Design, synthesis and in vitro degradation of a novel co-drug for the treatment of psoriasis

Psoriasis is a common, chronic and relapsing inflammatory skin disease. It affects approximately 2% of the western population and has no cure. Combination therapy for psoriasis often proves more efficacious and better tolerated than monotherapy with a single drug. Combination therapy could be administered in the form of a co-drug, where two or more therapeutic compounds active against the same condition are linked by a cleavable covalent bond. Similar to the pro-drug approach, the liberation of parent moieties post-administration, by enzymatic and/or chemical mechanisms, is a pre-requisite for effective treatment. In this study, a series of co-drugs incorporating dithranol in combination with one of several non-steroidal anti-inflammatory drugs, both useful for the treatment of psoriasis, were designed, synthesized and evaluated. An ester co-drug comprising dithranol and naproxen in a 1:1 stoichiometric ratio was determined to possess the optimal physicochemical properties for topical delivery. The co-drug was fully hydrolyzed in vitro by porcine liver esterase within four hours. When incubated with homogenized porcine skin, 9.5% of the parent compounds were liberated after 24 h, suggesting in situ esterase-mediated cleavage of the co-drug would occur within the skin. The kinetics of the reaction revealed first order kinetics, Vmax = 10.3 μM/min and Km = 65.1 μM. The co-drug contains a modified dithranol chromophore that was just 37% of the absorbance of dithranol at 375 nm and suggests reduced skin/clothes staining. Overall, these findings suggest that the dithranol-naproxen co-drug offers an attractive, novel approach for the treatment of psoriasis.

Cross-layer design for multiuser MIMO MRC systems with feedback constraints

Cross-layer techniques represent efficient means to enhance throughput and increase the transmission reliability of wireless communication systems. In this paper, a cross-layer design of aggressive adaptive modulation and coding (A-AMC), truncated automatic repeat request (T-ARQ), and user scheduling is proposed for multiuser multiple-input-multiple-output (MIMO) maximal ratio combining (MRC) systems, where the impacts of feedback delay (FD) and limited feedback (LF) on channel state information (CSI) are also considered. The A-AMC and T-ARQ mechanism selects the appropriate modulation and coding schemes (MCSs) to achieve higher spectral efficiency while satisfying the service requirement on the packet loss rate (PLR), profiting from the feasibility of using different MCSs to retransmit a packet, which is destined to a scheduled user selected to exploit multiuser diversity and enhance the system's performance in terms of both transmission efficiency and fairness. The system's performance is evaluated in terms of the average PLR, average spectral efficiency (ASE), outage probability, and average packet delay, which are derived in closed form, considering transmissions over Rayleigh-fading channels. Numerical results and comparisons are provided and show that A-AMC combined with T-ARQ yields higher spectral efficiency than the conventional scheme based on adaptive modulation and coding (AMC), while keeping the achieved PLR closer to the system's requirement and reducing delay. Furthermore, the effects of the number of ARQ retransmissions, numbers of transmit and receive antennas, normalized FD, and cardinality of the beamforming weight vector codebook are studied and discussed.

Cross-layer design for MIMO systems over spatially correlated and keyhole Nakagami-m fading channels

Cross-layer design is a generic designation for a set of efficient adaptive transmission schemes, across multiple layers of the protocol stack, that are aimed at enhancing the spectral efficiency and increasing the transmission reliability of wireless communication systems. In this paper, one such cross-layer design scheme that combines physical layer adaptive modulation and coding (AMC) with link layer truncated automatic repeat request (T-ARQ) is proposed for multiple-input multiple-output (MIMO) systems employing orthogonal space--time block coding (OSTBC). The performance of the proposed cross-layer design is evaluated in terms of achievable average spectral efficiency (ASE), average packet loss rate (PLR) and outage probability, for which analytical expressions are derived, considering transmission over two types of MIMO fading channels, namely, spatially correlated Nakagami-m fading channels and keyhole Nakagami-m fading channels. Furthermore, the effects of the maximum number of ARQ retransmissions, numbers of transmit and receive antennas, Nakagami fading parameter and spatial correlation parameters, are studied and discussed based on numerical results and comparisons. Copyright © 2009 John Wiley & Sons, Ltd.

Cross-layer design of enhanced AMC with truncated ARQ protocols

Using a cross-layer approach, two enhancement techniques applied for adaptive modulation and coding (AMC) with truncated automatic repeat request (T-ARQ) are investigated, namely, aggressive AMC (A-AMC) and constellation rearrangement (CoRe). Aggressive AMC selects the appropriate modulation and coding schemes (MCS) to achieve higher spectral efficiency, profiting from the feasibility of using different MCSs for retransmitting a packet, whereas in the CoRe-based AMC, retransmissions of the same data packet are performed using different mappings so as to provide different degrees of protection to the bits involved, thus achieving mapping diversity gain. The performance of both schemes is evaluated in terms of average spectral efficiency and average packet loss rate, which are derived in closed-form considering transmission over Nakagami-m fading channels. Numerical results and comparisons are provided. In particular, it is shown that A-AMC combined with T-ARQ yields higher spectral efficiency than the AMC-based conventional scheme while keeping the achieved packet loss rate closer to the system's requirement, and that it can achieve larger spectral efficiency objectives than that of the scheme using AMC along with CoRe.

Safe construction through design: perspectives from the site team

How does the work of designers impact on the safety of operatives at the construction site? Safety research and policy emphasize the importance of designing for safe construction, yet the interface between design and construction is poorly understood: accidents have multiple causes making it hard to establish causal links between design choices and safety outcomes. An in-depth case study of a major station project examines how professionals on the construction site perceive and manage the safety challenges of a building design. Analyses reveal understandings that, on the project studied, design has an impact on safety because of: (1) the timing of design work, where the volume of late design changes increased the difficulty of planning safe procedures, e.g. for working at height, lifting heavy items, refurbishing and demolishing old buildings; and (2) inputs from design stakeholders with insufficient practical knowledge of construction and operation required unplanned work-arounds, e.g. to coordinate different sub-systems, provide maintenance access, and manage loads during construction. These findings suggest that safety suffers where projects are under-designed, and that alongside regulation, there is a need for robust management attention to the contractual structures, incentives, processes and tools that enable clients and designers to understand material practices of construction and operation.

Evaluating relative impact of virtual reality system variables on architectural design comprehension and presence - A variable-centered approach using fractional factorial experiment

The relative contributions of five variables (Stereoscopy, screen size, field of view, level of realism and level of detail) of virtual reality systems on spatial comprehension and presence are evaluated here. Using a variable-centered approach instead of an object-centric view as its theoretical basis, the contributions of these five variables and their two-way interactions are estimated through a 25-1 fractional factorial experiment (screening design) of resolution V with 84 subjects. The experiment design, procedure, measures used, creation of scales and indices, results of statistical analysis, their meaning and agenda for future research are elaborated.

Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design?

The INSIG2 rs7566605 polymorphism was identified for obesity (BMI> or =30 kg/m(2)) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status ('healthy population', HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I(2) measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I(2) measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI> or =32.5, 35.0, 37.5, 40.0 kg/m(2) versus BMI<25 kg/m(2)) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.

Fractal geometry and architecture design: case study review

The idea of buildings in harmony with nature can be traced back to ancient times. The increasing concerns on sustainability oriented buildings have added new challenges in building architectural design and called for new design responses. Sustainable design integrates and balances the human geometries and the natural ones. As the language of nature, it is, therefore, natural to assume that fractal geometry could play a role in developing new forms of aesthetics and sustainable architectural design. This paper gives a brief description of fractal geometry theory and presents its current status and recent developments through illustrative review of some fractal case studies in architecture design, which provides a bridge between fractal geometry and architecture design.

Design of delay-tolerant space–time codes with limited feedback

In cooperative communication networks, owing to the nodes' arbitrary geographical locations and individual oscillators, the system is fundamentally asynchronous. Such a timing mismatch may cause rank deficiency of the conventional space-time codes and, thus, performance degradation. One efficient way to overcome such an issue is the delay-tolerant space-time codes (DT-STCs). The existing DT-STCs are designed assuming that the transmitter has no knowledge about the channels. In this paper, we show how the performance of DT-STCs can be improved by utilizing some feedback information. A general framework for designing DT-STC with limited feedback is first proposed, allowing for flexible system parameters such as the number of transmit/receive antennas, modulated symbols, and the length of codewords. Then, a new design method is proposed by combining Lloyd's algorithm and the stochastic gradient-descent algorithm to obtain optimal codebook of STCs, particularly for systems with linear minimum-mean-square-error receiver. Finally, simulation results confirm the performance of the newly designed DT-STCs with limited feedback.

Design of a computerised treatment for short-term memory deficits in aphasia

The treatment of auditory-verbal short-term memory (STM) deficits in aphasia is a growing avenue of research (Martin & Reilly, 2012; Murray, 2012). STM treatment requires time precision, which is suited to computerised delivery. We have designed software, which provides STM treatment for aphasia. The treatment is based on matching listening span tasks (Howard & Franklin, 1990), aiming to improve the temporal maintenance of multi-word sequences (Salis, 2012). The person listens to pairs of word-lists that differ in word-order and decides if the pairs are the same or different. This approach does not require speech output and is suitable for persons with aphasia who have limited or no output. We describe the software and how its review from clinicians shaped its design.

Chemistry and structure by design: ordered CuNi(CN)4 sheets with copper(II) in a square-planar environment

Layered copper–nickel cyanide, CuNi(CN)4, a 2-D negative thermal expansion material, is one of a series of copper(II)-containing cyanides derived from Ni(CN)2. In CuNi(CN)4, unlike in Ni(CN)2, the cyanide groups are ordered generating square-planar Ni(CN)4 and Cu(NC)4 units. The adoption of square-planar geometry by Cu(II) in an extended solid is very unusual.

Structure-based energetics of protein interfaces guides foot-and-mouth disease virus vaccine design

Virus capsids are primed for disassembly, yet capsid integrity is key to generating a protective immune response. Foot-and-mouth disease virus (FMDV) capsids comprise identical pentameric protein subunits held together by tenuous noncovalent interactions and are often unstable. Chemically inactivated or recombinant empty capsids, which could form the basis of future vaccines, are even less stable than live virus. Here we devised a computational method to assess the relative stability of protein-protein interfaces and used it to design improved candidate vaccines for two poorly stable, but globally important, serotypes of FMDV: O and SAT2. We used a restrained molecular dynamics strategy to rank mutations predicted to strengthen the pentamer interfaces and applied the results to produce stabilized capsids. Structural analyses and stability assays confirmed the predictions, and vaccinated animals generated improved neutralizing-antibody responses to stabilized particles compared to parental viruses and wild-type capsids.