Self-immolative linkers in polymeric delivery systems

There has been significant interest in the methodologies of controlled release for a diverse range of applications spanning drug delivery, biological and chemical sensors, and diagnostics. The advancement in novel substrate-polymer coupling moieties has led to the discovery of self-immolative linkers. This new class of linker has gained popularity in recent years in polymeric release technology as a result of stable bond formation between protecting and leaving groups, which becomes labile upon activation, leading to the rapid disassembly of the parent polymer. This ability has prompted numerous studies into the design and development of self-immolative linkers and the kinetics surrounding their disassembly. This review details the main concepts that underpin self-immolative linker technologies that feature in polymeric or dendritic conjugate systems and outlines the chemistries of amplified self-immolative elimination.

Synthesis of infrared filters for use in spaceflight systems

Progress is reported in the development of a new synthesis method for the design of filters and coatings for use in spaceborne infrared optics. This method uses the Golden Section optimization routine to make a search, using designated dielectric thin film combinations, for the coating design which fulfills the required spectral requirements. The final design is that which uses the least number of layers for the given thin film materials in the starting design. This synthesis method has successfully been used to design broadband anti-reflection coatings on infrared substrates. The 6 micrometers to 18 micrometers anti-reflection coating for the germanium optics of the HIRDLS instrument, to be flown on the NASA EOS-Chem satellite, is given as an example. By correctly defining the target function to describe any specific type of filter in the optimization part of the method, this synthesis method may be used to design general filters for use in spaceborne infrared optics.

Using pH abnormalities in diseased skin to trigger and target topical therapy

Abstract Purpose: The pH discrepancy between healthy and atopic dermatitis skin was identified as a site specific trigger for delivering hydrocortisone from microcapsules. Methods: Using Eudragit L100, a pH-responsive polymer which dissolves at pH 6, hydrocortisone-loaded microparticles were produced by oil-in-oil microencapsulation or spray drying. Release and permeation of hydrocortisone from microparticles alone or in gels was assessed and preliminary stability data was determined. Results: Drug release from microparticles was pH-dependent though the particles produced by spray drying also gave significant non-pH dependent burst release, resulting from their porous nature or from drug enrichment on the surface of these particles. This pH-responsive release was maintained upon incorporation of the oil-in-oil microparticles into Carbopol- and HPMC-based gel formulations. In-vitro studies showed 4 to 5-fold higher drug permeation through porcine skin from the gels at pH 7 compared to pH 5. Conclusions: Permeation studies showed that the oil-in-oil generated particles deliver essentially no drug at normal (intact) skin pH (5.0 – 5.5) but that delivery can be triggered and targeted to atopic dermatitis skin where the pH is elevated. The incorporation of these microparticles into Carbopol- and HPMC-based aqueous gel formulations demonstrated good stability and pH-responsive permeation into porcine skin.

Identification of potential mechanisms of toxicity after di-(2-ethylhexyl)-phthalate (DEHP) adult exposure in the liver using a systems biology approach

Phthalates are industrial additives widely used as plasticizers. In addition to deleterious effects on male genital development, population studies have documented correlations between phthalates exposure and impacts on reproductive tract development and on the metabolic syndrome in male adults. In this work we investigated potential mechanisms underlying the impact of DEHP on adult mouse liver in vivo. A parallel analysis of hepatic transcript and metabolic profiles from adult mice exposed to varying DEHP doses was performed. Hepatic genes modulated by DEHP are predominantly PPARalpha targets. However, the induction of prototypic cytochrome P450 genes strongly supports the activation of additional NR pathways, including Constitutive Androstane Receptor (CAR). Integration of transcriptomic and metabonomic profiles revealed a correlation between the impacts of DEHP on genes and metabolites related to heme synthesis and to the Rev-erbalpha pathway that senses endogenous heme level. We further confirmed the combined impact of DEHP on the hepatic expression of Alas1, a critical enzyme in heme synthesis and on the expression of Rev-erbalpha target genes involved in the cellular clock and in energy metabolism. This work shows that DEHP interferes with hepatic CAR and Rev-erbalpha pathways which are both involved in the control of metabolism. The identification of these new hepatic pathways targeted by DEHP could contribute to metabolic and endocrine disruption associated with phthalate exposure. Gene expression profiles performed on microdissected testis territories displayed a differential responsiveness to DEHP. Altogether, this suggests that impacts of DEHP on adult organs, including testis, could be documented and deserve further investigations.

Modelling phosphorus dynamics in multi-branch river systems: A study of the Black River, Lake Simcoe, Ontario, Canada

High rates of nutrient loading from agricultural and urban development have resulted in surface water eutrophication and groundwater contamination in regions of Ontario. In Lake Simcoe (Ontario, Canada), anthropogenic nutrient contributions have contributed to increased algal growth, low hypolimnetic oxygen concentrations, and impaired fish reproduction. An ambitious programme has been initiated to reduce phosphorus loads to the lake, aiming to achieve at least a 40% reduction in phosphorus loads by 2045. Achievement of this target necessitates effective remediation strategies, which will rely upon an improved understanding of controls on nutrient export from tributaries of Lake Simcoe as well as improved understanding of the importance of phosphorus cycling within the lake. In this paper, we describe a new model structure for the integrated dynamic and process-based model INCA-P, which allows fully-distributed applications, suited to branched river networks. We demonstrate application of this model to the Black River, a tributary of Lake Simcoe, and use INCA-P to simulate the fluxes of P entering the lake system, apportion phosphorus among different sources in the catchment, and explore future scenarios of land-use change and nutrient management to identify high priority sites for implementation of watershed best management practises.

Multi-target out-of-sequence data association

In data fusion systems, one often encounters measurements of past target locations and then wishes to deduce where the targets are currently located. Recent research on the processing of such out-of-sequence data has culminated in the development of a number of algorithms for solving the associated tracking problem. This paper reviews these different approaches in a common Bayesian framework and proposes an architecture that orthogonalises the data association and out-of-sequence problems such that any combination of solutions to these two problems can be used together. The emphasis is not on advocating one approach over another on the basis of computational expense, but rather on understanding the relationships between the algorithms so that any approximations made are explicit.

Deviant disabilities: the exclusion of drug and alcohol addiction from the Equality Act 2010

The Equality Act 2010, in keeping with the Disability Discrimination Act 1995, excludes those identified as drug and alcohol ‘addicted’ from the scope of provisions prohibiting discrimination against disabled people. This article addresses the significance of, and justification for, this exclusion. It begins with a legislative background to the relevant limitation and subsequently examines its rationale according to prevailing legal, medical and sociological discourses. The article then considers the relevance of the discussion for disability rights. Although ‘addiction’, or the preferred term, ‘substance dependence’, is classified as a disability for international systems of disease classification, the relevance of substance dependence for discussion on disability rights, and of disability for discussion on substance dependence, has largely escaped critical comment.

Janus PEG-based dendrimers for use in combination therapy: controlled multi-drug loading and sequential release

The increasing use of drug combinations to treat disease states, such as cancer, calls for improved delivery systems that are able to deliver multiple agents. Herein, we report a series of novel Janus dendrimers with potential for use in combination therapy. Different generations (first and second) of PEG-based dendrons containing two different “model drugs”, benzyl alcohol (BA) and 3-phenylpropionic acid (PPA), were synthesized. BA and PPA were attached via two different linkers (carbonate and ester, respectively) to promote differential drug release. The four dendrons were coupled together via (3 + 2) cycloaddition chemistries to afford four Janus dendrimers, which contained varying amounts and different ratios of BA and PPA, namely, (BA)2-G1-G1-(PPA)2, (BA)4-G2-G1-(PPA)2, (BA)2-G1-G2-(PPA)4, and (BA)4-G2-G2-(PPA)4. Release studies in plasma showed that the dendrimers provided sequential release of the two model drugs, with BA being released faster than PPA from all of the dendrons. The different dendrimers allowed delivery of increasing amounts (0.15–0.30 mM) and in exact molecular ratios (1:2; 2:1; 1:2; 2:2) of the two model drug compounds. The dendrimers were noncytotoxic (100% viability at 1 mg/mL) toward human umbilical vein endothelial cells (HUVEC) and nontoxic toward red blood cells, as confirmed by hemolysis studies. These studies demonstrate that these Janus PEG-based dendrimers offer great potential for the delivery of drugs via combination therapy.

Aspect selection in adult L2 Spanish and the competing systems hypothesis: when pedagogical and linguistic rules conflict.

Native-like use of preterit and imperfect morphology in all contexts by English learners of L2 Spanish is the exception rather than the rule, even for successful learners. Nevertheless, recent research has demonstrated that advanced English learners of L2 Spanish attain a native-like morphosyntactic competence for the preterit/imperfect contrast, as evidenced by their native-like knowledge of associated semantic entailments (Goodin-Mayeda and Rothman 2007, Montrul and Slabakova 2003, Slabakova and Montrul 2003, Rothman and Iverson 2007). In addition to an L2 disassociation of morphology and syntax (e.g., Bruhn de Garavito 2003, Lardiere 1998, 2000, 2005, Prévost and White 1999, 2000, Schwartz 2003), I hypothesize that a system of learned pedagogical rules contributes to target-deviant L2 performance in this domain through the most advanced stages of L2 acquisition via its competition with the generative system. I call this hypothesis the Competing Systems Hypothesis. To test its predictions, I compare and contrast the use of the preterit and imperfect in two production tasks by native, tutored (classroom), and naturalistic learners of L2 Spanish.

The evolutionary basis for differences between the immune systems of man, mouse, pig and ruminants

Studying the pathogenesis of an infectious disease like colibacillosis requires an understanding of the responses of target hosts to the organism both as a pathogen and as a commensal. The mucosal immune system constitutes the primary line of defence against luminal micro-organisms. The immunoglobulin-superfamily-based adaptive immune system evolved in the earliest jawed vertebrates, and the adaptive and innate immune system of humans, mice, pigs and ruminants co-evolved in common ancestors for approximately 300 million years. The divergence occurred only 100 mya and, as a consequence, most of the fundamental immunological mechanisms are very similar. However, since pressure on the immune system comes from rapidly evolving pathogens, immune systems must also evolve rapidly to maintain the ability of the host to survive and reproduce. As a consequence, there are a number of areas of detail where mammalian immune systems have diverged markedly from each other, such that results obtained in one species are not always immediately transferable to another. Thus, animal models of specific diseases need to be selected carefully, and the results interpreted with caution. Selection is made simpler where specific host species like cattle and pigs can be both target species and reservoirs for human disease, as in infections with Escherichia coli.

Effects of target expansion on selection performance in older computer users

Point and click interactions using a mouse are an integral part of computer use for current desktop systems. Compared with younger users though, older adults experience greater difficulties performing cursor positioning tasks, and this can present limitations to using a computer easily and effectively. Target expansion is a technique for improving pointing performance, where the target dynamically grows as the cursor approaches. This has the advantage that targets conserve screen real estate in their unexpanded state, yet can still provide the benefits of a larger area to click on. This paper presents two studies of target expansion with older and younger participants, involving multidirectional point-select tasks with a computer mouse. Study 1 compares static versus expanding targets, and Study 2 compares static targets with three alternative techniques for expansion. Results show that expansion can improve times by up to 14%, and reduce error rates by up to 50%. Additionally, expanding targets are beneficial even when the expansion happens late in the movement, i.e. after the cursor has reached the expanded target area or even after it has reached the original target area. Participants’ subjective feedback on the target expansion are generally favorable, and this lends further support for the technique.

Quantifying errors due to frequency changes and target location uncertainty for radar refractivity retrievals

Radar refractivity retrievals can capture near-surface humidity changes, but noisy phase changes of the ground clutter returns limit the accuracy for both klystron- and magnetron-based systems. Observations with a C-band (5.6 cm) magnetron weather radar indicate that the correction for phase changes introduced by local oscillator frequency changes leads to refractivity errors no larger than 0.25 N units: equivalent to a relative humidity change of only 0.25% at 20°C. Requested stable local oscillator (STALO) frequency changes were accurate to 0.002 ppm based on laboratory measurements. More serious are the random phase change errors introduced when targets are not at the range-gate center and there are changes in the transmitter frequency (ΔfTx) or the refractivity (ΔN). Observations at C band with a 2-μs pulse show an additional 66° of phase change noise for a ΔfTx of 190 kHz (34 ppm); this allows the effect due to ΔN to be predicted. Even at S band with klystron transmitters, significant phase change noise should occur when a large ΔN develops relative to the reference period [e.g., ~55° when ΔN = 60 for the Next Generation Weather Radar (NEXRAD) radars]. At shorter wavelengths (e.g., C and X band) and with magnetron transmitters in particular, refractivity retrievals relative to an earlier reference period are even more difficult, and operational retrievals may be restricted to changes over shorter (e.g., hourly) periods of time. Target location errors can be reduced by using a shorter pulse or identified by a new technique making alternate measurements at two closely spaced frequencies, which could even be achieved with a dual–pulse repetition frequency (PRF) operation of a magnetron transmitter.

Identification of potential drug targets in Salmonella Typhimurium using metabolic modelling and experimental validation

almonella enterica serovar Typhimurium is an established model organism for Gram-negative, intracellular pathogens. Owing to the rapid spread of resistance to antibiotics among this group of pathogens, new approaches to identify suitable target proteins are required. Based on the genome sequence of Salmonella Typhimurium and associated databases, a genome-scale metabolic model was constructed. Output was based on an experimental determination of the biomass of Salmonella when growing in glucose minimal medium. Linear programming was used to simulate variations in energy demand, while growing in glucose minimal medium. By grouping reactions with similar flux responses, a sub-network of 34 reactions responding to this variation was identified (the catabolic core). This network was used to identify sets of one and two reactions, that when removed from the genome-scale model interfered with energy and biomass generation. 11 such sets were found to be essential for the production of biomass precursors. Experimental investigation of 7 of these showed that knock-outs of the associated genes resulted in attenuated growth for 4 pairs of reactions, while 3 single reactions were shown to be essential for growth.