Functionalized mesoporous silica nanoparticles for stimuli-responsive and targeted drug delivery

Construction of functional supramolecular nanoassemblies has attracted great deal of attention in recent years for their wide spectrum of practical applications. Mesoporous silica nanoparticles (MSN) in particular were shown to be effective scaffolds for the construction of drug carriers, sensors and catalysts. Herein, we describe the synthesis and characterization of stimuli-responsive, controlled release MSN-based assemblies for drug delivery. First we report on devising a functional UV light responsive delivery system for doxorubicin, a widely used anticancer drug. A positively charged drug molecule is adsorbed on the surface of the MSN through charge interaction and hydrogen bonding with surface silanols. The surface of MSN contained nitroveratryl carbamate protected aminopropyl moieties which undergo deprotection upon irradiation with UV light. The drug delivery principle is based on charge repulsion between UV light-generated, positively charged propylammonium ions and positively charged doxorubicin molecules. Release of the drug also increases by lowering the pH from 7.4 to 6.4. This result is beneficial for selective drug delivery to tumor tissues, as most tumor tissues have low extracellular pH value. We then set forth to develop magnetic analogues of mesoporous silica nanoparticles in order investigate possibilities for magnetic field induced targeted drug delivery. A series of new materials was obtained with radial and hexagonal packing of the mesopores, containing magnetic nanoparticles inside the core of the mesoporous silicate framework. We monitored the ability of the magnetic materials to adsorb and deliver anticancer drugs, 9-aminoacridine and camptothecin, and interesting results were obtained. If 9-aminoacridine was adsorbed on the magnetic materials, its release from the surface in PBS buffer was promoted if the silica surface was not functionalized with organic moieties. If camptothecin was adsorbed on the same materials, the presence of phenylethyl functional groups inside the mesopores promoted the loading and delivery of the drug. The results were confirmed by in vitro drug delivery studies on Chinese hamster ovarian cells (CHO). We further applied the magnetic mesoporous silica nanomaterial to develop a magnetically active nanocarrier for photosensitive delivery of camptothecin to cancer cells. The mesopores were loaded with the drug and the pore entrances were blocked by functionalized cadmium-sulfide nanoparticles through an o-nitrobenzyl-based photolabile linker. Upon irradiation with UV light the photolabile linker was cleaved which induced release of the anticancer drug. The cooperative anticancer effect of capping CdS nanoparticles and loaded camptothecin was demonstrated by in vitro viability studies on CHO cells, upon exposure of the cell cultures to low power UV light. Finally, we constructed a mesoporous silica nanoparticle-based nanocarrier which was capable of delivering the mesopore-loaded molecules upon irradiation with visible light. The cargo molecules were entrapped inside the mercaptopropyl-functionalized mesopores of MSN by an S-coordinated metal complex. Upon exposure to visible light the metal-sulfur coordination bond is cleaved which allows release of the mesopore-loaded dye. Ligand substitution by nitrogen monoxide, imidazole and histidine was also shown to induce the release of cargo molecules, although with lower efficiency than with visible light

A High-Throughput Byzantine Fault-Tolerant Protocol

State-machine replication (SMR) is a software technique for tolerating failures and for providing high availability in large-scale systems, through the use of commodity hardware. A replicated state-machine comprises a number of replicas, each of which runs an agreement protocol, with the goal of ensuring a consistent state across all of the replicas. In hostile environments, such as the Internet, Byzantine fault tolerant state-machine replication (BFT) is an important technique for providing robust services. During the past decade, we have seen an emergence of various BFT protocols. In order to be adopted, besides providing correctness, a BFT must provide good performance as well. Consequently, all of the new protocols focus on improving performance under various conditions. However, a closer look at the performance of state-of-the-art BFT protocols reveals that even in best-case execution scenarios, they still remain far behind their theoretical maximum. Based on exhaustive evaluation and monitoring of existing BFT protocols, we highlight a few impediments to their scalability. These obstructions include the use of IP multicast, the presence of bottlenecks due to asymmetric replica processing, and an unbalanced network bandwidth utilization. The goal of this thesis is to evaluate the actual impact of these scalability impediments, and to offer a solution for a high-throughput BFT protocol in the case in which the network itself is the bottleneck. To that end, we have developed Ring, a new BFT protocol which circumvents the aforementioned impediments. As its name suggests, Ring uses the ring communication topology, in the fault-free case. In the ring topology, each replica only performs point-to-point communications with two other replicas, namely its neighbors on the ring. Moreover, all of the replicas equally accept requests from clients and perform symmetric processing. Our performance evaluation shows that, with the network as the bottleneck, Ring outperforms all other, state-of-the-art BFT protocols. Ring achieves 118 Mbps on the Fast Ethernet – a 24% improvement in throughput over previous protocols. Finally, we conducted an extensive practical and analytic evaluation of Ring. In order to analyse benefits (and drawbacks) of Ring (and other protocols) under different settings, without resorting to costly experimentation, we developed an analytical performance model. Our performance model is based on queueing theory, and relies only on a handful of protocolagnostic measurements of the environment

Consequences of Compliance and Deterrence Models of Law Enforcement for the Exercise of Police Discretion

The Internet is suffering from ossification. There has been substantial research on improving current protocols, but the vendors are reluctant to deploy new ones. We believe that this is in part due to the difficulty of evaluating protocols under realistic conditions. Recent wide-area testbeds can help alleviate this problem, but they require substantial resources (equipment, bandwidth) from each participant, and they have difficulty in providing repeatability and full control over the experiments. Existing in-house networking testbeds are capable of running controlled, repeatable experiments, but are typically small-scale (due to various overheads), limited in features, or expensive. The premise of our work is that it is possible to leverage the recent increases in computational power to improve the researchers' ability to experiment with new protocols in lab settings. We propose a cost-effective testbed, called MX, which emulates many programmable routers running over a realistic topology on multi-core commodity servers. We leverage open source implementations of programmable routers, such as Click, and modify them to allow coexistence of multiple instances in the same kernel in an effort to reduce packet forwarding overheads. Our initial results show that we outperform similar cost-effective solutions by a factor of 2. Next, we demonstrate that grouping and placing routers on to cores which share the L2 cache yields high performance.QC 20140707</p

The new face of East-West migration in Europe

In order to contextualise the papers in this special issue, this paper presents an overview and framework for understanding the importance of East–West migration in Europe associated with the EU enlargement process. The new patterns and forms of migration seen among East European migrants in the West—in terms of circular and temporary free movement, informal labour market incorporation, cultures of migration, transnational networks, and other phenomena documented in the following papers—illustrate the emergence of a new migration system in Europe. Textbook narratives, in terms of standard accounts of immigration, integration and citizenship based on models of post-colonial, guestworker and asylum migration, will need to be rethought. One particularly fertile source for this is the large body of theory and research developed in the study of Mexican–US migration, itself a part of a regional integration process of comparative relevance to the new European context. While the benefits of open migration from the East will likely triumph over populist political hostility, it is a system that may encourage an exploitative dual labour market for Eastern movers working in the West, as well as encouraging a more effective racial or ethnically-based closure to immigrants from South of the Mediterranean and further afield

The Next 700 BFT Protocols

International audienceCet article présente un framework permettant de faciliter le développent de protocoles de réplication de machines à états tolérant les fautes byzantines

Stretching BFT

State-of-the-art BFT protocols remain far from the maximum theoretical throughput. Based on exhaustive eval- uation and monitoring of existing BFT protocols, we highlight few impediments to their scaling. These include the use of IP multicast, the presence of bottlenecks due to asymmetric replica processing, and an unbalanced network bandwidth utilization. To better evaluate the actual impact of these scalability impediments, we devised Ring, a new BFT protocol, which circumvents them. As its name suggests, Ring uses a ring communication topology, where, in the fault-free case, each replica only performs point-to-point communications with two other replicas, namely its neighbors on the ring. Moreover, all replicas equally accept requests from clients and perform symmetric processing. Our experiments show that on a Fast Ethernet network Ring achieves an aggregate throughput of 118 Mbps, which is 27% higher than most efficient state-of-the-art BFT protocols. Ring approaches but does not reach the throughput theoret- ical maximum. Yet, its very performance makes it possible to envision a new generation of BFT protocols that might reach the actual theoretical maximum

The Next 700 BFT Protocols

International audienceCet article présente un framework permettant de faciliter le développent de protocoles de réplication de machines à états tolérant les fautes byzantines

The Next 700 BFT Protocols

Modern Byzantine fault-tolerant state machine replication (BFT) protocols involve about 20.000 lines of challenging C++ code encompassing synchronization, networking and cryptography. They are notoriously difficult to develop, test and prove. We present a new abstraction to simplify these tasks. We treat a BFT protocol as a composition of instances of our abstraction. Each instance is developed and analyzed independently. To illustrate our approach, we first show how, with our abstraction, the benefits of a BFT protocol like Zyzzyva could have been obtained with much less pain. Namely, we develop AZyzzyva, a new protocol that mimics the behavior of Zyzzyva in best-case situations (for which Zyzzyva was optimized) using less than 24% of the actual code of Zyzzyva. To cover worst-case situations, our abstraction enables to compose AZyzzyva with any existing BFT protocol, typically, a classical one like PBFT which has been proved correct and widely tested. We then present Aliph, a new BFT protocol that outperforms previous BFT protocols both in terms of latency (by up to 30%) and throughput (by up to 360%). Development of Aliph required two new instances of our abstraction. Each instance contains less than 25% of the code needed to develop state-of-the-art BFT protocols

The Next 700 BFT Protocols

We present Abstract (ABortable STate mAChine replicaTion), a new abstraction for designing and reconfiguring generalized replicated state machines that are, unlike traditional state machines, allowed to abort executing a client's request if "something goes wrong." Abstract can be used to considerably simplify the incremental development of efficient Byzantine faulttolerant state machine replication (BFT) protocols that are notorious for being difficult to develop. In short, we treat a BFT protocol as a composition of Abstract instances. Each instance is developed and analyzed independently and optimized for specific system conditions. We illustrate the power of Abstract through several interesting examples. We first show how Abstract can yield benefits of a state-of-the-art BFT protocol in a less painful and errorprone manner. Namely, we develop AZyzzyva, a new protocol that mimics the celebrated best-case behavior of Zyzzyva using less than 35% of the Zyzzyva code. To cover worst-case situations, our abstraction enables one to use in AZyzzyva any existing BFT protocol. We then present Aliph, a new BFT protocol that outperforms previous BFT protocols in terms of both latency (by up to 360%) and throughput (by up to 30%). Finally, we present R-Aliph, an implementation of Aliph that is robust, that is, whose performance degrades gracefully in the presence of Byzantine replicas and Byzantine clients

Analiza proizvodnje kukuruza na području Smedereva u periodu 2013-2015. godine

The agro-ecological conditions of the city of Smederevo, maize yields were studied over a three year period (2013-2015.). A total of 13 corn hybrids (8 hybrids of Maize Research Institute Zemun and 5 hybrids Istitute of Field and Vegetable Crops, Novi Sad). Meteorological conditions, especially temperature, distribution and quantity precipitation the growing season had a significant impact on the yield of hybrids during the three years of research. The most optimal climatic conditions for the growth of corn were in 2014, and on them were all tested hybrids reacted achieve significantly higher yields (average grain yield in 2014 amounted to 11.83 t ha-1) compared to the other two years (6.40 t ha-1 in 2013, and 5.97 t ha-1 in 2015). Optimal and adequate agricultural techniques, proper selection of hybrids, proper selection of hybrids for a specific localities, and the application of irrigation it is possible to achieve a stable and high yields of maize and to some extent mitigate the impact of unfavorable meteorological factors, primarily drought.U agroekološkim uslovima grada Smedereva ispitivani su prinosi kukuruza u trogodišnjem periodu (2013-2015. godina). Analizirano je ukupno 13 hibrida kukuruza (8 hibrida Instituta za kukuruz Zemun Polje i 5 hibrida Istituta za ratarstvo i povrtarstvo Novi Sad). Meteorološki uslovi, a posebno temperatura, raspored i količina padavina u toku vegetacionog perioda imale su značajan uticaj na prinos ispitivanih hibrida tokom sve tri godine ispitivanja. Najoptimalniji klimatski uslovi za uspevanje kukuruza bili su u 2014. godini, a na njih su svi ispitivani hibridi reagovali postizanjem znatno većih prinosa (prosečan prinos zrna kukuruza u 2014. godini iznosio je 11,83 t ha-1) u odnosu na ostale dve godine (6,40 t ha-1 u 2013. godini, odnosno 5,97 t ha-1 u 2015. godini). Optimalnom i adekvatnom agrotehnikom, pravilnim izborom hibrida za odredjeni lokalitet, kao i primenom navodnjavanja moguće je postići stabilne i visoke prinose kukuruza i donekle ublažiti uticaj nepovoljnih meteoroloških faktora, a pre svega suše