Regulation of the DLC3 tumor suppressor by a novel phosphoswitch.

Deleted in liver cancer 3 (DLC3) is a Rho GTPase-activating protein (RhoGAP) that plays a crucial role in maintaining adherens junction integrity and coordinating polarized vesicle transport by modulating Rho activity at the plasma membrane and endomembranes. By employing bioinformatical sequence analysis, in vitro experiments, and in cellulo assays we here identified a polybasic region (PBR) in DLC3 that facilitates the association of the protein with cellular membranes. Within the PBR, we mapped two serines whose phosphorylation can alter the electrostatic character of the region. Consequently, phosphomimetic mutations of these sites impaired the membrane association of DLC3. Furthermore, we found a new PBR-dependent localization of DLC3 at the midbody region, where the protein locally controlled Rho activity. Here, the phosphorylation-dependent regulation of DLC3 appeared to be required for proper cytokinesis. Our work thus provides a novel mechanism for spatiotemporal termination of Rho signaling by the RhoGAP protein DLC3.

Prmt6 represses the pro-adipogenic Ppar-gamma-C/ebp-alpha transcription factor loop.

The feed-forward loop between the transcription factors Ppar-gamma and C/ebp-alpha is critical for lineage commitment during adipocytic differentiation. Ppar-gamma interacts with epigenetic cofactors to activate C/ebp-alpha and the downstream adipocytic gene expression program. Therefore, knowledge of the epigenetic cofactors associated with Ppar-gamma, is central to understanding adipocyte differentiation in normal differentiation and disease. We found that Prmt6 is present with Ppar-gamma on the Ppar-gamma and C/ebp-alpha promoter. It contributes to the repression of C/ebp-alpha expression, in part through its ability to induce H3R2me2a. During adipocyte differentiation, Prmt6 expression is reduced and the methyltransferase leaves the promoters. As a result, the expression of Ppar-gamma and C/ebp-alpha is upregulated and the adipocytic gene expression program is established. Inhibition of Prmt6 by a small molecule enhances adipogenesis, opening up the possibility of epigenetic manipulation of differentiation. Our data provide detailed information on the molecular mechanism controlling the Ppar-gamma-C/ebp-alpha feed-forward loop. Thus, they advance our understanding of adipogenesis in normal and aberrant adipogenesis.

Embodied Displays of "Doing Thinking." Epistemic and Interactive Functions of Thinking Displays in Children's Argumentative Activities.

This study investigates moments in which one participant in an interaction embodies that he is "doing thinking," a display that is commonly referred to as "thinking face. " From an interactional perspective, it is assumed that embodied displays of "doing thinking" are a recurring social practice and serve interactive functions. While previous studies have examined thinking faces primarily in word searches and storytelling, the present study focuses on argumentative activities, in which children engage in processes of joint decision-making. The paper has two interrelated aims. The first aim is to describe how multiple modalities-beyond the face-are temporally coordinated to create multimodal gestalts of "doing thinking." It is shown that thinking displays not only involve dynamic imaginative gaze but also stylized bodily postures. The second aim is to generate knowledge about the functions of thinking displays in children's argumentative activities. The analysis describes how both speakers and recipients use thinking displays in different turn positions and align them with verbal talk or silence. The data for this study comprise video recordings of decision-making processes in groups of older children. Drawing on a multimodal approach to situated interaction, it will be proposed that embodied displays of "doing thinking" provide a resource to shape participation frameworks, mark epistemic stances and create epistemic ecologies for collaborative reasoning. By investigating thinking displays in a particular conversational activity, the study sheds light on the diversity and context-sensitive functionality of thinking displays. It also contributes to recent research on children's collaborative reasoning as an embodied discursive practice.

Helping as a Concurrent Activity: How Students Engage in Small Groups While Pursuing Classroom Tasks.

This study examines interactions in which students help each other with their learning during classroom instruction, forming groups in the process. From a conversation analytic perspective, helping is assumed to be a sequentially organized activity jointly accomplished by the participants. As an activity that proceeds alongside other ongoing classroom activities, helping can be conceived as part of a multiactivity that poses students with multi-faceted interactional and moral challenges. While previous research on helping in educational contexts has primarily focused on the influence of helping on learning outcomes and social dynamics in helping interactions, the present study investigates how students cope with the intricacies of moral commitments inherent in helping as a concurrent activity. The aim of this paper is two-fold. First, we aim to elaborate on how students' dual involvements - i.e., their involvement in classroom activities while simultaneously providing help - manifest in the ways in which groups are constituted, maintained, and dissolved. The analyses reveal that both the compatibility of helping with the activity already in progress as well as the students' problem definition are consequential for the sequential and bodily-spatial unfolding of the help interaction, inducing different arrangements that constitute a continuum, at each end of which there is a dominant orientation toward the shared space of helping or toward the individual/collective space. Furthermore, from a methodological perspective, our study aims to demonstrate the extent to which multimodal interaction analysis is applicable when examining naturally occurring groups, in this case, in interactive processes of helping. The study is based on a data corpus that comprises video recordings of mathematics and German lessons from two fifth-grade classrooms.

Reference as an Interactive Achievement: Sequential and Longitudinal Analyses of Labeling Interactions in Shared Book Reading and Free Play.

The present study examines how young children and their caregivers establish reference by jointly developing stable patterns of bodily, perceptual, and interactive coordination. Our longitudinal investigation focuses on two mother-child dyads engaged in picture-book reading and play. The dyads were videotaped at home once every 6 weeks while the children aged from 9 to 24 months. Inspired by conversation analysis and multimodal analysis, our developmental approach builds on the insight that the situated and embodied production of reference is fundamentally an interactive achievement. To examine the acquisition of reference, we developed a descriptive instrument that takes account of not only the dyad's joint accomplishment but also each participant's contributions to it. The instrument is based on the sequential reconstruction of the jobs that both participants have to accomplish jointly in order to achieve reference: establishing visual perception as a relevant resource, constituting a domain of scrutiny, locating a target, and construing the (meaning of the) referent. Methodologically, these jobs serve as a tertium comparationis for the longitudinal comparison of both the adult's as well as the child's contributions to establishing reference. We used this instrument to examine (1) what bodily and verbal resources the participants employed, and (2) how their contributions to accomplishing the jobs changed over time. Findings showed that the acquisition of reference was closely related to the child's increasing ability to recognize, fulfill, and set up conditional relevancies. We conclude that the adult's dynamic and contextualized use of conditional relevancies, recipient design, and observability is a crucial driving force in the acquisition of reference.