Quantum Dots for Multiplexed Detection and Characterisation of Prostate Cancer Cells Using a Scanning Near-Field Optical Microscope

In this study scanning near-field optical microscopy (SNOM) has been utilised in conjunction with quantum dot labelling to interrogate the biomolecular composition of cell membranes. The technique overcomes the limits of optical diffraction found in standard fluorescence microscopy and also yields vital topographic information. The technique has been applied to investigate cell-cell adhesion in human epithelial cells. This has been realised through immunofluorescence labelling of the cell-cell adhesion protein E-cadherin. Moreover, a dual labelling protocol has been optimised to facilitate a comparative study of the adhesion mechanisms and the effect of aberrant adhesion protein expression in both healthy and cancerous epithelial cells. This study reports clear differences in the morphology and phenotype of healthy and cancerous cells. In healthy prostate epithelial cells (PNT2), E-cadherin was predominantly located around the cell periphery and within filopodial extensions. The presence of E-cadherin appeared to be enhanced when cell-cell contact was established. In contrast, examination of metastatic prostate adenocarcinoma cells (PC-3) revealed no E-cadherin labelling around the periphery of the cells. This lack of functional E-cadherin in PC-3 cells coincided with a markedly different morphology and PC-3 cells were not found to form close cell-cell associations with their neighbours. We have demonstrated that with a fully optimised sample preparation methodology, multiplexed quantum dot labelling in conjunction with SNOM imaging can be successfully applied to interrogate biomolecular localisation within delicate cellular membranes

Cognitive style modulates semantic interference effects: evidence from field dependency

The so-called semantic interference effect is a delay in selecting an appropriate target word in a context where semantic neighbours are strongly activated. Semantic interference effect has been described to vary from one individual to another. These differences in the susceptibility to semantic interference may be due to either differences in the ability to engage in lexical-specific selection mechanisms or to differences in the ability to engage more general, top-down inhibition mechanisms which suppress unwanted responses based on task-demands. However, semantic interference may also be modulated by an individual’s disposition to separate relevant perceptual signals from noise, such as a field-independent (FI) or a field-dependent (FD) cognitive style. We investigated the relationship between semantic interference in picture naming and in an STM probe task and both the ability to inhibit responses top-down (measured through a Stroop task) and a FI/FD cognitive style measured through the embedded figures test (EFT). We found a significant relationship between semantic interference in picture naming and cognitive style—with semantic interference increasing as a function of the degree of field dependence—but no associations with the semantic probe and the Stroop task. Our results suggest that semantic interference can be modulated by cognitive style, but not by differences in the ability to engage top-down control mechanisms, at least as measured by the Stroop task

A physicochemical descriptor-based scoring scheme for effective and rapid filtering of kinase-like chemical space

<p>Abstract</p> <p>Background</p> <p>The current chemical space of known small molecules is estimated to exceed 10⁶⁰structures. Though the largest physical compound repositories contain only a few tens of millions of unique compounds, virtual screening of databases of this size is still difficult. In recent years, the application of physicochemical descriptor-based profiling, such as Lipinski's rule-of-five for drug-likeness and Oprea's criteria of lead-likeness, as early stage filters in drug discovery has gained widespread acceptance. In the current study, we outline a kinase-likeness scoring function based on known kinase inhibitors.</p> <p>Results</p> <p>The method employs a collection of 22,615 known kinase inhibitors from the ChEMBL database. A kinase-likeness score is computed using statistical analysis of nine key physicochemical descriptors for these inhibitors. Based on this score, the kinase-likeness of four publicly and commercially available databases, i.e., National Cancer Institute database (NCI), the Natural Products database (NPD), the National Institute of Health's Molecular Libraries Small Molecule Repository (MLSMR), and the World Drug Index (WDI) database, is analyzed. Three of these databases, i.e., NCI, NPD, and MLSMR are frequently used in the virtual screening of kinase inhibitors, while the fourth WDI database is for comparison since it covers a wide range of known chemical space. Based on the kinase-likeness score, a kinase-focused library is also developed and tested against three different kinase targets selected from three different branches of the human kinome tree.</p> <p>Conclusions</p> <p>Our proposed methodology is one of the first that explores how the narrow chemical space of kinase inhibitors and its relevant physicochemical information can be utilized to build kinase-focused libraries and prioritize pre-existing compound databases for screening. We have shown that focused libraries generated by filtering compounds using the kinase-likeness score have, on average, better docking scores than an equivalent number of randomly selected compounds. Beyond library design, our findings also impact the broader efforts to identify kinase inhibitors by screening pre-existing compound libraries. Currently, the NCI library is the most commonly used database for screening kinase inhibitors. Our research suggests that other libraries, such as MLSMR, are more kinase-like and should be given priority in kinase screenings.</p

Confidence in uncertainty: Error cost and commitment in early speech hypotheses

© 2018 Loth et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Interactions with artificial agents often lack immediacy because agents respond slower than their users expect. Automatic speech recognisers introduce this delay by analysing a user’s utterance only after it has been completed. Early, uncertain hypotheses of incremental speech recognisers can enable artificial agents to respond more timely. However, these hypotheses may change significantly with each update. Therefore, an already initiated action may turn into an error and invoke error cost. We investigated whether humans would use uncertain hypotheses for planning ahead and/or initiating their response. We designed a Ghost-in-the-Machine study in a bar scenario. A human participant controlled a bartending robot and perceived the scene only through its recognisers. The results showed that participants used uncertain hypotheses for selecting the best matching action. This is comparable to computing the utility of dialogue moves. Participants evaluated the available evidence and the error cost of their actions prior to initiating them. If the error cost was low, the participants initiated their response with only suggestive evidence. Otherwise, they waited for additional, more confident hypotheses if they still had time to do so. If there was time pressure but only little evidence, participants grounded their understanding with echo questions. These findings contribute to a psychologically plausible policy for human-robot interaction that enables artificial agents to respond more timely and socially appropriately under uncertainty

Classification of Types of Stuttering Symptoms Based on Brain Activity

Among the non-fluencies seen in speech, some are more typical (MT) of stuttering speakers, whereas others are less typical (LT) and are common to both stuttering and fluent speakers. No neuroimaging work has evaluated the neural basis for grouping these symptom types. Another long-debated issue is which type (LT, MT) whole-word repetitions (WWR) should be placed in. In this study, a sentence completion task was performed by twenty stuttering patients who were scanned using an event-related design. This task elicited stuttering in these patients. Each stuttered trial from each patient was sorted into the MT or LT types with WWR put aside. Pattern classification was employed to train a patient-specific single trial model to automatically classify each trial as MT or LT using the corresponding fMRI data. This model was then validated by using test data that were independent of the training data. In a subsequent analysis, the classification model, just established, was used to determine which type the WWR should be placed in. The results showed that the LT and the MT could be separated with high accuracy based on their brain activity. The brain regions that made most contribution to the separation of the types were: the left inferior frontal cortex and bilateral precuneus, both of which showed higher activity in the MT than in the LT; and the left putamen and right cerebellum which showed the opposite activity pattern. The results also showed that the brain activity for WWR was more similar to that of the LT and fluent speech than to that of the MT. These findings provide a neurological basis for separating the MT and the LT types, and support the widely-used MT/LT symptom grouping scheme. In addition, WWR play a similar role as the LT, and thus should be placed in the LT type

Distractor strength and selective attention in picture-naming performance

Contains fulltext : 102442pub.pdf (publisher's version ) (Open Access)Whereas it has long been assumed that competition plays a role in lexical selection in word production (e.g., Levelt, Roelofs, & Meyer, 1999), recently Finkbeiner and Caramazza (2006) argued against the competition assumption on the basis of their observation that visible distractors yield semantic interference in picture naming, whereas masked distractors yield semantic facilitation. We examined an alternative account of these findings that preserves the competition assumption. According to this account, the interference and facilitation effects of distractor words reflect whether or not distractors are strong enough to exceed a threshold for entering the competition process. We report two experiments in which distractor strength was manipulated by means of coactivation and visibility. Naming performance was assessed in terms of mean response time (RT) and RT distributions. In Experiment 1, with low coactivation, semantic facilitation was obtained from clearly visible distractors, whereas poorly visible distractors yielded no semantic effect. In Experiment 2, with high coactivation, semantic interference was obtained from both clearly and poorly visible distractors. These findings support the competition threshold account of the polarity of semantic effects in naming.14 p

Distinct patterns of brain activity characterise lexical activation and competition in spoken word production

Contains fulltext : 126491.pdf (publisher's version ) (Open Access)According to a prominent theory of language production, concepts activate multiple associated words in memory, which enter into competition for selection. However, only a few electrophysiological studies have identified brain responses reflecting competition. Here, we report a magnetoencephalography study in which the activation of competing words was manipulated by presenting pictures (e.g., dog) with distractor words. The distractor and picture name were semantically related (cat), unrelated (pin), or identical (dog). Related distractors are stronger competitors to the picture name because they receive additional activation from the picture relative to other distractors. Picture naming times were longer with related than unrelated and identical distractors. Phase-locked and non-phase-locked activity were distinct but temporally related. Phase-locked activity in left temporal cortex, peaking at 400 ms, was larger on unrelated than related and identical trials, suggesting differential activation of alternative words by the picture-word stimuli. Non-phase-locked activity between roughly 350-650 ms (4-10 Hz) in left superior frontal gyrus was larger on related than unrelated and identical trials, suggesting differential resolution of the competition among the alternatives, as reflected in the naming times. These findings characterise distinct patterns of activity associated with lexical activation and competition, supporting the theory that words are selected by competition.11 p