Formation of Complex and Unstable Chromosomal Translocations in Yeast

Genome instability, associated with chromosome breakage syndromes and most human cancers, is still poorly understood. In the yeast Saccharomyces cerevisiae, numerous genes with roles in the preservation of genome integrity have been identified. DNA-damage-checkpoint-deficient yeast cells that lack Sgs1, a RecQ-like DNA helicase related to the human Bloom's-syndrome-associated helicase BLM, show an increased rate of genome instability, and we have previously shown that they accumulate recurring chromosomal translocations between three similar genes, CAN1, LYP1 and ALP1. Here, the chromosomal location, copy number and sequence similarity of the translocation targets ALP1 and LYP1 were altered to gain insight into the formation of complex translocations. Among 844 clones with chromosomal rearrangements, 93 with various types of simple and complex translocations involving CAN1, LYP1 and ALP1 were identified. Breakpoint sequencing and mapping showed that the formation of complex translocation types is strictly dependent on the location of the initiating DNA break and revealed that complex translocations arise via a combination of interchromosomal translocation and template-switching, as well as from unstable dicentric intermediates. Template-switching occurred between sequences on the same chromosome, but was inhibited if the genes were transferred to different chromosomes. Unstable dicentric translocations continuously gave rise to clones with multiple translocations in various combinations, reminiscent of intratumor heterogeneity in human cancers. Base substitutions and evidence of DNA slippage near rearrangement breakpoints revealed that translocation formation can be accompanied by point mutations, and their presence in different translocation types within the same clone provides evidence that some of the different translocation types are derived from each other rather than being formed de novo. These findings provide insight into eukaryotic genome instability, especially the formation of translocations and the sources of intraclonal heterogeneity, both of which are often associated with human cancers

Propagation of RML Prions in Mice Expressing PrP Devoid of GPI Anchor Leads to Formation of a Novel, Stable Prion Strain

PrPC, a host protein which in prion-infected animals is converted to PrPSc, is linked to the cell membrane by a GPI anchor. Mice expressing PrPC without GPI anchor (tgGPI- mice), are susceptible to prion infection but accumulate anchorless PrPSc extra-, rather than intracellularly. We investigated whether tgGPI− mice could faithfully propagate prion strains despite the deviant structure and location of anchorless PrPSc. We found that RML and ME7, but not 22L prions propagated in tgGPI− brain developed novel cell tropisms, as determined by the Cell Panel Assay (CPA). Surprisingly, the levels of proteinase K-resistant PrPSc (PrPres) in RML- or ME7-infected tgGPI− brain were 25–50 times higher than in wild-type brain. When returned to wild-type brain, ME7 prions recovered their original properties, however RML prions had given rise to a novel prion strain, designated SFL, which remained unchanged even after three passages in wild-type mice. Because both RML PrPSc and SFL PrPSc are stably propagated in wild-type mice we propose that the two conformations are separated by a high activation energy barrier which is abrogated in tgGPI− mice

The development of gaze following in monolingual and bilingual infants: A multi-lab study

Determining the meanings of words requires language learners to attend to what other people say. However, it behooves a young language learner to simultaneously attend to what other people attend to, for example, by following the direction of their eye gaze. Sensitivity to cues such as eye gaze might be particularly important for bilingual infants, as they encounter less consistency between words and objects than monolinguals, and do not always have access to the same word learning heuristics (e.g., mutual exclusivity). In a pre-registered study, we tested the hypothesis that bilingual experience would lead to a more pronounced ability to follow another’s gaze. We used the gaze-following paradigm developed by Senju & Csibra (2008) to test a total of 93 6–9 month-old and 229 12–15 month-old monolingual and bilingual infants, in 11 labs located in 8 countries. Monolingual and bilingual infants showed similar gaze-following abilities, and both groups showed age-related improvements in speed, accuracy, frequency and duration of fixations to congruent objects. Unexpectedly, bilinguals tended to make more frequent fixations to onscreen objects, whether or not they were cued by the actor. These results suggest that gaze sensitivity is a fundamental aspect of development that is robust to variation in language exposure

The development of gaze following in monolingual and bilingual infants: A multi-lab study

Determining the meanings of words requires language learners to attend to what other people say. However, it behooves a young language learner to simultaneously attend to what other people attend to, for example, by following the direction of their eye gaze. Sensitivity to cues such as eye gaze might be particularly important for bilingual infants, as they encounter less consistency between words and objects than monolinguals, and do not always have access to the same word learning heuristics (e.g., mutual exclusivity). In a pre-registered study, we tested the hypothesis that bilingual experience would lead to a more pronounced ability to follow another’s gaze. We used the gaze-following paradigm developed by Senju and Csibra (2008) to test a total of 93 6–9 month-old and 229 12–15 month-old monolingual and bilingual infants, in 11 labs located in 8 countries. Monolingual and bilingual infants showed similar gaze-following abilities, and both groups showed age-related improvements in speed, accuracy, frequency and duration of fixations to congruent objects. Unexpectedly, bilinguals tended to make more frequent fixations to onscreen objects, whether or not they were cued by the actor. These results suggest that gaze sensitivity is a fundamental aspect of development that is robust to variation in language exposure

The Development of gaze following in monolingual and bilingual infants: A multi‐laboratory study

Determining the meanings of words requires language learners to attend to what other people say. However, it behooves a young language learner to simultaneously encode relevant non-verbal cues, for example, by following the direction of their eye gaze. Sensitivity to cues such as eye gaze might be particularly important for bilingual infants, as they encounter less consistency between words and objects than monolingual infants, and do not always have access to the same word-learning heuristics (e.g., mutual exclusivity). In a preregistered study, we tested the hypothesis that bilingual experience would lead to a more pronounced ability to follow another's gaze. We used a gaze-following paradigm developed by Senju and Csibra (Current Biology, 18, 2008, 668) to test a total of 93 6- to 9-month-old and 229 12- to 15-month-old monolingual and bilingual infants, in 11 laboratories located in 8 countries. Monolingual and bilingual infants showed similar gaze-following abilities, and both groups showed age-related improvements in speed, accuracy, frequency, and duration of fixations to congruent objects. Unexpectedly, bilinguals tended to make more frequent fixations to on-screen objects, whether or not they were cued by the actor. These results suggest that gaze sensitivity is a fundamental aspect of development that is robust to variation in language exposure.Individual participatin laboratories acknowledge funding support from: the Natural Sciences and Engineering Research Council of Canada (402470-2011; 2018-04390); the National Science Foundation (BCS-155719); the UK Economic and Social Research Council (ESRC ES/L008955/1); the European Research Council Advanced Grant, UNDER CONTROL (323961); the European Research Council Marie Sklodowska-Curie grant (798658); the Leverhulme Trust (ECF-2015-009); the National Institute of Child Health and Human Development (R01HD083312); the European Research Council Synergy Grant (SOMICS 609819); the Early Career Research Grant & Start-up Grant, Western Sydney University; Research Manitoba University of Manitoba, Children's Hospital Research Institute of Manitoba; and the ODPRT funds, National University of Singapore

Interactions in new product development: How the nature of the NPD process influences interaction between teams and management

Effective interaction across organisational boundaries is a critical success factor in new product development (NPD). However, few studies have investigated how different mechanisms enable effective interaction across organisational and particularly hierarchical boundaries.This study explores how the formality of the NPD process influences the nature of interactions across different organisational boundaries and specifically identifies interaction mechanisms used across hierarchical boundaries. Cross-sectional interviews were conducted in nine firms. Findings highlight that in firms with a formalised NPD process, interactions tend to have a transactional/managerial bias. In contrast, in firms where the NPD process is flexible, interactions have a more social objective.<br/