Role of P-glycoprotein in limiting the brain penetration of glabridin, an active isoflavan from the root of Glycyrrhiza glabra.

Purpose. Glabridin is a major active constituent of Glycyrrhiza glabra which is commonly used in the treatment of cardiovascular and central nervous system (CNS) diseases. Recently, we have found that glabridin is a substrate of P-glycoprotein (PgP/MDR1). This study aimed to investigate the role of PgP in glabridin penetration across the blood–brain barrier (BBB) using several in vitro and in vivo models.
Materials and Methods. Cultured primary rat brain microvascular endothelial cells (RBMVECs) were used in the uptake, efflux and transcellular transport studies. A rat bilateral in situ brain perfusion model was used to investigate the brain distribution of glabridin. The brain and tissue distribution of glabridin in rats with or without coadministered verapamil or quinidine were examined with correction for the tissue residual blood. In addition, the brain distribution of glabridin in mdr1a(-/-) mice was compared with the wild-type mice. Glabridin in various biological matrices was determined by a validated liquid chromatography mass spectrometric method.
Results. The uptake and efflux of glabridin in cultured RBMVECs were ATP-dependent and significantly altered in the presence of a PgP or multi-drug resistance protein (Mrp1/2) inhibitor (e.g. verapamil or MK-571). A polarized transport of glabridin was found in RBMVEC monolayers with
facilitated efflux from the abluminal (BL) to luminal (AP) side. Addition of a PgP or Mrp1/2 inhibitor in both luminal and abluminal sides attenuated the polarized transport across RBMVECs. In a bilateral in situ brain perfusion model, the uptake of glabridin into the cerebrum increased from 0.42 T 0.09% at 1 min to 9.27 T 1.69% (ml/100 g tissue) at 30 min and was significantly greater than that for sucrose. Coperfusion of a PgP or Mrp1/2 inhibitor significantly increased the brain distribution of glabridin by 33.6j142.9%. The rat brain levels of glabridin were only about 27% of plasma levels when corrected by tissue residual blood and it was increased to up to 44% when verapamil or quinidine was coadministered. The area under the brain concentration-time curve (AUC) of glabridin in mdr1a(-/-) mice was 6.0-fold higher than the wild-type mice.
Conclusions. These findings indicate that PgP limits the brain penetration of glabridin through the BBB and PgP may cause drug resistance to glabridin (licorice) therapy for CNS diseases and potential drugglabridin interactions. However, further studies are needed to explore the role of other drug transporters (e.g. Mrp1-4) in restricting the brain penetration of glabridin.

Transport of cryptotanshinone, a major active triterpenoid in Salvia miltiorrhiza Bunge widely used in the treatment of stroke and Alzheimers disease, across the blood-brain

Cryptotanshinone (CTS), a major constituent from the roots of Salvia miltiorrhiza (Danshen), is widely used in the treatment of coronary heart disease, stroke and less commonly Alzheimer's disease. Our recent study indicates that CTS is a substrate for Pglycoprotein (PgP/MDR1/ABCB1). This study has investigated the nature of the brain distribution of CTS across the brain-blood barrier (BBB) using several in vitro and in vivo rodent models. A polarized transport of CTS was found in rat primary microvascular endothelial cell (RBMVEC) monolayers, with facilitated efflux from the abluminal side to luminal side. Addition of a PgP (e.g. verapamil and quinidine) or multi-drug resistance protein 1/2 (MRP1/2) inhibitor (e.g. probenecid and MK-571) in both luminal and abluminal sides attenuated the polarized transport. In a bilateral in situ brain perfusion model, the uptake of CTS into the cerebrum increased from 0.52 ± 0.1% at 1 min to 11.13 ± 2.36 ml/100 g tissue at 30 min and was significantly greater than that of sucrose. Co-perfusion of a PgP/MDR1 (e.g. verapamil) or MRP1/2 inhibitor (e.g. probenecid) significantly increased the brain distribution of CTS by 35.1-163.6%. The brain levels of CTS were only about 21% of those in plasma, and were significantly increased when coadministered with verapamil or probenecid in rats. The brain levels of CTS in rats subjected to middle cerebral artery occlusion and rats treated with quinolinic acid (a neurotoxin) were about 2- to 2.5-fold higher than the control rats. Moreover, the brain levels in mdr1a(-/-) and mrp1(-/-) mice were 10.9- and 1.5-fold higher than those in the wild-type mice, respectively. Taken collectively, these findings indicate that PgP and Mrp1 limit the brain penetration of CTS in rodents, suggesting a possible role of PgP and MRP1 in limiting the brain penetration of CTS in patients and causing drug resistance to Danshen therapy and interactions with conventional drugs that are substrates of PgP and MRP1. Further studies are needed to explore the role of other drug transporters in restricting the brain penetration of CTS and the clinical relevance.

Route maintenance using mobility prediction for mobile ad hoc networks

Next generation networks (3G & beyond) will support real-time multimedia applications through traditional wide-area networking concepts as well as hot-spot (WLAN) and ad hoc networking concepts. In order to fulfill the vision of next generation networks a method of maintaining a real-time flow despite frequent topology changes and irregularity in user movement is required. Mobility prediction has been identified as having applications in the areas of link availability estimation and pro-active routing in ad hoc networks. In this work we present the mobility prediction based algorithm for route maintenance in mobile ad hoc networks. Simulation study of the algorithm proves it to offer significant benefits to dynamic source routing (DSR)

Multimedia campaign on a shoestring : promoting 'Stay Active - Stay Independent' among seniors

Issue addressed: This paper describes a multimedia campaign implemented in rural New South Wales on a budget smaller than that typical of many published campaigns. The 'To Be Young at Heart- Stay Active Stay Independent' (SASI) campaign was one arm of a multi- strategic program to reduce falls among seniors by promoting physical activity. Methods: This 18-month campaign used social marketing techniques. Central to this campaign was strong formative research, significant use of corporate, community and media partnerships and a detailed, strategic distribution plan. Campaign reach was evaluated by a community intercept survey. Results: A variety of high quality information, education and communication (IEC) resources were developed. Overall, the campaign cost was calculated at $191,000. The actual cost of $42,000 (excluding staff time) was used to generate almost double this amount in sponsorship ($82,000). In the mid-campaign reach survey, 36% recognised the campaign and attributed this to television (58%), newspaper (33%), poster (13%) and bus-back advertising (8%). Of these respondents, 21% reported seeking information about physical activity, 33% reported increased intention to be more active, and 22% reported becoming more active as a result of the campaign. Conclusions: It is possible to develop and deliver a well designed, multimedia campaign on a limited budget by using sound formative research and engaging community and corporate partners to generate sponsorship. An effective distribution strategy is crucial and may require additional partnerships at State or national level.

The crossroads approach to information discovery in wireless sensor networks

Wireless sensor networks (WSN) are attractive for information gathering in large-scale data rich environments. In order to fully exploit the data gathering and dissemination capabilities of these networks, energy-efficient and scalable solutions for data storage and information discovery are essential. In this paper, we formulate the information discovery problem as a load-balancing problem, with the combined aim being to maximize network lifetime and minimize query processing delay resulting in QoS improvements. We propose a novel information storage and distribution mechanism that takes into account the residual energy levels in individual sensors. Further, we propose a hybrid push-pull strategy that enables fast response to information discovery queries.

Simulations results prove the proposed method(s) of information discovery offer significant QoS benefits for global as well as individual queries in comparison to previous approaches.

Entropy-based collaborative detection of DDOS attacks on community networks

A community network often operates with the same Internet service provider domain or the virtual network of different entities who are cooperating with each other. In such a federated network environment, routers can work closely to raise early warning of DDoS attacks to void catastrophic damages. However, the attackers simulate the normal network behaviors, e.g. pumping the attack packages as poisson distribution, to disable detection algorithms. It is an open question: how to discriminate DDoS attacks from surge legitimate accessing. We noticed that the attackers use the same mathematical functions to control the speed of attack package pumping to the victim. Based on this observation, the different attack flows of a DDoS attack share the same regularities, which is different from the real surging accessing in a short time period. We apply information theory parameter, entropy rate, to discriminate the DDoS attack from the surge legitimate accessing. We proved the effectiveness of our method in theory, and the simulations are the work in the near future. We also point out the future directions that worth to explore in the future.

Finite-time consensus algorithm of multi-agent networks

This paper is concerned with leader-follower finite-time consensus control of multi-agent networks with input disturbances. Terminal sliding mode control scheme is used to design the distributed control law. A new terminal sliding mode surface is proposed to guarantee finite-time consensus under fixed topology, with the common assumption that the position and the velocity of the active leader is known to its neighbors only. By using the finite-time Lyapunov stability theorem, it is shown that if the directed graph of the network has a directed spanning tree, then the terminal sliding mode control law can guarantee finite-time consensus even under the assumption that the time-varying control input of the active leader is unknown to any follower.

Energy-efficient medium access control in wireless sensor networks

Medium access control for wireless sensor networks has been an active
research area in the past decade. This chapter discusses a set of important medium access control (MAC) attributes and possible design trade-offs in protocol design, with an emphasis on energy efficiency. Then we categorize existing MAC protocols into five groups, outline the representative protocols, and compare their advantages and disadvantages in the context of wireless sensor network. Finally, thoughts for practitioners are presented and open research issues are also discussed.

Fuzzy neural networks for control of dynamic systems

This thesis provides a unified and comprehensive treatment of the fuzzy neural networks as the intelligent controllers. This work has been motivated by a need to develop the solid control methodologies capable of coping with the complexity, the nonlinearity, the interactions, and the time variance of the processes under control. In addition, the dynamic behavior of such processes is strongly influenced by the disturbances and the noise, and such processes are characterized by a large degree of uncertainty. Therefore, it is important to integrate an intelligent component to increase the control system ability to extract the functional relationships from the process and to change such relationships to improve the control precision, that is, to display the learning and the reasoning abilities. The objective of this thesis was to develop a self-organizing learning controller for above processes by using a combination of the fuzzy logic and the neural networks. An on-line, direct fuzzy neural controller using the process input-output measurement data and the reference model with both structural and parameter tuning has been developed to fulfill the above objective. A number of practical issues were considered. This includes the dynamic construction of the controller in order to alleviate the bias/variance dilemma, the universal approximation property, and the requirements of the locality and the linearity in the parameters. Several important issues in the intelligent control were also considered such as the overall control scheme, the requirement of the persistency of excitation and the bounded learning rates of the controller for the overall closed loop stability. Other important issues considered in this thesis include the dependence of the generalization ability and the optimization methods on the data distribution, and the requirements for the on-line learning and the feedback structure of the controller. Fuzzy inference specific issues such as the influence of the choice of the defuzzification method, T-norm operator and the membership function on the overall performance of the controller were also discussed. In addition, the e-completeness requirement and the use of the fuzzy similarity measure were also investigated. Main emphasis of the thesis has been on the applications to the real-world problems such as the industrial process control. The applicability of the proposed method has been demonstrated through the empirical studies on several real-world control problems of industrial complexity. This includes the temperature and the number-average molecular weight control in the continuous stirred tank polymerization reactor, and the torsional vibration, the eccentricity, the hardness and the thickness control in the cold rolling mills. Compared to the traditional linear controllers and the dynamically constructed neural network, the proposed fuzzy neural controller shows the highest promise as an effective approach to such nonlinear multi-variable control problems with the strong influence of the disturbances and the noise on the dynamic process behavior. In addition, the applicability of the proposed method beyond the strictly control area has also been investigated, in particular to the data mining and the knowledge elicitation. When compared to the decision tree method and the pruned neural network method for the data mining, the proposed fuzzy neural network is able to achieve a comparable accuracy with a more compact set of rules. In addition, the performance of the proposed fuzzy neural network is much better for the classes with the low occurrences in the data set compared to the decision tree method. Thus, the proposed fuzzy neural network may be very useful in situations where the important information is contained in a small fraction of the available data.

A distributed active defense system against DDoS attacks

This thesis proposes a novel architecture of Distributed Active Defense System (DADS) against Distibuted Denial of Service (DDoS) attacks. Three sub-systems of DADS were built. For each sub-system corresponding algorithms were developed, prototypes implemented, criteria for evaluation were set up and experiments in both simulation and real network laboratory environments were carried out.

Network resilience in low-resource mobile wireless sensor networks

Wireless sensor networks (WSNs) are deployed in numerous mission critical applications in which the network needs to remain active for as long as possible while delivering quality information to a base station. However, WSNs suffer from a wide range of attacks due to their limited processing and energy capabilities. Their resiliency, however, depends on fast recovery from such attacks being achieved. In recent work, the authors developed and implemented clustering, reprogramming and authentication protocols involved in recovering stationary WSNs with low resources. In this paper, we determine the additional resources required in implementing these protocols in a mobile WSN.

We present recovery protocols on TinyOS motes for a low-resourced, mobile deployment. We describe the issues we encountered in the implementation. We present times, RAM and ROM needed to run the recovery protocols and compare these with the stationary case, demonstrating that the additional cost of reprogramming in a mobile WSN is less than 25% of that in a stationary WSN and the additional cost of re-clustering in a mobile WSN is less than 9% of that in a stationary WSN. Authentication has an insignificant cost increase.

Coming soon (to a theatre near you) : the temporality of global film distribution to Australia

This article explores the changing contexts of international film exhibition in Australia over a 20-year period (1989–2009) by examining in some empirical detail Australia’s position in the global flow of films during this time. It argues that, at the most abstract level, distributors are engaged in the management and mediation of time and space in the field of global communications. It is proposed that distributors, through the organisation of temporal differentiation, are explicitly active in the creation of both cultural and commodity value. This is particularly apparent as film distributors explore and engage new methodologies of film release, which emphasise overlapping, intersecting and contradictory temporalities in the cinema experience.

Direction-specific diaphyseal geometry and mineral mass distribution of tibia and fibula: A pQCT study of female athletes representing different exercise loading types

Bones adapt to prevalent loading, which comprises mainly forces caused by muscle contractions. Therefore, we hypothesized that similar associations would be observed between neuromuscular performance and rigidity of bones located in the same body segment. These associations were assessed among 221 premenopausal women representing athletes in high-impact, odd-impact, highmagnitude, repetitive low-impact, and repetitive nonimpact sports and physically active referents aged 17–40 years. The whole group mean age and body mass were 23 (5) and 63 (9) kg, respectively. Bone cross sections at the tibial and fibular mid-diaphysis were assessed with peripheral quantitative computed tomography (pQCT). Density-weighted polar section modulus (SSI) and minimal and maximal crosssectional moments of inertia (Imin, Imax) were analyzed. Bone morphology was described as the Imax/Imin ratio. Neuromuscular performance was assessed by maximal power during countermovement jump (CMJ). Tibial SSI was 31% higher in the high-impact, 19% in the odd-impact, and 30% in the repetitive low-impact groups compared with the reference group (P\0.005). Only the high-impact group differed from the referents in fibular SSI (17%, P\0.005). Tibial morphology differed between groups (P = 0.001), but fibular morphology did not (P = 0.247). The bone-bygroup interaction was highly significant (P\0.001). After controlling for height, weight, and age, the CMJ peak power correlated moderately with tibial SSI (r = 0.31, P\0.001) but not with fibular SSI (r = 0.069, P = 0.313). In conclusion, observed differences in the association between neuromuscular performance and tibial and fibular traits suggest
that the tibia and fibula experience different loading

Engineering molecular self-assembled fibrillar networks by ultrasound

The architecture of self-organized three-dimensionally interconnected nanocrystal fibrillar networks has been achieved by ultrasound from a solution consisting of separate spherulites. The ultrasound stimulated structural transformation is correlated to the striking ultrasonic effects on turning nongelled solutions or weak gels into strong gels instantly, with enhancement of the storage modulus up to 3 magnitudes and up to 4 times more gelling capability. The basic principle involved in the ultrasound-induced structural transformation is established on the basis of the nucleation-and-growth model of a fiber network formation, and the mechanism of seeding multiplication, aggregation suppressing, and fiber distribution and growth promotion is proposed. This novel technique enables us to produce self-supporting gel functional materials possessing significantly modified macroscopic properties, from materials previously thus far considered to be “useless”, without the use of chemical stimuli. Moreover, it provides a general strategy for the engineering of self-organized fiber network architectures, and we are consequently able to achieve the supramolecular functional materials with controllable macroscopic properties.

Spherulitic networks : from structure to rheological property

A finite element method based on ABAQUS is employed to examine the correlation between the microstructure and the elastic response of planar Cayley treelike fiber networks. It is found that the elastic modulus of the fiber network decreases drastically with the fiber length, following the power law. The power law of elastic modulus G′ vs the correlation length ξ obtained from this simulation has an exponent of −1.71, which is close to the exponent of −1.5 for a single-domain network of agar gels. On the other hand, the experimental results from multidomain networks give rise to a power law index of −0.49. The difference between −1.5 and −0.49 can be attributed to the multidomain structure, which weakens the structure of the overall system and therefore suppresses the increase in G′. In addition, when the aspect ratio of the fiber is smaller than 20, the radius of the fiber cross-section has a great impact on the network elasticity, while, when the aspect ratio is larger than 20, it has almost no effect on the elastic property of the network. The stress distribution in the network is uniform due to the symmetrical network structure. This study provides a general understanding of the correlation between microscopic structure and the macroscopic properties of soft functional materials.