Iodoetherification as a strategy towards sp3-rich scaffolds for drug discovery.

Functionalised tetrahydropyran and spirooxepane scaffolds were prepared utilising an iodoetherification strategy and elaborated to demonstrate their potential use in library synthesis. The iodoetherification products could be readily transformed to the corresponding azides that could be further functionalised via copper-catalysed azide-alkyne cycloaddition or reduction to the amine. The lead-likeness and three-dimensionality of the scaffolds were examined and compared to commercial libraries.

Neural Coding of Visual Objects Rapidly Reconfigures to Reflect Subtrial Shifts in Attentional Focus.

Every day, we respond to the dynamic world around us by choosing actions to meet our goals. Flexible neural populations are thought to support this process by adapting to prioritize task-relevant information, driving coding in specialized brain regions toward stimuli and actions that are currently most important. Accordingly, human fMRI shows that activity patterns in frontoparietal cortex contain more information about visual features when they are task-relevant. However, if this preferential coding drives momentary focus, for example, to solve each part of a task in turn, it must reconfigure more quickly than we can observe with fMRI. Here, we used multivariate pattern analysis of magnetoencephalography data to test for rapid reconfiguration of stimulus information when a new feature becomes relevant within a trial. Participants saw two displays on each trial. They attended to the shape of a first target then the color of a second, or vice versa, and reported the attended features at a choice display. We found evidence of preferential coding for the relevant features in both trial phases, even as participants shifted attention mid-trial, commensurate with fast subtrial reconfiguration. However, we only found this pattern of results when the stimulus displays contained multiple objects and not in a simpler task with the same structure. The data suggest that adaptive coding in humans can operate on a fast, subtrial timescale, suitable for supporting periods of momentary focus when complex tasks are broken down into simpler ones, but may not always do so.

The speed and phase of locomotion dictate saccade probability and simultaneous low-frequency power spectra.

Every day we make thousands of saccades and take thousands of steps as we explore our environment. Despite their common co-occurrence in a typical active state, we know little about the coordination between eye movements, walking behaviour and related changes in cortical activity. Technical limitations have been a major impediment, which we overcome here by leveraging the advantages of an immersive wireless virtual reality (VR) environment with three-dimensional (3D) position tracking, together with simultaneous recording of eye movements and mobile electroencephalography (EEG). Using this approach with participants engaged in unencumbered walking along a clear, level path, we find that the likelihood of eye movements at both slow and natural walking speeds entrains to the rhythm of footfall, peaking after the heel-strike of each step. Compared to previous research, this entrainment was captured in a task that did not require visually guided stepping - suggesting a persistent interaction between locomotor and visuomotor functions. Simultaneous EEG recordings reveal a concomitant modulation entrained to heel-strike, with increases and decreases in oscillatory power for a broad range of frequencies. The peak of these effects occurred in the theta and alpha range for slow and natural walking speeds, respectively. Together, our data show that the phase of the step-cycle influences other behaviours such as eye movements, and produces related modulations of simultaneous EEG following the same rhythmic pattern. These results reveal gait as an important factor to be considered when interpreting saccadic and time-frequency EEG data in active observers, and demonstrate that saccadic entrainment to gait may persist throughout everyday activities.

Fractionating distraction: How past- and future-relevant distractors influence integrated decisions.

Many everyday tasks require us to integrate information from multiple steps to make a decision. Dominant accounts of flexible cognition suggest that we are able to navigate such complex tasks by attending to each step in turn, yet few studies measure how we direct our attention to immediate and future task steps. Here, we used a two-step task to test whether participants are sensitive to information that is currently irrelevant but will be relevant in a future task step. Participants viewed two displays in sequence, each containing two superimposed moving dot clouds of different colors. Participants attended to one cued target color in each display and reported the average direction of the two target dot clouds. In a subset of trials, we presented a "decoy" distractor: the second target color appeared as the distractor in the first display. We regressed behavioral responses on the dot clouds' motion directions to track how this future-relevant "decoy" distractor influenced participants' reporting of the average target direction. We compared the influence of decoy distractors to never-relevant, recently relevant, and globally relevant distractor baselines. Across four experiments, we found that responses reflected what was immediately relevant, as well as the broader historical relevance of the distractors. However, relevance for a future task step did not reliably influence attention. We propose that attention in multistep tasks is shaped by what has been relevant in the current setting, and by the immediate demands of each task step. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Word Detection in Individual Subjects Is Difficult to Probe With Fast Periodic Visual Stimulation.

Measuring cognition in single subjects presents unique challenges. On the other hand, individually sensitive measurements offer extraordinary opportunities, from informing theoretical models to enabling truly individualised clinical assessment. Here, we test the robustness of fast, periodic, and visual stimulation (FPVS), an emerging method proposed to elicit detectable responses to written words in the electroencephalogram (EEG) of individual subjects. The method is non-invasive, passive, and requires only a few minutes of testing, making it a potentially powerful tool to test comprehension in those who do not speak or who struggle with long testing procedures. In an initial study, Lochy et al. (2015) used FPVS to detect word processing in eight out of 10 fluent French readers. Here, we attempted to replicate their study in a new sample of 10 fluent English readers. Participants viewed rapid streams of pseudo-words with words embedded at regular intervals, while we recorded their EEG. Based on Lochy et al. (2015) we expected that words would elicit a steady-state response at the word-presentation frequency (2 Hz) over parieto-occipital electrode sites. However, across 40 datasets (10 participants, two conditions, and two regions of interest-ROIs), only four datasets met the criteria for a unique response to words. This corresponds to a 10% detection rate. We conclude that FPVS should be developed further before it can serve as an individually-sensitive measure of written word processing.

Free-Wilson Analysis of Comprehensive Data on Phosphoinositide-3-kinase (PI3K) Inhibitors Reveals Importance of N-Methylation for PI3Kδ Activity.

Phosphoinositide-3-kinase δ (PI3Kδ) is a critical regulator of cell growth and transformation and has been explored as a therapeutic target for a range of diseases. Through the exploration of the thienopyrimidine scaffold, we have identified a ligand-efficient methylation that leads to remarkable selectivity for PI3Kδ over the closely related isoforms. Interrogation through the Free-Wilson analysis highlights the innate selectivity the thienopyrimidine scaffold has for PI3Kδ and provides a predictive model for the activity against the PI3K isoforms.