Discovery and Development of a Potent and Highly Selective Small Molecule Muscarinic Acetylcholine Receptor Subtype I (mAChR 1 or M-1) Antagonist In Vitro and In Vivo Probe

This article describes the discovery and development of the first highly selective, small molecule antagonist of the muscarinic acetylcholine receptor subtype I (mAChR1 or M-1). An M-1 functional, cell-based, calcium-mobilization assay identified three distinct chemical series with initial selectivity for M-1 versus M-4. An iterative parallel synthesis approach was employed to optimize all three series in parallel, which led to the development of novel microwave-assisted chemistry and provided important take home lessons for probe development projects. Ultimately, this effort produced VU0255035, a potent (IC50 = 130 nM) and selective (>75-fold vs. M-2-M-5 and >10 mu M vs. a panel of 75 GPCRs, ion channels and transporters) small molecule M-1 antagonist. Further profiling demonstrated that VU0255035 was centrally penetrant (Brain(AUC)/Plasma(AUC) of 0.48) and active in vivo, rendering it acceptable as both an in vitro and in vivo MLSCN/MLPCN probe molecule for studying and dissecting M-1 function.

UNUSUAL CHROMOSOME-NUMBER OF GRACILARIA-VERRUCOSA (GRACILARIALES, RHODOPHYTA) IN THE CAPE-GRIS-NEZ AREA, NORTHERN FRANCE

The chromosome number of Gracilaria verrucosa (Hudson) Papenfuss was estimated in numerous individuals from different populations of the Cape Gris-Nez area of Northern France. To optimize estimates and to minimize counting errors, several counts were made on the same nucleus and in different nuclei of the same individual. The haploid chromosome number was estimated in vegetative gametophytic cells and tetrasporocytic cells; the diploid number was estimated from tetrasporophytic vegetative cells. The basic haploid number was n = 17 +/- 1, whereas all other Gracilaria species for which chromosome numbers are available are reported to have n = 24. These include populations of G. verrucosa from Norway and Wales that have previously been shown to be conspecific with the Cape Gris-Nez populations by comparison of plastid DNA data. G. verrucosa is therefore one of the few red algae for which populations with different chromosome numbers are known.

Randomized caches for power-efficiency

Embedded processors are used in numerous devices executing dedicated applications. This setting makes it worthwhile to optimize the processor to the application it executes, in order to increase its power-efficiency. This paper proposes to enhance direct mapped data caches with automatically tuned randomized set index functions to achieve that goal. We show how randomization functions can be automatically generated and compare them to traditional set-associative caches in terms of performance and energy consumption. A 16 kB randomized direct mapped cache consumes 22% less energy than a 2-way set-associative cache, while it is less than 3% slower. When the randomization function is made configurable (i.e., it can be adapted to the program), the additional reduction of conflicts outweighs the added complexity of the hardware, provided there is a sufficient amount of conflict misses.

Improved structure optimization for fuzzy-neural networks

Fuzzy-neural-network-based inference systems are well-known universal approximators which can produce linguistically interpretable results. Unfortunately, their dimensionality can be extremely high due to an excessive number of inputs and rules, which raises the need for overall structure optimization. In the literature, various input selection methods are available, but they are applied separately from rule selection, often without considering the fuzzy structure. This paper proposes an integrated framework to optimize the number of inputs and the number of rules simultaneously. First, a method is developed to select the most significant rules, along with a refinement stage to remove unnecessary correlations. An improved information criterion is then proposed to find an appropriate number of inputs and rules to include in the model, leading to a balanced tradeoff between interpretability and accuracy. Simulation results confirm the efficacy of the proposed method.

Population-based study reveals new risk-stratification biomarker panel for Barrett's esophagus

BACKGROUND & AIMS: The risk of progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) is low and difficult to calculate. Accurate tools to determine risk are needed to optimize surveillance and intervention. We assessed the ability of candidate biomarkers to predict which cases of BE will progress to EAC or high-grade dysplasia and identified those that can be measured in formalin-fixed tissues. METHODS: We analyzed data from a nested case-control study performed using the population-based Northern Ireland BE Register (1993-2005). Cases who progressed to EAC (n = 89) or high-grade dysplasia =6 months after diagnosis with BE were matched to controls (nonprogressors, n = 291), for age, sex, and year of BE diagnosis. Established biomarkers (abnormal DNA content, p53, and cyclin A expression) and new biomarkers (levels of sialyl Lewis(a), Lewis(x), and Aspergillus oryzae lectin [AOL] and binding of wheat germ agglutinin) were assessed in paraffin-embedded tissue samples from patients with a first diagnosis of BE. Conditional logistic regression analysis was applied to assess odds of progression for patients with dysplastic and nondysplastic BE, based on biomarker status. RESULTS: Low-grade dysplasia and all biomarkers tested, other than Lewis(x), were associated with risk of EAC or high-grade dysplasia. In backward selection, a panel comprising low-grade dysplasia, abnormal DNA ploidy, and AOL most accurately identified progressors and nonprogressors. The adjusted odds ratio for progression of patients with BE with low-grade dysplasia was 3.74 (95% confidence interval, 2.43-5.79) for each additional biomarker and the risk increased by 2.99 for each additional factor (95% confidence interval, 1.72-5.20) in patients without dysplasia. CONCLUSIONS: Low-grade dysplasia, abnormal DNA ploidy, and AOL can be used to identify patients with BE most likely to develop EAC or high-grade dysplasia.

Free-space optoelectronic switching cores with MPLS for SANs over WDM ring networks

With increasing demands on storage devices in the modern communication environment, the storage area network (SAN) has evolved to provide a direct connection allowing these storage devices to be accessed efficiently. To optimize the performance of a SAN, a three-stage hybrid electronic/optical switching node architecture based on the concept of a MPLS label switching mechanism, aimed at serving as a multi-protocol label switching (MPLS) ingress label edge router (LER) for a SAN-enabled application, has been designed. New shutter-based free-space multi-channel optical switching cores are employed as the core switch fabric to solve the packet contention and switching path conflict problems. The system-level node architecture design constraints are evaluated through self-similar traffic sourced from real gigabit Ethernet network traces and storage systems. The extension performance of a SAN over a proposed WDM ring network, aimed at serving as an MPLS-enabled transport network, is also presented and demonstrated.

Evaluating the impact of network density, hidden nodes and capture effect for throughput guarantee in multi-hop wireless networks

To optimize the performance of wireless networks, one needs to consider the impact of key factors such as interference from hidden nodes, the capture effect, the network density and network conditions (saturated versus non-saturated). In this research, our goal is to quantify the impact of these factors and to propose effective mechanisms and algorithms for throughput guarantees in multi-hop wireless networks. For this purpose, we have developed a model that takes into account all these key factors, based on which an admission control algorithm and an end-to-end available bandwidth estimation algorithm are proposed. Given the necessary network information and traffic demands as inputs, these algorithms are able to provide predictive control via an iterative approach. Evaluations using analytical comparison with simulations as well as existing research show that the proposed model and algorithms are accurate and effective.

Computational identification of self-inhibitory peptides from envelope proteins

Fusion process is known to be the initial step of viral infection and hence targeting the entry process is a promising strategy to design antiviral therapy. The self-inhibitory peptides derived from the enveloped (E) proteins function to inhibit the proteinprotein interactions in the membrane fusion step mediated by the viral E protein. Thus, they have the potential to be developed into effective antiviral therapy. Herein, we have developed a Monte Carlo-based computational method with the aim to identify and optimize potential peptide hits from the E proteins. The stability of the peptides, which indicates their potential to bind in situ to the E proteins, was evaluated by two different scoring functions, dipolar distance-scaled, finite, ideal-gas reference state and residue-specific all-atom probability discriminatory function. The method was applied to a-helical Class I HIV-1 gp41, beta-sheet Class II Dengue virus (DENV) type 2 E proteins, as well as Class III Herpes Simplex virus-1 (HSV-1) glycoprotein, a E protein with a mixture of a-helix and beta-sheet structural fold. The peptide hits identified are in line with the druggable regions where the self-inhibitory peptide inhibitors for the three classes of viral fusion proteins were derived. Several novel peptides were identified from either the hydrophobic regions or the functionally important regions on Class II DENV-2 E protein and Class III HSV-1 gB. They have potential to disrupt the proteinprotein interaction in the fusion process and may serve as starting points for the development of novel inhibitors for viral E proteins. 

Treatment of lung infection in patients with cystic fibrosis:Current and future strategies

In patients with cystic fibrosis (CF) lung damage secondary to chronic infection is the main cause of death. Treatment of lung disease to reduce the impact of infection, inflammation and subsequent lung injury is therefore of major importance. Here we discuss the present status of antibiotic therapy for the major pathogens in CF airways, including prophylaxis against infection, eradication of early infection, suppression of chronic infection, and the treatment of infective exacerbations. We outline measures to optimize maintenance treatment for infection in the light of novel antibiotic drug formulations. We discuss new developments in culture-independent microbiological diagnostic techniques and the use of tools for monitoring the success of antibiotic treatment courses. Finally, cost-effectiveness analyses for antibiotic treatment in CF patients are discussed.

Effect of precursor on the performance of alumina for the dehydration of methanol to dimethyl ether

Dimethyl ether (DME) is amongst one of the most promising alternative, renewable and clean fuels being considered as a future energy carrier. In this study, the comparative catalytic performance of γ-Al2O3 prepared from two common precursors (aluminum nitrate (AN) and aluminum chloride (AC)) is presented. The impact of calcination temperature was evaluated in order to optimize both the precursor and pre-treatment conditions for the production of DME from methanol in a fixed bed reactor. The catalysts were characterized by TGA, XRD, BET and TPD-pyridine. Under reaction conditions where the temperature ranged from 180 °C to 300 °C with a WHSV = 12.1 h−1 it was found that all the catalysts prepared from AN(η-Al2O3) showed higher activity, at all calcination temperatures, than those prepared from AC(γ-Al2O3). In this study the optimum catalyst was produced from AN and calcined at 550 °C. This catalyst showed a high degree of stability and had double the activity of the commercial γ-Al2O3 or 87% of the activity of commercial ZSM-5(80) at 250 °C.

Optimisation of time/temperature treatment, for heat treated soft wheat flour

Chlorination of wheat flour in the EU countries has been replaced in recent years, to some extent, by heat treated flour which is used to produce high ratio cakes. Heat treated flour allows high ratio recipes to be developed which generate products with longer shelf life, finer texture, moist crumb and sweeter taste. The mechanism by which heat treatment improves the flour is not fully understood, but it is known that during the heat treatment process, protein denaturation and partial gelatinisation of the starch granules occurs, as well as an increase in batter viscosity. Therefore, it is important to optimize the flour heat treatment process, in order to enhance baking quality. Laboratory preparation of heat treated base wheat flour (culinary, soft, low protein) was carried out in a fluidised bed drier using a range of temperatures and times. The gluten was extracted from the final product and its quality was tested, to obtain objective and comparative information on the extent of protein denaturation. The results indicated that heat treatment of flour decreases gluten extensibility and partial gelatinisation of the starch granules occurred. After heat treatment the gluten appeared to retain moisture. The optimum time/temperature for the heat treatment of base flour was 120-130°C for 30 min with moisture content of ˜12.5%.© 2012 Elsevier Ltd. All rights reserved.

Barriers and Facilitators to Providing Palliative Care in Rural Communities: A Nursing Perspective

Nursing plays a key role in the coordination and delivery of palliative care services in rural settings. The purpose of this study is to identify barriers and enablers to providing palliative care in rural communities from a nursing perspective. This study utilized a qualitative descriptive design. Findings highlighted that the remoteness, limited access to resources and professional practice barriers created challenges for nurses as they tried to provide quality palliative care to their clients. System-related barriers were identified and included: lack of services, funding issues, and poor continuity of care. Despite these barriers, nurses drew from supports to optimize palliative care such as using a team approach to care, centers, utilizing local case managers and informal community members, and using palliative care resources. These results may help inform policy decisions around the needs of nurses who practice in rural settings to provide quality care to individuals who are dying and their families.

How Much Multiuser Diversity is Required for Energy Limited Multiuser Systems?

Multiuser diversity (MUDiv) is one of the central concepts in multiuser (MU) systems. In particular, MUDiv allows for scheduling among users in order to eliminate the negative effects of unfavorable channel fading conditions of some users on the system performance. Scheduling, however, consumes energy (e.g., for making users' channel state information available to the scheduler). This extra usage of energy, which could potentially be used for data transmission, can be very wasteful, especially if the number of users is large. In this paper, we answer the question of how much MUDiv is required for energy limited MU systems. Focusing on uplink MU wireless systems, we develop MU scheduling algorithms which aim at maximizing the MUDiv gain. Toward this end, we introduce a new realistic energy model which accounts for scheduling energy and describes the distribution of the total energy between scheduling and data transmission stages. Using the fact that such energy distribution can be controlled by varying the number of active users, we optimize this number by either i) minimizing the overall system bit error rate (BER) for a fixed total energy of all users in the system or ii) minimizing the total energy of all users for fixed BER requirements. We find that for a fixed number of available users, the achievable MUDiv gain can be improved by activating only a subset of users. Using asymptotic analysis and numerical simulations, we show that our approach benefits from MUDiv gains higher than that achievable by generic greedy access algorithm, which is the optimal scheduling method for energy unlimited systems. © 2010 IEEE.

Rotman Lens Used as a Demultiplexer/Multiplexer

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A new type of microwave demultiplexer is proposed which combines an arrayed waveguide grating (AWG) and a Rotman lens. The dispersion property of an AWG is employed to produce different phase slope responses for different frequencies, while the Rotman lens routes the frequency components onto different ports. To optimize isolation performance, the design constraints of both the AWG and the Rotman lens are re-examined and new design criteria elaborated. The optimized design is demonstrated of being capable of achieving 15 dB channel isolation over a 25% band range centered at 10 GHz. While a design based on a conventional Rotman lens yields isolation level of around 6 dB over a 9% band range centered at 10GHz.

Novel Radio Link Buffer Management Schemes for End-User Multi-class Traffic in High Speed Packet Access Networks

The requirement to provide multimedia services with QoS support in mobile networks has led to standardization and deployment of high speed data access technologies such as the High Speed Downlink Packet Access (HSDPA) system. HSDPA improves downlink packet data and multimedia services support in WCDMA-based cellular networks. As is the trend in emerging wireless access technologies, HSDPA supports end-user multi-class sessions comprising parallel flows with diverse Quality of Service (QoS) requirements, such as real-time (RT) voice or video streaming concurrent with non real-time (NRT) data service being transmitted to the same user, with differentiated queuing at the radio link interface. Hence, in this paper we present and evaluate novel radio link buffer management schemes for QoS control of multimedia traffic comprising concurrent RT and NRT flows in the same HSDPA end-user session. The new buffer management schemes—Enhanced Time Space Priority (E-TSP) and Dynamic Time Space Priority (D-TSP)—are designed to improve radio link and network resource utilization as well as optimize end-to-end QoS performance of both RT and NRT flows in the end-user session. Both schemes are based on a Time-Space Priority (TSP) queuing system, which provides joint delay and loss differentiation between the flows by queuing (partially) loss tolerant RT flow packets for higher transmission priority but with restricted access to the buffer space, whilst allowing unlimited access to the buffer space for delay-tolerant NRT flow but with queuing for lower transmission priority. Experiments by means of extensive system-level HSDPA simulations demonstrates that with the proposed TSP-based radio link buffer management schemes, significant end-to-end QoS performance gains accrue to end-user traffic with simultaneous RT and NRT flows, in addition to improved resource utilization in the radio access network.