Eye movements of developing Chinese readers: Effects of word frequency and predictability.

The frequency and contextual predictability of words have a fundamental role in determining where and when the eyes move during reading in both alphabetic and non-alphabetic languages. However, surprising little is known about the how the influence of these variables develops, although this is important for understanding how children learn to read. Accordingly, to gain insight into their use during reading development, we examined the effects of orthogonally manipulating the frequency and contextual predictability of a specific target word in sentences on the eye movements of developing Chinese readers. The findings show that both factors influence eye movement behavior associated with the early processing of words during reading, but that effects of contextual predictability are mediated by the lexical frequency of words. We consider these effects in the context of visual and linguistic demands associated with reading Chinese and in relation to current models of eye movement control during reading.</p

Effects of Irrelevant Background Speech on Eye Movements during Reading.

The irrelevant speech effect (ISE) refers to the impairment of visual information processing by background speech. Prior research on the ISE has focused on short-term memory for visually-presented word lists. The present research extends this work by using measurements of eye movements to examine effects of irrelevant background speech during Chinese reading. This enabled an examination of the ISE for a language in which access to semantic representations is not strongly mediated by phonology. Participants read sentences while exposed to meaningful irrelevant speech, meaningless speech (scrambled meaningful speech) or silence. A target word of high or low lexical frequency was embedded in each sentence. The results show that meaningful, but not meaningless, background speech produced increased re-reading. In addition, the appearance of a normal word frequency effect, characterised by longer fixation times on low compared to high frequency words, was delayed when meaningful or meaningless speech was present in the background. These findings show that irrelevant background speech can disrupt normal processes of reading comprehension and, in addition, that background noise can interfere with the early processing of words. The findings add to evidence showing that normal reading processes can be disrupted by environmental noise such as irrelevant background speech

A Structural and Energetic Model for the Slow-Onset Inhibition of the <i>Mycobacterium tuberculosis</i> Enoyl-ACP Reductase InhA

Slow-onset enzyme inhibitors are of great interest for drug discovery programs since the slow dissociation of the inhibitor from the drug–target complex results in sustained target occupancy leading to improved pharmacodynamics. However, the structural basis for slow-onset inhibition is often not fully understood, hindering the development of structure-kinetic relationships and the rational optimization of drug-target residence time. Previously we demonstrated that slow-onset inhibition of the <i>Mycobacterium tuberculosis</i> enoyl-ACP reductase InhA correlated with motions of a substrate-binding loop (SBL) near the active site. In the present work, X-ray crystallography and molecular dynamics simulations have been used to map the structural and energetic changes of the SBL that occur upon enzyme inhibition. Helix-6 within the SBL adopts an open conformation when the inhibitor structure or binding kinetics is substrate-like. In contrast, slow-onset inhibition results in large-scale local refolding in which helix-6 adopts a closed conformation not normally populated during substrate turnover. The open and closed conformations of helix-6 are hypothesized to represent the EI and EI* states on the two-step induced-fit reaction coordinate for enzyme inhibition. These two states were used as the end points for nudged elastic band molecular dynamics simulations resulting in two-dimensional potential energy profiles that reveal the barrier between EI and EI*, thus rationalizing the binding kinetics observed with different inhibitors. Our findings indicate that the structural basis for slow-onset kinetics can be understood once the structures of both EI and EI* have been identified, thus providing a starting point for the rational control of enzyme–inhibitor binding kinetics

Synthetic Antibodies with a Human Framework That Protect Mice from Lethal Sudan Ebolavirus Challenge

The ebolaviruses cause severe and rapidly progressing hemorrhagic fever. There are five ebolavirus species; although much is known about Zaire ebolavirus (EBOV) and its neutralization by antibodies, little is known about Sudan ebolavirus (SUDV), which is emerging with increasing frequency. Here we describe monoclonal antibodies containing a human framework that potently inhibit infection by SUDV and protect mice from lethal challenge. The murine antibody 16F6, which binds the SUDV envelope glycoprotein (GP), served as the starting point for design. Sequence and structural alignment revealed similarities between 16F6 and YADS1, a synthetic antibody with a humanized scaffold. A focused phage library was constructed and screened to impart 16F6-like recognition properties onto the YADS1 scaffold. A panel of 17 antibodies were characterized and found to have a range of neutralization potentials against a pseudotype virus infection model. Neutralization correlated with GP binding as determined by ELISA. Two of these clones, E10 and F4, potently inhibited authentic SUDV and conferred protection and memory immunity in mice from lethal SUDV challenge. E10 and F4 were further shown to bind to the same epitope on GP as 16F6 with comparable affinities. These antibodies represent strong immunotherapeutic candidates for treatment of SUDV infection