginal Utility of Deploying Measurement Infrastructure

The cost and complexity of deploying measurement infrastructure in the Internet for the purpose of analyzing its structure and behavior is considerable. Basic questions about the utility of increasing the number of measurements and/or measurement sites have not yet been addressed which has lead to a "more is better" approach to wide-area measurements. In this paper, we quantify the marginal utility of performing wide-area measurements in the context of Internet topology discovery. We characterize topology in terms of nodes, links, node degree distribution, and end-to-end flows using statistical and information-theoretic techniques. We classify nodes discovered on the routes between a set of 8 sources and 1277 destinations to differentiate nodes which make up the so called "backbone" from those which border the backbone and those on links between the border nodes and destination nodes. This process includes reducing nodes that advertise multiple interfaces to single IP addresses. We show that the utility of adding sources goes down significantly after 2 from the perspective of interface, node, link and node degree discovery. We show that the utility of adding destinations is constant for interfaces, nodes, links and node degree indicating that it is more important to add destinations than sources. Finally, we analyze paths through the backbone and show that shared link distributions approximate a power law indicating that a small number of backbone links in our study are very heavily utilized.

Comparison of K-ary N-cube and de Bruijn Overlays in QoS-Constrained Multicast Applications

Research on the construction of logical overlay networks has gained significance in recent times. This is partly due to work on peer-to-peer (P2P) systems for locating and retrieving distributed data objects, and also scalable content distribution using end-system multicast techniques. However, there are emerging applications that require the real-time transport of data from various sources to potentially many thousands of subscribers, each having their own quality-of-service (QoS) constraints. This paper primarily focuses on the properties of two popular topologies found in interconnection networks, namely k-ary n-cubes and de Bruijn graphs. The regular structure of these graph topologies makes them easier to analyze and determine possible routes for real-time data than complete or irregular graphs. We show how these overlay topologies compare in their ability to deliver data according to the QoS constraints of many subscribers, each receiving data from specific publishing hosts. Comparisons are drawn on the ability of each topology to route data in the presence of dynamic system effects, due to end-hosts joining and departing the system. Finally, experimental results show the service guarantees and physical link stress resulting from efficient multicast trees constructed over both kinds of overlay networks.

An Adaptive Policy Management Approach to BGP Convergence

The Border Gateway Protocol (BGP) is the current inter-domain routing protocol used to exchange reachability information between Autonomous Systems (ASes) in the Internet. BGP supports policy-based routing which allows each AS to independently adopt a set of local policies that specify which routes it accepts and advertises from/to other networks, as well as which route it prefers when more than one route becomes available. However, independently chosen local policies may cause global conflicts, which result in protocol divergence. In this paper, we propose a new algorithm, called Adaptive Policy Management Scheme (APMS), to resolve policy conflicts in a distributed manner. Akin to distributed feedback control systems, each AS independently classifies the state of the network as either conflict-free or potentially-conflicting by observing its local history only (namely, route flaps). Based on the degree of measured conflicts (policy conflict-avoidance vs. -control mode), each AS dynamically adjusts its own path preferences—increasing its preference for observably stable paths over flapping paths. APMS also includes a mechanism to distinguish route flaps due to topology changes, so as not to confuse them with those due to policy conflicts. A correctness and convergence analysis of APMS based on the substability property of chosen paths is presented. Implementation in the SSF network simulator is performed, and simulation results for different performance metrics are presented. The metrics capture the dynamic performance (in terms of instantaneous throughput, delay, routing load, etc.) of APMS and other competing solutions, thus exposing the often neglected aspects of performance.

An Adaptive Management Approach to Resolving Policy Conflicts

The Border Gateway Protocol (BGP) is the current inter-domain routing protocol used to exchange reachability information between Autonomous Systems (ASes) in the Internet. BGP supports policy-based routing which allows each AS to independently define a set of local policies on which routes it accepts and advertises from/to other networks, as well as on which route it prefers when more than one route becomes available. However, independently chosen local policies may cause global conflicts, which result in protocol divergence. In this paper, we propose a new algorithm, called Adaptive Policy Management Scheme(APMS), to resolve policy conflicts in a distributed manner. Akin to distributed feedback control systems, each AS independently classifies the state of the network as either conflict-free or potentially conflicting by observing its local history only (namely, route flaps). Based on the degree of measured conflicts, each AS dynamically adjusts its own path preferences---increasing its preference for observably stable paths over flapping paths. APMS also includes a mechanism to distinguish route flaps due to topology changes, so as not to confuse them with those due to policy conflicts. A correctness and convergence analysis of APMS based on the sub-stability property of chosen paths is presented. Implementation in the SSF network simulator is performed, and simulation results for different performance metrics are presented. The metrics capture the dynamic performance (in terms of instantaneous throughput, delay, etc.) of APMS and other competing solutions, thus exposing the often neglected aspects of performance.

Scalable Overlay Multicast Tree Construction for QoS-Constrained Media Streaming

Overlay networks have become popular in recent times for content distribution and end-system multicasting of media streams. In the latter case, the motivation is based on the lack of widespread deployment of IP multicast and the ability to perform end-host processing. However, constructing routes between various end-hosts, so that data can be streamed from content publishers to many thousands of subscribers, each having their own QoS constraints, is still a challenging problem. First, any routes between end-hosts using trees built on top of overlay networks can increase stress on the underlying physical network, due to multiple instances of the same data traversing a given physical link. Second, because overlay routes between end-hosts may traverse physical network links more than once, they increase the end-to-end latency compared to IP-level routing. Third, algorithms for constructing efficient, large-scale trees that reduce link stress and latency are typically more complex. This paper therefore compares various methods to construct multicast trees between end-systems, that vary in terms of implementation costs and their ability to support per-subscriber QoS constraints. We describe several algorithms that make trade-offs between algorithmic complexity, physical link stress and latency. While no algorithm is best in all three cases we show how it is possible to efficiently build trees for several thousand subscribers with latencies within a factor of two of the optimal, and link stresses comparable to, or better than, existing technologies.

Design, synthesis and development of novel indolocarbazole derivatives as potential anti-cancer agents

This thesis describes work carried out on the design of new routes to a range of bisindolylmaleimide and indolo[2,3-a]carbazole analogs, and investigation of their potential as successful anti-cancer agents. Following initial investigation of classical routes to indolo[2,3-a]pyrrolo[3,4-c]carbazole aglycons, a new strategy employing base-mediated condensation of thiourea and guanidine with a bisindolyl β-ketoester intermediate afforded novel 5,6-bisindolylpyrimidin-4(3H)-ones in moderate yields. Chemical diversity within this H-bonding scaffold was then studied by substitution with a panel of biologically relevant electrophiles, and by reductive desulfurisation. Optimisation of difficult heterogeneous literature conditions for oxidative desulfurisation of thiouracils was also accomplished, enabling a mild route to a novel 5,6-bisindolyluracil pharmacophore to be developed within this work. The oxidative cyclisation of selected acyclic bisindolyl systems to form a new planar class of indolo[2,3-a]pyrimido[5,4-c]carbazoles was also investigated. Successful conditions for this transformation, as well as the limitations currently prevailing for this approach are discussed. Synthesis of 3,4-bisindolyl-5-aminopyrazole as a potential isostere of bisindolylmaleimide agents was encountered, along with a comprehensive derivatisation study, in order to probe the chemical space for potential protein backbone H-bonding interactions. Synthesis of a related 3,4-arylindolyl-5-aminopyrazole series was also undertaken, based on identification of potent kinase inhibition within a closely related heterocyclic template. Following synthesis of approximately 50 novel compounds with a diversity of H-bonding enzyme-interacting potential within these classes, biological studies confirmed that significant topo II inhibition was present for 9 lead compounds, in previously unseen pyrazolo[1,5-a]pyrimidine, indolo[2,3-c]carbazole and branched S,N-disubstituted thiouracil derivative series. NCI-60 cancer cell line growth inhibition data for 6 representative compounds also revealed interesting selectivity differences between each compound class, while a new pyrimido[5,4-c]carbazole agent strongly inhibited cancer cell division at 10 µM, with appreciable cytotoxic activity observed across several tumour types.

Semiconductor nanowire fabrication via bottom-up & top-down paradigms

Semiconductor nanowires are pseudo 1-D structures where the magnitude of the semiconducting material is confined to a length of less than 100 nm in two dimensions. Semiconductor nanowires have a vast range of potential applications, including electronic (logic devices, diodes), photonic (laser, photodetector), biological (sensors, drug delivery), energy (batteries, solar cells, thermoelectric generators), and magnetic (spintronic, memory) devices. Semiconductor nanowires can be fabricated by a range of methods which can be categorised into one of two paradigms, bottom-up or top-down. Bottom-up processes can be defined as those where structures are assembled from their sub-components in an additive fashion. Top-down fabrication strategies use sculpting or etching to carve structures from a larger piece of material in a subtractive fashion. This seminar will detail a number of novel routes to fabricate semiconductor nanowires by both bottom-up and top-down paradigms. Firstly, a novel bottom-up route to fabricate Ge nanowires with controlled diameter distributions in the sub-20 nm regime will be described. This route details nanowire synthesis and diameter control in the absence of a foreign seed metal catalyst. Additionally a top-down route to nanowire array fabrication will be detailed outlining the importance of surface chemistry in high-resolution electron beam lithography (EBL) using hydrogen silsesquioxane (HSQ) on Ge and Bi2Se3 surfaces. Finally, a process will be described for the directed self-assembly of a diblock copolymer (PS-b-PDMS) using an EBL defined template. This section will also detail a route toward selective template sidewall wetting of either block in the PS-b-PDMS system, through tailored functionalisation of the template and substrate surfaces.

Planning the deployment of fault-tolerant wireless sensor networks

Since Wireless Sensor Networks (WSNs) are subject to failures, fault-tolerance becomes an important requirement for many WSN applications. Fault-tolerance can be enabled in different areas of WSN design and operation, including the Medium Access Control (MAC) layer and the initial topology design. To be robust to failures, a MAC protocol must be able to adapt to traffic fluctuations and topology dynamics. We design ER-MAC that can switch from energy-efficient operation in normal monitoring to reliable and fast delivery for emergency monitoring, and vice versa. It also can prioritise high priority packets and guarantee fair packet deliveries from all sensor nodes. Topology design supports fault-tolerance by ensuring that there are alternative acceptable routes to data sinks when failures occur. We provide solutions for four topology planning problems: Additional Relay Placement (ARP), Additional Backup Placement (ABP), Multiple Sink Placement (MSP), and Multiple Sink and Relay Placement (MSRP). Our solutions use a local search technique based on Greedy Randomized Adaptive Search Procedures (GRASP). GRASP-ARP deploys relays for (k,l)-sink-connectivity, where each sensor node must have k vertex-disjoint paths of length ≤ l. To count how many disjoint paths a node has, we propose Counting-Paths. GRASP-ABP deploys fewer relays than GRASP-ARP by focusing only on the most important nodes – those whose failure has the worst effect. To identify such nodes, we define Length-constrained Connectivity and Rerouting Centrality (l-CRC). Greedy-MSP and GRASP-MSP place minimal cost sinks to ensure that each sensor node in the network is double-covered, i.e. has two length-bounded paths to two sinks. Greedy-MSRP and GRASP-MSRP deploy sinks and relays with minimal cost to make the network double-covered and non-critical, i.e. all sensor nodes must have length-bounded alternative paths to sinks when an arbitrary sensor node fails. We then evaluate the fault-tolerance of each topology in data gathering simulations using ER-MAC.