Targeting of cancer cells using click-functionalized polymer capsules

Targeted delivery of drugs to specific cells allows a high therapeutic dose to be delivered to the target site with minimal harmful side effects. Combining targeting molecules with nanoengineered drug carriers, such as polymer capsules, micelles and polymersomes, has significant potential to improve the therapeutic delivery and index of a range of drugs. We present a general approach for functionalization of low-fouling, nanoengineered polymer capsules with antibodies using click chemistry. We demonstrate that antibody (Ab)-functionalized capsules specifically bind to colorectal cancer cells even when the target cells constitute less than 0.1% of the total cell population. This precise targeting offers promise for drug delivery applications.     

Pronounced negative thermal expansion from a simple structure: cubic ScF(3)

Scandium trifluoride maintains a cubic ReO(3) type structure down to at least 10 K, although the pressure at which its cubic to rhombohedral phase transition occurs drops from >0.5 GPa at ～300 K to 0.1-0.2 GPa at 50 K. At low temperatures it shows strong negative thermal expansion (NTE) (60-110 K, α(l) ≈ -14 ppm K(-1)). On heating, its coefficient of thermal expansion (CTE) smoothly increases, leading to a room temperature CTE that is similar to that of ZrW(2)O(8) and positive thermal expansion above ～1100 K. While the cubic ReO(3) structure type is often used as a simple illustration of how negative thermal expansion can arise from the thermally induced rocking of rigid structural units, ScF(3) is the first material with this structure to provide a clear experimental illustration of this mechanism for NTE.     

The importance for speech intelligibility of random fluctuations in "steady" background noise

Spectrally shaped steady noise is commonly used as a masker of speech. The effects of inherent random fluctuations in amplitude of such a noise are typically ignored. Here, the importance of these random fluctuations was assessed by comparing two cases. For one, speech was mixed with steady speech-shaped noise and N-channel tone vocoded, a process referred to as signal-domain mixing (SDM); this preserved the random fluctuations of the noise. For the second, the envelope of speech alone was extracted for each vocoder channel and a constant was added corresponding to the root-mean-square value of the noise envelope for that channel. This is referred to as envelope-domain mixing (EDM); it removed the random fluctuations of the noise. Sinusoidally modulated noise and a single talker were also used as backgrounds, with both SDM and EDM. Speech intelligibility was measured for N?=?12, 19, and 30, with the target-to-background ratio fixed at -7 dB. For SDM, performance was best for the speech background and worst for the steady noise. For EDM, this pattern was reversed. Intelligibility with steady noise was consistently very poor for SDM, but near-ceiling for EDM, demonstrating that the random fluctuations in steady noise have a large effect.     

A decision support tool for Public Rights of Way officers based on the Analytic Hierarchy Process

Local Government Authorities (LGA) in England and Wales have statutory responsibility for the maintenance of Public Rights of Way (PROW), such as pathways and byways open to non-motorised traffic. The departments responsible have to compete for budgets and justify their expenditure in terms of councils’ priorities, such as well-being and environment. A need was identified for a simple decision support tool to provide a consistent and transparent framework for assessing the range of possible social and economic benefits from expenditure on PROW. The tool uses the Analytic Hierarchy Process to elicit weights forming the links from path attributes to users and usage to benefits, with a final stage to combine the benefits according to LGA priorities. It was successfully tested through case studies, where improving signage was generally found to be the most cost effective option, giving moderate benefits at low cost, whereas improving the physical conditions of the surface gave greater benefits at relatively high cost.     

Affective bases of likelihood judgments

Analyses of likelihood judgments for 515 events support the idea that the perceived likelihood of an event is partly a function of affective processes. Production of affective disturbances makes events seem unlikely. Event likelihoods also are influenced by specific kinds of people and behaviors which are involved in the events. Affective determination of likelihood is stronger when actors have institutionally‐clear identities rather than institutionally‐vague identities; indeed, affect accounts for more than half of the variance in likelihoods of events within clear institutional contexts.     

Aspects of column fabrication for packed capillary electrochromatography

Various parameters have been evaluated to develop a process for optimization of column manufacture for packed capillary electrochromatography (CEC). Spherisorb ODS-1 was packed into 75 microm I.D. capillaries to establish a standard set of packing conditions to afford high-performance columns free of voids. Numerous silica-based packing materials including porous and non-porous reversed-phase and ion-exchange phases were employed to evaluate the applicability of the standard conditions. Success of column manufacture and performance demonstrate a relationship to the colligative properties of the packing materials under the applied conditions. Frequently encountered difficulties arising from inadequate column conditioning and void formation in the packed bed are identified and discussed.     

A vending machine for drug-like molecules – automated synthesis of virtual screening hits

As a result of high false positive rates in virtual screening campaigns, prospective hits must be synthesised for validation. When done manually, this is a time consuming and laborious process. Large “on-demand” virtual libraries (>7 × 10¹² members), suitable for preparation using capsule-based automated synthesis and commercial building blocks, were evaluated to determine their structural novelty. One sub-library, constructed from iSnAP capsules, aldehydes and amines, contains unique scaffolds with drug-like physicochemical properties. Virtual screening hits from this iSnAP library were prepared in an automated fashion for evaluation against Aedes aegypti and Phytophthora infestans. In comparison to manual workflows, this approach provided a 10-fold improvement in user efficiency. A streamlined method of relative stereochemical assignment was also devised to augment the rapid synthesis. User efficiency was further improved to 100-fold by downscaling and parallelising capsule-based chemistry on 96-well plates equipped with filter bases. This work demonstrates that automated synthesis consoles can enable the rapid and reliable preparation of attractive virtual screening hits from large virtual libraries.

A compact and operationally simple automation technology can prepare virtual screening hits from a large on-demand library of drug-like molecules.