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1.  The informative value of emotional expressions: ‘social referencing’ in mother–child pretense 
Developmental Science  2007;10(2):205-212.
Mothers begin to pretend with their children during the second year, when children still have much to learn about the real world. Although it would be easy to confuse what is pretend with what is real, children at this young age often demonstrate comprehension during pretense situations. It is plausible that social referencing, in which the child uses the mother’s emotional expression as a guide to behavior, might facilitate this emerging knowledge by signaling to the child not to take the pretend situation seriously. Data from 32 pairs of mothers and their 18-month-olds who had engaged in pretend and real snack behaviors were subjected to a sequential analysis to investigate a social referencing interpretation. Consistent with our hypothesis, behaviors suggestive of a baby’s understanding pretense were more likely to follow a specific combination of behaviors consistent with social referencing than other combinations of behaviors. These results provide support for the possibility that children use information obtained through social referencing to assist understanding during pretense interactions.
doi:10.1111/j.1467-7687.2007.00581.x
PMCID: PMC3334327  PMID: 17286845
2.  Preschooler’s Understanding of the Role of Mental States and Action in Pretense 
This research investigated 3- to 5-year-old’s understanding of the role of intentional states and action in pretense. There are two main perspectives on how children conceptualize pretense. One view is that children understand the mental aspects of pretending (the rich interpretation). The alternative view is that children conceptualize pretense as “acting-like” and do not appreciate that the mind is crucial to pretense (the lean interpretation). The experiments in this article used a novel approach to test these two interpretations. Children were presented with two types of videotaped scenarios. In Experiment 1, children were presented with a scenario in which people wanted to be like something else (e.g., a kangaroo) and either acted like it or did not act like it. Children were asked whether the protagonists were pretending and whether they were thinking about the pretend entity. In Experiment 2, children were presented with the Experiment 1 scenarios and also with a scenario in which a person had the intention to do something else (e.g., look for her keys) but whose actions were similar to those of a pretend entity (e.g., a bear). Children were asked about the pretense, thoughts, and the intentions of the protagonists. Experiment 3 tested for the effect of asking an open-ended versus a forced-choice question on the Experiment 2 tasks. The results of this study suggest that in certain facilitating conditions (e.g., intention information salient, forced-choice question) children have an early understanding of the role of mind in pretense.
doi:10.1207/s15327647jcd0502_3
PMCID: PMC3336197  PMID: 22545006
3.  Mothers’ Behavior Modifications During Pretense and Their Possible Signal Value for Toddlers 
Developmental Psychology  2004;40(1):95-113.
An important issue for understanding early cognition is why very young children’s real-world representations do not get confused by pretense events. One possible source of information for children is the pretender’s behaviors. Pretender behaviors may vary systematically across real and pretend scenarios, perhaps signaling to toddlers to interpret certain events as not real. Pretender behaviors were examined in 2 experiments in which mothers were asked both to pretend to have a snack and really to have a snack with their 18-month-olds. Episodes were analyzed for condition differences in verbal and nonverbal behaviors, including smiling, looking, laughter, and functional movements. Reliable differences were found across conditions for several variables. In a 3rd experiment, children’s apparent understanding of pretense in relation to their mothers’ behaviors was examined, and significant associations were found with some of the mothers’ behavioral changes but not others. This work provides a first inroad into the issue of how children learn to interpret pretense acts as pretense.
doi:10.1037/0012-1649.40.1.95
PMCID: PMC3334333  PMID: 14700467
4.  Signs of Pretense Across Age and Scenario 
Participation in imagined worlds is a hallmark of the human species, and yet we know little about the context of its early emergence. The experiments reported here replicated and extended in 2 directions Lillard and Witherington’s (2004) study of how mothers pretend to have snacks, across different ages of children (15- to 24-month-olds, Experiment 1) and to a different scenario (personal grooming, Experiment 2). Mothers’ pretend behaviors changed little as infants aged, but there were some scenario differences. Most striking in this research was the consistency with which particular maternal pretend behaviors were associated with children engaging in pretense behaviors and smiling. The findings are discussed with reference to the child’s emerging skills in joint attention and social referencing.
doi:10.1207/s15327078in1101_1
PMCID: PMC3544155  PMID: 23326208
5.  Where Is the Real Cheese? Young Children’s Ability to Discriminate Between Real and Pretend Acts 
Child Development  2006;77(6):1762-1777.
This study examined 2- to 3-year-olds’ ability to make a pretend – real distinction in the absence of content cues. Children watched two actors side by side. One was really eating, and the other was pretending to eat, but in neither case was information about content available. Following the displays, children were asked to retrieve the real food (Experiment 1) or point to the container with the real food (Experiments 2 and 3). 3- and 2.5-year-olds distinguished between the real and pretend acts based on behavioral cues alone. Two-year-olds chose the containers at random, but their spontaneous reactions suggested that they discriminated the real acts from pretense to some degree. Possible accounts for the discrepancy between the different behavioral measures are discussed.
doi:10.1111/j.1467-8624.2006.00972.x
PMCID: PMC3334330  PMID: 17107459
6.  Detecting continuity violations in infancy: a new account and new evidence from covering and tube events 
Cognition  2005;95(2):129-173.
Recent research on infants’ responses to occlusion and containment events indicates that, although some violations of the continuity principle are detected at an early age e.g. Aguiar, A., & Baillargeon, R. (1999). 2.5-month-old infants’ reasoning about when objects should and should not be occluded. Cognitive Psychology 39, 116–157; Hesposs, S. J., & Baillargeon, R. (2001). Knowledge about containment events in very young infants. Cognition 78, 207–245; Luo, Y., & Baillargeon, R. (in press). When the ordinary seems unexpected: Evidence for rule-based reasoning in young infants. Cognition; Wilcox, T., Nadel, L., & Rosser, R. (1996). Location memory in healthy preterm and full-term infants. Infant Behavior & Development 19, 309–323, others are not detected until much later e.g. Baillargeon, R., & DeVos, J. (1991). Object permanence in young infants: Further evidence. Child Development 62, 1227–1246; Hespos, S. J., & Baillargeon, R. (2001). Infants’ knowledge about occlusion and containment events: A surprising discrepancy. Psychological Science 12, 140–147; Luo, Y., & Baillargeon, R. (2004). Infants’ reasoning about events involving transparent occluders and containers. Manuscript in preparation; Wilcox, T. (1999). Object individuation: Infants’ use of shape, size, pattern, and color. Cognition 72, 125–166. The present research focused on events involving covers or tubes, and brought to light additional examples of early and late successes in infants’ ability to detect continuity violations. In Experiment 1, 2.5- to 3-month-old infants were surprised (1) when a cover was lowered over an object, slid to the right, and lifted to reveal no object; and (2) when a cover was lowered over an object, slid behind the left half of a screen, lifted above the screen, moved to the right, lowered behind the right half of the screen, slid past the screen, and finally lifted to reveal the object. In Experiments 2 and 3, 9- and 11-month-old infants were not surprised when a short cover was lowered over a tall object until it became fully hidden; only 12-month-old infants detected this violation. Finally, in Experiment 4, 9-, 12-, and 13-month-old infants were not surprised when a tall object was lowered inside a short tube until it became fully hidden; only 14-month-old infants detected this violation. A new account of infants’ physical reasoning attempts to make sense of all of these results. New research directions suggested by the account are also discussed.
doi:10.1016/j.cognition.2002.11.001
PMCID: PMC3357327  PMID: 15694644
Physical reasoning in infancy; Continuity violations; Event categories
7.  Twelve-Month-Olds' Understanding of Intention Transfer through Communication 
PLoS ONE  2012;7(9):e46168.
Do infants understand that intention can be transferred through communication? We answered this question by examining 12-month-olds' looking times in a violation-of-expectation paradigm with two human agents. In familiarization, the non-acting agent spoke, clapped her hands, read aloud a book, or remained silent before the acting agent grasped one (the target) of two objects. During test only the non-actor remained, grasping either the target or distractor. The infants looked longer in the distractor than target condition, suggesting violation of expectation, only if the non-actor had spoken or clapped in familiarization. Because the non-actor never had grasped any of the objects in familiarization, the infants' expectation on her behavior could have developed from the understanding that her intention was transferred to the actor, who executed it by grasping the target in familiarization, via speaking and clapping as acts of communication (but not reading aloud and remaining silent).
doi:10.1371/journal.pone.0046168
PMCID: PMC3454325  PMID: 23029427
8.  Neural correlates of observing pretend play in which one object is represented as another 
Observers were scanned while they watched a video of an actor using an object. Three conditions were contrasted in which the same object was used: (i) normally (e.g. using a tennis racket to hit a ball), (ii) in an unusual way (e.g. using a tennis racket to strain spaghetti), (iii) in a pretend play (e.g. playing a tennis racket like a banjo). Observing real and unusual uses of objects activated areas previously seen in studies of tool use including areas associated with a mirror system for action. Observing pretend play activated additional areas previously associated with theory of mind tasks and listening to narrative, including medial prefrontal cortex, posterior superior temporal sulcus and temporal poles. After presentation of each video, observers were asked to name the object as used in the preceding action video (e.g. racket, sieve or banjo). Naming the pretend object elicited activity in medial prefrontal cortex. These results are consistent with proposals that pretend play is a form of communicative narrative, associated with the ability to mentalize. However, this leaves open the question as to whether pretence or mentalizing is the more basic process.
doi:10.1093/scan/nsp021
PMCID: PMC2799949  PMID: 19535615
pretence; mirror neurons; theory of mind; narrative; medial prefrontal cortex
9.  Violations of the international code of marketing of breast milk substitutes: prevalence in four countries 
BMJ : British Medical Journal  1998;316(7138):1117-1122.
Objective: To estimate the prevalence of violations of the international code of marketing of substitutes for breast milk in one city in each of Bangladesh, Poland, South Africa, and Thailand.
Design: Multistage random sampling was used to select pregnant women and mothers of infants ⩽6 months old to interview at health facilities. Women were asked whether they had received free samples of substitutes for breast milk (including infant formula designed to meet the nutritional needs of infants from birth to 4 to 6 months of age, follow on formula designed to replace infant formula at the age of 4 to 6 months, and complementary foods for infants aged ⩽6 months), bottles, or teats. The source of the free sample and when it had been given to the women was also determined. 3 health workers were interviewed at each facility to assess whether the facility had received free samples, to determine how they had been used, and to determine whether gifts had been given to health workers by companies that manufactured or distributed breast milk substitutes. Compliance with the marketing code for information given to health workers was evaluated using a checklist.
Setting: Health facilities in Dhaka, Bangladesh; Warsaw, Poland; Durban, South Africa; and Bangkok, Thailand.
Subjects: 1468 pregnant women, 1582 mothers of infants aged ⩽6 months, and 466 health workers at 165 health facilities.
Main outcome measures: Number of free samples received by pregnant women, mothers, and health workers; number of gifts given to health workers; and availability of information that violated the code in health facilities.
Results: 97 out of 370 (26%) mothers in Bangkok reported receiving free samples of breast milk substitutes, infant formula, bottles, or teats compared with only 1 out of 385 mothers in Dhaka. Across the four cities from 3 out of 40 (8%) to 20 out of 40 (50%) health facilities had received free samples which were not being used for research or professional evaluation; from 2 out of 123 (2%) to 21 out of 119 (18%) health workers had received gifts from companies involved in the manufacturing or distribution of breast milk substitutes. From 6 out of 40 (15%) to 22 out of 39 (56%) health facilities information that violated the code had been provided by companies and was available to staff.
Conclusion: Violations of the code were detected with a simple survey instrument in all of the four countries studied. Governmental and non-governmental agencies should monitor the prevalence of code violations using the simple methodology developed for this study.
Key messages A simple multistage random sampling procedure can be used to interview women and health professionals to assess whether violations of the international code of marketing of substitutes for breast milk are occurring 3050 women and 466 health professionals were interviewed at 165 health facilities in Bangladesh, Poland, South Africa, and Thailand 97 out of 370 mothers in Bangkok reported receiving free samples of breast milk substitutes, infant formula, bottles, or teats compared with only 1 out of 385 mothers in Dhaka. In Bangkok health workers reported that 20 out of 40 health facilities had also received free samples. Most free samples were distributed by health facilities In Warsaw 56% of facilities surveyed were found to have information available for health workers that had been provided by manufacturers or distributors of breast milk substitutes in contravention of the code; 18% of health workers in Warsaw had received free gifts from manufacturers
PMCID: PMC28512  PMID: 9552947
10.  Evidence for a relation between executive function and pretense representation in preschool children 
Cognitive development  2014;29:10.1016/j.cogdev.2013.09.001.
Several theoretical formulations suggest a relation between children’s pretense and executive function (EF) skills. However, there is little empirical evidence for a correlation between these constructs in early development. Preschool children (N = 104; M age = 4-0) were given batteries of EF and pretense representation measures, as well as verbal, memory, and appearance-reality control tasks. Confirmatory factor analysis revealed two separable but overlapping aspects of EF (Conflict and Delay). EF was significantly related to pretense after accounting for all controls. Understanding the pretend-reality distinction was strongly related to Conflict EF, whereas performing pretend actions was more strongly related to Delay EF. These results, although correlational, are consistent with the claim that EF skills are implicated in pretense, such as inhibiting reality and flexibly manipulating dual representations, and offer a potential mechanism by which pretend play interventions may enhance childhood EF.
doi:10.1016/j.cogdev.2013.09.001
PMCID: PMC3864685  PMID: 24357896
Executive function; inhibitory control; pretense; representation
11.  Observers’ proficiency at identifying pretense acts based on behavioral cues 
Cognitive development  2004;19(2):223-240.
Discriminating what is pretense from what is real is a fundamental problem in development. Research has addressed the proficiency with which adults and children discriminate between play fighting and real fighting, and yet none (to our knowledge) has investigated discrimination of other kinds of pretense and real acts. In addition, little is known about what aspects of pretender behavior (as opposed to pretend content) might cue pretense interpretations. In two experiments, 8–20 s clips showing pretense and real snack behaviors were presented to adult and child participants. All participants distinguished between pretense and real behaviors at better than chance level. Furthermore, certain features (specific looking patterns and mistimed behaviors) were most prominent in the videotapes that were most often correctly identified. This provides empirical support for the suggestion that these cues, as opposed to more commonly cited cues, like smiles, might serve as important indicators of pretense for children and adults.
PMCID: PMC3336202  PMID: 22544997
Pretense; Discrimination; Development; Social cognition; Behavioral cues
12.  Do 18-months-olds really attribute mental states to others? A critical test 
Psychological science  2011;22(7):878-880.
The current study investigated whether 18-months-olds attribute opaque mental states when they solve false belief tests, or simply rely on behavioural cues available in the stimuli. Infants experienced either a trick blindfold that looked opaque but could be seen through, or an opaque blindfold. Then both groups of infants observed an actor wearing the same blindfold that they had themselves experienced, whilst a puppet removed an object from its location. Anticipatory eye movements revealed that infants who experienced the opaque blindfold expected the actor’s action in accord with her having a false belief about the object’s location, but infants who experienced the trick blindfold did not. The results suggest that 18-months-olds used self-experience with the blindfold to assess the actor’s visual access, and updated her knowledge/belief state accordingly. These data constitute compelling evidence that 18-months-olds infer perceptual access and appreciate its causal role in altering epistemic states of others.
doi:10.1177/0956797611411584
PMCID: PMC3799747  PMID: 21642553
Theory of mind; infants; eye-tracking; social cognition
13.  “I pick you”: the impact of fairness and race on infants’ selection of social partners 
By 15 months of age infants are sensitive to violations of fairness norms as assessed via their enhanced visual attention to unfair versus fair outcomes in violation-of-expectation paradigms. The current study investigated whether 15-month-old infants select social partners on the basis of prior fair versus unfair behavior, and whether infants integrate social selections on the basis of fairness with the race of the distributors and recipients involved in the exchange. Experiment 1 demonstrated that after witnessing one adult distribute toys to two recipients fairly (2:2 distribution), and another adult distribute toys to two recipients unfairly (1:3 distribution), Caucasian infants selected fair over unfair distributors when both distributors were Caucasian; however, this preference was not present when the fair actor was Asian and the unfair actor was Caucasian. In Experiment 2, when fairness, the race of the distributor, and the race of the recipients were fully crossed, Caucasian infants’ social selections varied as a function of the race of the recipient advantaged by the unfair distributor. Specifically, infants were more likely to select the fair distributor when the unfair recipient advantaged the Asian (versus the Caucasian) recipient. These findings provide evidence that infants select social partners on the basis of prior fair behavior and that infants also take into account the race of distributors and recipients when making their social selections.
doi:10.3389/fpsyg.2014.00093
PMCID: PMC3921677  PMID: 24575069
fairness; race; social partners; social selections; resource distribution
14.  Neural Correlates of True Memory, False Memory, and Deception 
Cerebral Cortex (New York, NY)  2008;18(12):2811-2819.
We used functional magnetic resonance imaging (fMRI) to determine whether neural activity can differentiate between true memory, false memory, and deception. Subjects heard a series of semantically related words and were later asked to make a recognition judgment of old words, semantically related nonstudied words (lures for false recognition), and unrelated new words. They were also asked to make a deceptive response to half of the old and unrelated new words. There were 3 main findings. First, consistent with the notion that executive function supports deception, 2 types of deception (pretending to know and pretending not to know) recruited prefrontal activity. Second, consistent with the sensory reactivation hypothesis, the difference between true recognition and false recognition was found in the left temporoparietal regions probably engaged in the encoding of auditorily presented words. Third, the left prefrontal cortex was activated during pretending to know relative to correct rejection and false recognition, whereas the right anterior hippocampus was activated during false recognition relative to correct rejection and pretending to know. These findings indicate that fMRI can detect the difference in brain activity between deception and false memory despite the fact that subjects respond with “I know” to novel events in both processes.
doi:10.1093/cercor/bhn037
PMCID: PMC2583150  PMID: 18372290
false recognition; fMRI; lying; medial temporal lobe; prefrontal cortex
15.  Perseverative responding in a violation-of-expectation task in 6.5-month-old infants 
Cognition  2003;88(3):277-316.
In the present research, 6.5-month-old infants perseverated in a violation-of-expectation task designed to examine their reasoning about width information in containment events. After watching a familiarization event in which a ball was lowered into a wide container, the infants failed to detect the violation in a test event in which the same ball was lowered into a container only half as wide as the ball (narrow-container test event). This negative result (which was replicated in another experiment) was interpreted in terms of a recent problem-solving account of infants’ perseverative errors in various means-end tasks (Aguiar, A., & Baillargeon, R. (2000). Perseveration and problem solving in infancy. In H. W. Reese (Ed.), Advances in child development and behavior (Vol. 27, pp. 135–180). San Diego, CA: Academic Press). It was assumed that the infants in the present experiments (1) did not attend to the relative widths of the ball and container in their initial analysis of the narrow-container test event, (2) categorized the event as similar to the familiarization event shown on the preceding trials, and (3) retrieved the expectation they had formed for that event (“the ball will fit into the container”), resulting in a perseverative error. This interpretation was supported by additional experiments in which different modifications were introduced that led to non-perseverative responding, indicating that 6.5-month-old infants could detect the violation in the narrow-container test event. The present findings are important for several reasons. First, they provide the first demonstration of perseverative responding in a violation-of-expectation task. Second, they make clear the breadth and usefulness of the problem-solving account mentioned above. Finally, they add to the evidence for some degree of continuity between infants’ and adults’ problem-solving abilities.
PMCID: PMC4212222  PMID: 12804814
Infant cognition; Physical reasoning; Violation-of-expectation task; Perseveration
16.  Representations for phonotactic learning in infancy 
Infants rapidly learn novel phonotactic constraints from brief listening experience. Four experiments explored the nature of the representations underlying this learning. 16.5- and 10.5-month-old infants heard training syllables in which particular consonants were restricted to particular syllable positions (first-order constraints) or to syllable positions depending on the identity of the adjacent vowel (second-order constraints). Later, in a headturn listening-preference task, infants were presented with new syllables that either followed the experimental constraints or violated them. Infants at both ages learned first- and second-order constraints on consonant position (Experiments 1 and 2) but found second-order constraints more difficult to learn (Experiment 2). Infants also spontaneously generalized first-order constraints to syllables containing a new, transfer vowel; they did so whether the transfer vowel was similar to the familiarization vowels (Experiment 3), or dissimilar from them (Experiment 4). These findings suggest that infants recruit representations of individuated segments during phonological learning. Furthermore, like adults, they represent phonological sequences in a flexible manner that allows them to detect patterns at multiple levels of phonological analysis.
doi:10.1080/15475441.2011.580447
PMCID: PMC3326355  PMID: 22511851
speech perception; phonological development; statistical learning; phonotactic learning; infancy
17.  Young infants’ reasoning about hidden objects: evidence from violation-of-expectation tasks with test trials only 
Cognition  2004;93(3):167-198.
The present research examined alternative accounts of prior violation-of-expectation (VOE) reports that young infants can represent and reason about hidden objects. According to these accounts, young infants’ apparent success in these VOE tasks reflects only novelty and familiarity preferences induced by the habituation or familiarization trials in the tasks. In two experiments, 4-month-old infants were tested in VOE tasks with test trials only. The infants still gave evidence that they could represent and reason about hidden objects: they were surprised, as indicated by greater attention, when a wide object became fully hidden behind a narrow occluder (Experiment 1) or inside a narrow container (Experiment 2). These and control results demonstrate that young infants can succeed at VOE tasks involving hidden objects even when given no habituation or familiarization trials. The present research thus provides additional support for the conclusion that young infants possess expectations about hidden objects. Methodological issues concerning the use of habituation or familiarization trials in VOE tasks are also discussed.
doi:10.1016/j.cognition.2003.09.012
PMCID: PMC4215956  PMID: 15178376
Infants’ physical reasoning; Violation-of-expectation findings; Novelty and familiarity preferences
18.  Can infants attribute to an agent a disposition to perform a particular action? 
Cognition  2005;98(2):B45-B55.
The present research investigated whether 13.5-month-old infants would attribute to an actor a disposition to perform a recurring action, and would then use this information to predict which of two new objects—one that could be used to perform the action and one that could not—the actor would grasp next. During familiarization, the infants watched an actor slide various objects forward and backward on an apparatus floor. During test, the infants saw two new identical objects placed side by side: one stood inside a short frame that left little room for sliding; the other stood inside a longer frame that left ample room for sliding. The infants who saw the actor grasp the object inside the short frame looked reliably longer than those who saw the actor grasp the object inside the long frame. This and control results from a lifting condition provide evidence that by 13.5 months, infants can attribute to an actor a disposition to perform a particular action.
doi:10.1016/j.cognition.2005.04.004
PMCID: PMC3357324  PMID: 15993398
19.  Action experience alters 3-month-old infants’ perception of others’ actions 
Cognition  2005;96(1):B1-11.
An intervention facilitated 3-month-old infants’ apprehension of objects either prior to (reach first), or after (watch first) viewing another person grasp similar objects in a visual habituation procedure. Action experience facilitated action perception: reach-first infants focused on the relation between the actor and her goal, but watch-first infants did not. Infants’ sensitivity to the actor’s goal was correlated with their engagement in object-directed contact with the toys. These findings indicate that infants can rapidly form goal-based action representations and suggest a developmental link between infants’ goal directed actions and their ability to detect goals in the actions of others.
doi:10.1016/j.cognition.2004.07.004
PMCID: PMC3908452  PMID: 15833301
Action/perception; Intentional structure; Infant cognitive development
20.  Developments in young infants’ reasoning about occluded objects☆ 
Cognitive psychology  2002;45(2):267-336.
Eight experiments were conducted to examine 3- and 3.5-month-old infants’ responses to occlusion events. The results revealed two developments, one in infants’ knowledge of when objects should and should not be occluded and the other in infants’ ability to posit additional objects to make sense of events that would otherwise violate their occlusion knowledge. The first development is that, beginning at about 3 months of age, infants expect an object to become temporarily visible when passing behind an occluder with an opening extending from its lower edge. The second development is that, beginning at about 3.5 months of age, infants generate a two-object explanation when shown a violation in which an object fails to become visible when passing behind an occluder with an opening in its lower edge. Unless given information contradicting such an explanation, infants infer that two identical objects are involved in the event, one traveling to the left and one to the right of the opening. These and related findings provide the basis for a model of young infants’ responses to occlusion events; alternative models are also discussed.
PMCID: PMC4241364  PMID: 12528903
21.  Cross-Over between Discrete and Continuous Protein Structure Space: Insights into Automatic Classification and Networks of Protein Structures 
PLoS Computational Biology  2009;5(3):e1000331.
Structural classifications of proteins assume the existence of the fold, which is an intrinsic equivalence class of protein domains. Here, we test in which conditions such an equivalence class is compatible with objective similarity measures. We base our analysis on the transitive property of the equivalence relationship, requiring that similarity of A with B and B with C implies that A and C are also similar. Divergent gene evolution leads us to expect that the transitive property should approximately hold. However, if protein domains are a combination of recurrent short polypeptide fragments, as proposed by several authors, then similarity of partial fragments may violate the transitive property, favouring the continuous view of the protein structure space. We propose a measure to quantify the violations of the transitive property when a clustering algorithm joins elements into clusters, and we find out that such violations present a well defined and detectable cross-over point, from an approximately transitive regime at high structure similarity to a regime with large transitivity violations and large differences in length at low similarity. We argue that protein structure space is discrete and hierarchic classification is justified up to this cross-over point, whereas at lower similarities the structure space is continuous and it should be represented as a network. We have tested the qualitative behaviour of this measure, varying all the choices involved in the automatic classification procedure, i.e., domain decomposition, alignment algorithm, similarity score, and clustering algorithm, and we have found out that this behaviour is quite robust. The final classification depends on the chosen algorithms. We used the values of the clustering coefficient and the transitivity violations to select the optimal choices among those that we tested. Interestingly, this criterion also favours the agreement between automatic and expert classifications. As a domain set, we have selected a consensus set of 2,890 domains decomposed very similarly in SCOP and CATH. As an alignment algorithm, we used a global version of MAMMOTH developed in our group, which is both rapid and accurate. As a similarity measure, we used the size-normalized contact overlap, and as a clustering algorithm, we used average linkage. The resulting automatic classification at the cross-over point was more consistent than expert ones with respect to the structure similarity measure, with 86% of the clusters corresponding to subsets of either SCOP or CATH superfamilies and fewer than 5% containing domains in distinct folds according to both SCOP and CATH. Almost 15% of SCOP superfamilies and 10% of CATH superfamilies were split, consistent with the notion of fold change in protein evolution. These results were qualitatively robust for all choices that we tested, although we did not try to use alignment algorithms developed by other groups. Folds defined in SCOP and CATH would be completely joined in the regime of large transitivity violations where clustering is more arbitrary. Consistently, the agreement between SCOP and CATH at fold level was lower than their agreement with the automatic classification obtained using as a clustering algorithm, respectively, average linkage (for SCOP) or single linkage (for CATH). The networks representing significant evolutionary and structural relationships between clusters beyond the cross-over point may allow us to perform evolutionary, structural, or functional analyses beyond the limits of classification schemes. These networks and the underlying clusters are available at http://ub.cbm.uam.es/research/ProtNet.php
Author Summary
Making order of the fast-growing information on proteins is essential for gaining evolutionary and functional knowledge. The most successful approaches to this task are based on classifications of protein structures, such as SCOP and CATH, which assume a discrete view of the protein structure space as a collection of separated equivalence classes (folds). However, several authors proposed that protein domains should be regarded as assemblies of polypeptide fragments, which implies that the protein–structure space is continuous. Here, we assess these views of domain space through the concept of transitivity; i.e., we test whether structure similarity of A with B and B with C implies that A and C are similar, as required for consistent classification. We find that the domain space is approximately transitive and discrete at high similarity and continuous at low similarity, where transitivity is severely violated. Comparing our classification at the cross-over similarity with CATH and SCOP, we find that they join proteins at low similarity where classification is inconsistent. Part of this discrepancy is due to structural divergence of homologous domains, which are forced to be in a single cluster in CATH and SCOP. Structural and evolutionary relationships between consistent clusters are represented as a network in our approach, going beyond current protein classification schemes. We conjecture that our results are related to a change of evolutionary regime, from uniparental divergent evolution for highly related domains to assembly of large fragments for which the classical tree representation is unsuitable.
doi:10.1371/journal.pcbi.1000331
PMCID: PMC2654728  PMID: 19325884
22.  HIV-1 Drug Resistance Emergence among Breastfeeding Infants Born to HIV-Infected Mothers during a Single-Arm Trial of Triple-Antiretroviral Prophylaxis for Prevention of Mother-To-Child Transmission: A Secondary Analysis 
PLoS Medicine  2011;8(3):e1000430.
Analysis of a substudy of the Kisumu breastfeeding trial by Clement Zeh and colleagues reveals the emergence of HIV drug resistance in HIV-positive infants born to HIV-infected mothers treated with antiretroviral drugs.
Background
Nevirapine and lamivudine given to mothers are transmitted to infants via breastfeeding in quantities sufficient to have biologic effects on the virus; this may lead to an increased risk of a breastfed infant's development of resistance to maternal antiretrovirals. The Kisumu Breastfeeding Study (KiBS), a single-arm open-label prevention of mother-to-child HIV transmission (PMTCT) trial, assessed the safety and efficacy of zidovudine, lamivudine, and either nevirapine or nelfinavir given to HIV-infected women from 34 wk gestation through 6 mo of breastfeeding. Here, we present findings from a KiBS trial secondary analysis that evaluated the emergence of maternal ARV-associated resistance among 32 HIV-infected breastfed infants.
Methods and Findings
All infants in the cohort were tested for HIV infection using DNA PCR at multiple study visits during the 24 mo of the study, and plasma RNA viral load for all HIV-PCR–positive infants was evaluated retrospectively. Specimens from mothers and infants with viral load >1,000 copies/ml were tested for HIV drug resistance mutations. Overall, 32 infants were HIV infected by 24 mo of age, and of this group, 24 (75%) infants were HIV infected by 6 mo of age. Of the 24 infants infected by 6 mo, nine were born to mothers on a nelfinavir-based regimen, whereas the remaining 15 were born to mothers on a nevirapine-based regimen. All infants were also given single-dose nevirapine within 48 hours of birth. We detected genotypic resistance mutations in none of eight infants who were HIV-PCR positive by 2 wk of age (specimens from six infants were not amplifiable), for 30% (6/20) at 6 wk, 63% (14/22) positive at 14 wk, and 67% (16/24) at 6 mo post partum. Among the 16 infants with resistance mutations by 6 mo post partum, the common mutations were M184V and K103N, conferring resistance to lamivudine and nevirapine, respectively. Genotypic resistance was detected among 9/9 (100%) and 7/15 (47%) infected infants whose mothers were on nelfinavir and nevirapine, respectively. No mutations were detected among the eight infants infected after the breastfeeding period (age 6 mo).
Conclusions
Emergence of HIV drug resistance mutations in HIV-infected infants occurred between 2 wk and 6 mo post partum, most likely because of exposure to maternal ARV drugs through breast milk. Our findings may impact the choice of regimen for ARV treatment of HIV-infected breastfeeding mothers and their infected infants.
Trial Registration
ClinicalTrials.gov NCT00146380
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Globally, more than 2 million children are infected with the human immunodeficiency virus (HIV) that causes acquired immunodeficiency syndrome (AIDS), and half a million children are newly infected every year. These infections are mainly the result of mother-to-child transmission (MTCT) of HIV during pregnancy, labor and delivery, or through breastfeeding. MTCT can be greatly reduced by treating HIV-positive mothers and their babies with antiretroviral drugs (ARVs). Without ARVs, up to half of babies born to HIV-positive mothers become infected with HIV. This rate of transmission falls to below 5% if a combination of three ARVs is given to the mother throughout pregnancy. Unfortunately, this triple-ARV therapy is too expensive for use in the resource-limited countries where most MTCT occurs. Instead, many such countries have introduced simpler, shorter ARV regimens such as a daily dose of zidovudine (a nucleoside reverse transcriptase inhibitor or NRTI) given to HIV-positive women during late pregnancy coupled with single-dose nevirapine (a non-nucleoside reverse transcriptase inhibitor or NNRTI) at the onset of labor, zidovudine and lamivudine (another NRTI) during labor and delivery, and single-dose nevirapine given to the baby at birth.
Why Was This Study Done?
More than 95% of HIV-exposed children are born in resource-limited settings where breastfeeding is the norm and is crucial for child survival even though it poses a risk of HIV transmission. Consequently, several recent studies have investigated whether MTCT can be further reduced by giving the mother ARVs while she is breastfeeding. In the Kisumu Breastfeeding Study (KiBS), for example, researchers assessed the effects of giving zidovudine, lamivudine, and either nevirapine or nelfinavir (a protease inhibitor) to HIV-infected women from 34 weeks of pregnancy through 6 months of breastfeeding. The results of KiBS indicate that this approach might be a safe, feasible way to reduce MTCT (see the accompanying paper by Thomas and colleagues). However, low amounts of nevirapine and lamivudine are transferred from mother to infant in breast milk and this exposure to ARVs could induce the development of resistance to ARVs among HIV-infected infants. In this KiBS substudy, the researchers investigate whether HIV drug resistance emerged in any of the HIV-positive infants in the parent study.
What Did the Researchers Do and Find?
In KiBS, 32 infants were HIV-positive at 24 months old; 24 were HIV-positive at 6 months old when their mothers stopped taking ARVs and when breastfeeding was supposed to stop. The researchers analyzed blood samples taken from these infants at various ages and from their mothers for the presence of HIV drug resistance mutations (DNA changes that make HIV resistant to killing by ARVs). They detected no resistance mutations in samples taken from 2-week old HIV-positive infants or from the infants who became infected after the age of 6 months. However, they found resistance mutations in a third and two-thirds of samples taken from 6-week and 6-month old HIV-positive infants, respectively. The commonest mutations conferred resistance to lamivudine and nevirapine. Moreover, resistance mutations were present in samples taken from all the HIV-positive infants whose mothers who had received nelfinavir but in only half those taken from infants whose mothers who had received nevirapine. Finally, most of the mothers of HIV-positive infants had no HIV drug resistance mutations, and only one mother-infant pair had an overlapping pattern of HIV drug resistance mutations.
What Do These Findings Mean?
These findings indicate that, in this KiBS substudy, the emergence of HIV drug resistance mutations in HIV-infected infants whose mothers were receiving ARVs occurred between 2 weeks and 6 months after birth. The pattern of mutations suggests that drug resistance most likely arose through exposure of the infants to low levels of ARVs in breast milk rather than through MTCT of drug-resistant virus. These findings need confirming but suggest that infants exposed to ARVs through breast milk—a situation that may become increasingly common given the reduction in MTCT seen in KiBS and other similar trials—should be carefully monitored for HIV infection. Providers should consider the mothers' regimen when choosing treatment for infants who are found to be HIV-infected despite maternal triple drug prophylaxis. Infants exposed to a maternal regimen with NNRTI drugs should receive first-line therapy with lopinavir/ritonavir, a protease inhibitor. The significance of the NRTI mutations such as M184V with regard to response to therapy needs further evaluation. The M184V mutation may result in hypersensitization to other NRTI drugs and delay or reverse zidovudine resistance. Given the limited availability of alternative drugs for infants in resource-limited settings, provision of the standard WHO-recommended first-line NRTI backbone, which includes 3TC, with enhanced monitoring of the infant to ensure virologic suppression, could be considered. Such an approach should reduce both illness and morbidity among infants who become HIV positive through breastfeeding.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1000430.
The accompanying PLoS Medicine Research article by Thomas and colleagues describes the primary findings of the Kisumu Breastfeeding Study
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
HIV InSite has comprehensive information on HIV/AIDS
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including information on children, HIV, and AIDS and on preventing mother-to-child transmission of HIV (in English and Spanish)
UNICEF also has information about children and HIV and AIDS (in several languages)
The World Health organization has information on mother-to-child transmission of HIV (in several languages), and guidance on the use of ARVs for preventing MTCT
doi:10.1371/journal.pmed.1000430
PMCID: PMC3066134  PMID: 21468304
23.  Health and Human Rights in Chin State, Western Burma: A Population-Based Assessment Using Multistaged Household Cluster Sampling 
PLoS Medicine  2011;8(2):e1001007.
Sollom and colleagues report the findings from a household survey study carried out in Western Burma; they report a high prevalence of human rights violations such as forced labor, food theft, forced displacement, beatings, and ethnic persecution.
Background
The Chin State of Burma (also known as Myanmar) is an isolated ethnic minority area with poor health outcomes and reports of food insecurity and human rights violations. We report on a population-based assessment of health and human rights in Chin State. We sought to quantify reported human rights violations in Chin State and associations between these reported violations and health status at the household level.
Methods and Findings
Multistaged household cluster sampling was done. Heads of household were interviewed on demographics, access to health care, health status, food insecurity, forced displacement, forced labor, and other human rights violations during the preceding 12 months. Ratios of the prevalence of household hunger comparing exposed and unexposed to each reported violation were estimated using binomial regression, and 95% confidence intervals (CIs) were constructed. Multivariate models were done to adjust for possible confounders. Overall, 91.9% of households (95% CI 89.7%–94.1%) reported forced labor in the past 12 months. Forty-three percent of households met FANTA-2 (Food and Nutrition Technical Assistance II project) definitions for moderate to severe household hunger. Common violations reported were food theft, livestock theft or killing, forced displacement, beatings and torture, detentions, disappearances, and religious and ethnic persecution. Self reporting of multiple rights abuses was independently associated with household hunger.
Conclusions
Our findings indicate widespread self-reports of human rights violations. The nature and extent of these violations may warrant investigation by the United Nations or International Criminal Court.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
More than 60 years after the adoption of the Universal Declaration of Human Rights, thousands of people around the world are still deprived of their basic human rights—life, liberty, and security of person. In many countries, people live in fear of arbitrary arrest and detention, torture, forced labor, religious and ethnic persecution, forced displacement, and murder. In addition, ongoing conflicts and despotic governments deprive them of the ability to grow sufficient food (resulting in food insecurity) and deny them access to essential health care. In Burma, for example, the military junta, which seized power in 1962, frequently confiscates land unlawfully, demands forced labor, and uses violence against anyone who protests. Burma is also one of the world's poorest countries in terms of health indicators. Its average life expectancy is 54 years, its maternal mortality rate (380 deaths among women from pregnancy-related causes per 100,000 live births) is nearly ten times higher than that of neighboring Thailand, and its under-five death rate (122/1000 live births) is twice that of nearby countries. Moreover, nearly half of Burmese children under 5 are stunted, and a third of young children are underweight, indicators of malnutrition in a country that, on paper, has a food surplus.
Why Was This Study Done?
Investigators are increasingly using population-based methods to quantify the associations between human rights violations and health outcomes. In eastern Burma, for example, population-based research has recently revealed a link between human rights violations and reduced access to maternal health-care services. In this study, the researchers undertake a population-based assessment of health and human rights in Chin State, an ethnic minority area in western Burma where multiple reports of human rights abuses have been documented and from which thousands of people have fled. In particular, the researchers investigate correlations between household hunger and household experiences of human rights violations—food security in Chin State is affected by periodic expansions of rat populations that devastate crop yields, by farmers being forced by the government to grow an inedible oil crop (jatropha), and by the Burmese military regularly stealing food and livestock.
What Did the Researchers Do and Find?
Local surveyors questioned the heads of randomly selected households in Chin State about their household's access to health care and its health status, and about forced labor and other human rights violations experienced by the household during the preceding 12 months. They also asked three standard questions about food availability, the answers to which were combined to provide a measure of household hunger. Of the 621 households interviewed, 91.9% reported at least one episode of a household member being forced to work in the preceding 12 months. The Burmese military imposed two-thirds of these forced labor demands. Other human rights violations reported included beating or torture (14.8% of households), religious or ethnic persecutions (14.1% of households), and detention or imprisonment of a family member (5.9% of households). Forty-three percent of the households met the US Agency for International Development Food and Nutrition Technical Assistance (FANTA) definition for moderate to severe household hunger, and human rights violations related to food insecurity were common. For example, more than half the households were forced to give up food out of fear of violence. A statistical analysis of these data indicated that the prevalence of household hunger was 6.51 times higher in households that had experienced three food-related human rights violations than in households that had not experienced such violations.
What Do These Findings Mean?
These findings quantify the extent to which the Chin ethnic minority in Burma is subjected to multiple human rights violations and indicate the geographical spread of these abuses. Importantly, they show that the health impacts of human rights violations in Chin State are substantial. In addition, they suggest that the indirect health outcomes of human rights violations probably dwarf the mortality from direct killings. Although this study has some limitations (for example, surveyors had to work in secret and it was not safe for them to collect biological samples that could have given a more accurate indication of the health status of households than questions alone), these findings should encourage the international community to intensify its efforts to reduce human rights violations in Burma.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001007.
The UN Universal Declaration of Human Rights is available in numerous languages
The Burma Campaign UK and Human Rights Watch provide detailed information about human rights violations in Burma (in several languages)
The World Health Organization provides information on health in Burma and on human rights (in several languages)
The Mae Tao clinic also provides general information about Burma and its health services (including some information in Thai)
A PLoS Medicine Research Article by Luke Mullany and colleagues provides data on human rights violations and maternal health in Burma
The Chin Human Rights Organization is working to protect and promote the rights of the Chin people
The Global Health Access Program (GHAP) provides information on health in Burma
FANTA works to improve nutrition and global food security policies
doi:10.1371/journal.pmed.1001007
PMCID: PMC3035608  PMID: 21346799
24.  Using Goal- and Grip-Related Information for Understanding the Correctness of Other’s Actions: An ERP Study 
PLoS ONE  2012;7(5):e36450.
Detecting errors in other’s actions is of pivotal importance for joint action, competitive behavior and observational learning. Although many studies have focused on the neural mechanisms involved in detecting low-level errors, relatively little is known about error-detection in everyday situations. The present study aimed to identify the functional and neural mechanisms whereby we understand the correctness of other’s actions involving well-known objects (e.g. pouring coffee in a cup). Participants observed action sequences in which the correctness of the object grasped and the grip applied to a pair of objects were independently manipulated. Observation of object violations (e.g. grasping the empty cup instead of the coffee pot) resulted in a stronger P3-effect than observation of grip errors (e.g. grasping the coffee pot at the upper part instead of the handle), likely reflecting a reorienting response, directing attention to the relevant location. Following the P3-effect, a parietal slow wave positivity was observed that persisted for grip-errors, likely reflecting the detection of an incorrect hand-object interaction. These findings provide new insight in the functional significance of the neurophysiological markers associated with the observation of incorrect actions and suggest that the P3-effect and the subsequent parietal slow wave positivity may reflect the detection of errors at different levels in the action hierarchy. Thereby this study elucidates the cognitive processes that support the detection of action violations in the selection of objects and grips.
doi:10.1371/journal.pone.0036450
PMCID: PMC3350525  PMID: 22606261
25.  Using Social Information to Guide Action: Infants’ Locomotion Over Slippery Slopes 
In uncertain situations such as descending challenging slopes, social signals from caregivers can provide infants with important information for guiding action. Previous work showed that 18- month-old walking infants use social information selectively, only when risk of falling is uncertain. Experiment 1 was designed to alter infants’ region of uncertainty for walking down slopes. Slippery Teflon-soled shoes drastically impaired 18-month-olds’ ability to walk down slopes compared with walking barefoot or in standard crepe-soled shoes, shifting the region of uncertainty to shallower range of slopes. In Experiment 2, infants wore Teflon-soled shoes while walking down slopes as their mothers encouraged and discouraged them from walking. Infants relied on social information on shallow slopes, even at 0°, where the probability of walking successfully was uncertain in the Teflon-soled shoes. Findings indicate that infants’ use of social information is dynamically attuned to situational factors and the state of their current abilities.
doi:10.1016/j.neunet.2010.08.012
PMCID: PMC2963195  PMID: 20875725
infant locomotion; social cognition; perceptual exploration; walking; communication

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