This study explores the emergence of triadic interactions through the example of book sharing. As part of a naturalistic study, 10 infants were visited in their homes from 3–12 months. We report that (1) book sharing as a form of infant-caregiver-object interaction occurred from as early as 3 months. Using qualitative video analysis at a micro-level adapting methodologies from conversation and interaction analysis, we demonstrate that caregivers and infants practiced book sharing in a highly co-ordinated way, with caregivers carving out interaction units and shaping actions into action arcs and infants actively participating and co-ordinating their attention between mother and object from the beginning. We also (2) sketch a developmental trajectory of book sharing over the first year and show that the quality and dynamics of book sharing interactions underwent considerable change as the ecological situation was transformed in parallel with the infants' development of attention and motor skills. Social book sharing interactions reached an early peak at 6 months with the infants becoming more active in the coordination of attention between caregiver and book. From 7 to 9 months, the infants shifted their interest largely to solitary object exploration, in parallel with newly emerging postural and object manipulation skills, disrupting the social coordination and the cultural frame of book sharing. In the period from 9 to 12 months, social book interactions resurfaced, as infants began to effectively integrate manual object actions within the socially shared activity. In conclusion, to fully understand the development and qualities of triadic cultural activities such as book sharing, we need to look especially at the hitherto overlooked early period from 4 to 6 months, and investigate how shared spaces of meaning and action are structured together in and through interaction, creating the substrate for continuing cooperation and cultural learning.

Tumor protein 53 (p53) is a critical regulator of cell cycle and apoptosis that is frequently disabled in human tumors. In many tumor types, p53 is deleted or mutated, but in others p53 is inactivated by overexpression or amplification of its negative regulator mouse double minute 2 (MDM2). A high-throughput screening effort identified 6,7-bis(4-bromophenyl)-7,12-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine as a potent inhibitor of the MDM2-p53 protein-protein interaction. This screening hit was found to be chemically unstable and difficult to handle due to poor DMSO solubility. Co-crystallization with the target protein helped to direct further optimization and provided a tractable lead series of novel MDM2-p53 inhibitors. In cellular assays, these compounds were shown to upregulate p53 protein levels and p53 signaling and to cause p53-dependent inhibition of proliferation and apoptosis.

Small peptides exhibit a wide range of biological activities, but although there are some notable exceptions, they are not generally useful as drugs. This has spurred widespread interest in designing peptidomimetics and introducing them as replacements of portions of native peptides to enhance their biological properties. Special attention has been focused upon rigid replacements because of their potential to preorganize the resulting pseudopeptide in a conformation corresponding to its bound structure. Toward this goal, we invented trisubstituted cyclopropanes as novel peptidomimetics, anticipating that the cyclopropane ring would locally orient the backbone and the corresponding amino acid side chain in the biologically active conformation. Selected aspects of the syntheses and applications of these cyclopropane-derived peptidomimetics are presented in this Account.

The ability to predict accurately the weights of objects is essential for skilled and dexterous manipulation. A potentially important source of information about object weight is through the observation of other people lifting objects. Here, we tested the hypothesis that when watching an actor lift an object, people naturally learn the object's weight and use this information to scale forces when they subsequently lift the object themselves. Participants repeatedly lifted an object in turn with an actor. Object weight unpredictably changed between 2 and 7 N every 5th to 9th of the actor's lifts, and the weight lifted by the participant always matched that previously lifted by the actor. Even though the participants were uninformed about the structure of the experiment, they appropriately adapted their lifting force in the first trial after a weight change. Thus, participants updated their internal representation about the object's weight, for use in action, when watching a single lift performed by the actor. This ability presumably involves the comparison of predicted and actual sensory information related to actor's actions, a comparison process that is also fundamental in action.

A convergent synthesis of the marine natural product (+)-peloruside has been reported. This target has been assembled through the successive application of two methyl ketone boron aldol addition reactions to the latent C 7 -C 11 dialdehyde synthon. This approach afforded a 22-step synthesis of this natural product. The influence of resident stereocenters on aldol reaction diastereoselection has been examined in detail.Peloruside A (1) is a secondary metabolite of a marine sponge (Mycale genus) collected from Pelorus Sound, New Zealand. In addition to its structure elucidation, the initial disclosure by Northcote 1 also demonstrated peloruside A to be cytotoxic to P388 murine leukemia cells at nanomolar concentrations. Subsequent investigations 2 revealed peloruside's anti-proliferation potency is similar to that exhibited by paclitaxel. The first synthesis of 1, reported by De Brabander, established the absolute stereochemistry of this natural product. 3 In the interim, two additional syntheses have been published. 4,5 The purpose of this communication is to report a convergent approach to this natural product suitable for analogue synthesis.The deconstruction of 1 relies on the two highlighted aldol disconnections illustrated in Scheme 1. Based on prior art, 6 we anticipated that the C 3 and C 15 stereocenters would favorably influence the stereochemical outcome of these two bond constructions. In the following discussion, the syntheses of subunits 3 and 4 will be described along with their elaboration to (+)-peloruside A (1). The synthesis of 5 is included in the Supplementary Information.The synthesis of C 1 -C 6 synthon 3 requires six steps from commercially available (S)-4-benzyl-2-oxazolidinone 7a and is summarized in Scheme 2. Notably, the illustrated imideevans@chemistry.harvard.edu. Supporting Information Available: Experimental details and analytical data including copies of 1 H and 13 C NMR spectra for all new compounds (xx pages) (PDF). The synthesis of methyl ketone 5 is also included. This material is available free of charge via the Internet at http://pubs.acs.org. The synthesis of synthon 4, based on the use of (S)-pantolactone, is summarized in Scheme 3. The chelate-controlled borohydride reduction was quite diastereoselective (95:5); however, competing conjugate reduction was noted as a minor side reaction. NIH Public AccessSelection of the illustrated C 9 hydroxyl configuration in subunit 4 bears comment. On the basis of previous model studies probing the influence of β-oxygen stereocenters on aldehyde face selectivity, 8 we concluded that the (R)-C 3 , (S)-C 8 and (R)-C 9 stereocenters in fragments 3 and 4 would be mutually reinforcing in this double stereodifferentiating aldol addition. A recent study by Paterson documents the diminished selectivities if the other C 9 epimer is employed in a similar aldol addition.9The aldol union of methyl ketone 3 and aldehyde 4 is summarized in Scheme 4. In developing this reaction, we noted a surprising diastereoselectivity dependence on the par...