Infants Discriminate the Affective Expressions of their Peers: The Roles of Age and Familiarization Time.

Research examining infants' discrimination of affect often uses unfamiliar faces and voices of adults. Recently, research has examined infant discrimination of affect in familiar faces and voices. In much of this research, infants were habituated to the affective expressions using a "standard" 50% habituation criterion. We extend this line of research by examining infants' discrimination of unfamiliar peers', that is, 4-month-olds, dynamic, facial, and vocal affective expressions and assessing how discrimination is affected by changing the habituation criterion. In two experiments, using an infant-controlled habituation design, we explored 3- and 5-month-olds' discrimination of their peers' dynamic audiovisual displays of positive and negative expressions of affect. Results of Experiment 1, using a 50% habituation criterion, revealed that 5-month-olds, but not 3-month-olds discriminated the affective expressions of their peers. In Experiment 2, we examined whether 3-month-olds' lack of discrimination in Experiment 1 was a result of insufficient habituation (i.e., familiarization). Specifically, 3-month-olds were habituated using a 70% habituation criterion, providing them with longer familiarization time. Results revealed that using the more stringent habituation criterion, 3-month-olds showed longer habituation times, that is increased familiarization, and discriminated their peers' affective expressions. Results are discussed in terms of infants' discrimination of affect, the role of familiarization time, and limitations of the 50% habituation criterion.

Dynamics of infant habituation: infants' discrimination of musical excerpts.

Schöner and Thelen (2006) summarized the results of many habituation studies as a set of generalizations about the emergence of novelty preferences in infancy. One is that novelty preferences emerge after fewer trials for older than for younger infants. Yet in habituation studies using an infant-controlled procedure, the standard criterion of habituation is a 50% decrement in looking regardless of he ages of the participants. If younger infants require more looking to habituate than do older infants, it might follow that novelty preferences will emerge for younger infants when a more stringent criterion is imposed, e.g., a 70% decrement in looking. Our earlier investigation of infants' discrimination of musical excerpts provides a basis and an opportunity for assessing this idea. Flom et al. (2008) found that 9-month-olds, but not younger infants, unambiguously discriminate "happy" and "sad" musical excerpts. The purpose of the current study was to examine younger infants' discrimination of happy and sad musical excerpts using a more stringent, 70% habituation criterion. In Experiment 1, 5- and 7-month olds were habituated to three musical excerpts rated as happy or sad. Following habituation infants were presented with two musical excerpts from the other affect group. Infants at both ages showed significant discrimination. In Experiment 2, 5- and 7-month-olds were presented with two new excerpts from the same affective group as the habituation excerpts. The infants did not discriminate these novel, yet affectively similar excerpts. In Experiment 3, 5- and 7-month-olds discriminated individual happy and sad excerpts. These results replicate those for the older, 9-month-olds in the previous investigation. The results are important as they demonstrate that whether infants show discrimination using an infant-controlled procedure is affected by the researchers' chosen criterion of habituation.

Tyrosine kinase inhibitors influence ABCG2 expression in EGFR-positive MDCK BCRP cells via the PI3K/Akt signaling pathway.

Multidrug resistance observed in cancer chemotherapy is commonly attributed to overexpression of efflux transporter proteins. These proteins act as ATP-dependent drug efflux pumps, actively extruding chemotherapeutic agents from cells and causing a decrease in intracellular drug accumulation. Besides the well-recognized role of P-glycoprotein (P-gp, ABCB1), the breast cancer resistance protein (BCRP, ABCG2) is becoming increasingly accepted as playing an important role in multidrug resistance. In contrast to P-glycoprotein, only a few inhibitors of ABCG2 are known. According to the literature, tyrosine kinase inhibitors (TKIs) can be considered to be broad-spectrum inhibitors, interacting with ABCB1, ABCC1 and ABCG2. Here, we investigated seven different TKIs, gefitinib, erlotinib, AG1478, PD158780, PD153035, nilotinib and imatinib, for their potential to restore ABCG2 sensitivity to cells. Furthermore, we analyzed the alteration of ABCG2 expression caused by TKIs and demonstrated that EGFR inhibitors such as gefitinib and PD158780 reduced both total and surface expression of ABCG2 in EGRF-positive MDCK BCRP cells by interaction with the PI3K/Akt signaling pathway. The reduced ABCG2 content led to an increased effect of XR9577, a well-known ABCG2 modulator, lowering the concentration required for half maximal inhibition. On the other hand, BCR-ABL inhibitors had no influence on ABCG2 expression and modulator activity. Interestingly, a combination of an EGFR inhibitor with the PI3K/Akt inhibitor LY294002 led to a significant reduction of ABCG2 expression at low concentrations of the drugs. Based on our results, we assume that EGFR exerts a post-transcriptional enhancing effect on ABCG2 expression via the PI3K/Akt signaling pathway, which can be attenuated by EGFR inhibitors. Blocking the key signaling pathway regulating ABCG2 expression with EGFR inhibitors, combined with the inhibition of ABCG2 with potent modulators might be a promising approach to circumvent MDR in cancer cells.

To Grasp or Not to Grasp: Infants' Actions Toward Objects and Pictures.

We conducted two experiments to address questions over whether 9-month-old infants believe that objects depicted in realistic photographs can be picked up. In Experiment 1, we presented 9-month-old infants with realistic color photographs of objects, colored outlines of objects, abstract colored "blobs," and blank pages. Infants most commonly rubbed or patted depictions of all types. They also showed significantly more grasps toward the realistic photographs than toward the colored outlines, blobs, and blank pages, but only 24% of infants directed grasping exclusively at the photographs. In Experiment 2, we further explored infants' actions toward objects and pictures while controlling for tactile information. We presented 9-month-old infants with objects and pictures of objects under a glass cover in a false-bottom table. Although there were no significant differences between the proportion of rubs and pats infants directed toward the objects versus the photographs, infants exhibited significantly more grasping toward the objects than the photographs. Together, these findings show that 9-month-old infants largely direct appropriate actions toward realistic photographs and real objects, indicating that they perceive different affordances for pictures and objects.

Structure-activity relationships of flavonoids as inhibitors of breast cancer resistance protein (BCRP).

Flavonoids are an interesting group of natural products ubiquitously present in human diet. Their consumption has been associated with various and differing beneficial health effects. However, several flavonoids have been reported to inhibit the breast cancer resistance protein (BCRP) encoded by the ABCG2 gene. Thus, the consumption of flavonoids with high inhibitory activity could change pharmacokinetics and drug levels of drugs that are BCRP substrates. In cancer patients receiving chemotherapy an increased intake of such flavonoids could lead to adverse effects. We investigated a structurally diverse set of flavonoids, including derivatives with a rare C-methylated structure that were isolated from plants used in traditional medicine. The flavones retusin and ayanin were found to be highly potent inhibitors of BCRP, showing only slightly less potency than Ko143, the most potent ABCG2 inhibitor known so far. The activity data were analyzed by 2D and 3D QSAR analyses and the results revealed the impact of the different substituents at the various positions of the flavonoid core on activity. Additionally, a lateral 2D QSAR analysis of data collected from the literature was performed aiming to derive more general information about the influence of distinct structural features on the inhibitory potency of flavonoids. The comparative QSAR analyses led to a consistent picture of the effects of the different substituents at various positions of the flavone backbone. The following structural features were found to contribute positively to BCRP inhibition: a hydroxyl group in position 5, double bond between position 2 and 3, and a methoxy group in position 3. The exchange of a 3-methoxy group by an OH-group acting also as a hydrogen bond donor, resulted in decrease in activity underlining the potential role of the hydrogen bond acceptor 3-OCH(3) for the interaction with BCRP.

Specific inhibitors of the breast cancer resistance protein (BCRP).

A new class of specific breast cancer resistance protein (BCRP) inhibitors was identified, showing no inhibition of the ATP binding cassette (ABC) transporters P-gp and MRP1. Some of these modulators inhibit BCRP with high potency; they are only slightly less potent than Ko143 and could serve as promising lead structures for the design of novel effective BCRP inhibitors. These inhibitors are structurally related to tariquidar (XR9576) and belong to a library of multidrug-resistance modulators synthesized by our research group. The absence of the tetrahydroisoquinoline substructure appears to play a crucial role for specificity; we found that the presence of this substructure is not essential for interaction with BCRP. To determine the type of interaction between pheophorbide A and compounds with and without the tetrahydroisoquinoline substructure, various substrate pheophorbide A concentrations were used in enzyme kinetics assays. The resulting data show that these compounds share a noncompetitive-type interaction with pheophorbide A. Experiments with imatinib and pheophorbide A revealed a mixed-type interaction. The combination of imatinib and compounds with and without the tetrahydroisoquinoline substructure resulted in a positive cooperative effect, indicating that imatinib engages a binding site distinct from that of the new compounds on one side and distinct from that of pheophorbide A on the other side as well. The results of this study suggest that the category of BCRP-specific inhibitors, which includes only fumitremorgin C, Ko143 and analogues, and novobiocin needs to be extended by this new class of inhibitors, which possess three key characteristics: specificity, potency, and low toxicity.

Novel lead for potent inhibitors of breast cancer resistance protein (BCRP).

From our modulator library an interesting inhibitor of breast cancer resistance protein (BCRP) was identified. Due to its high inhibitory potency, this compound may serve as a promising novel lead for the design of new and potent modulators. This adds a new structural class to the few known highly active BCRP inhibitors.

Structure-activity relationships of new inhibitors of breast cancer resistance protein (ABCG2).

At the end of the last century tariquidar (XR9576) was synthesized, pharmacologically investigated, and classified as a promising 3rd generation P-glycoprotein (P-gp) modulator. Following the discovery of BCRP in 1998 an increasing number of substances were studied in relation to their potency to interact with this transporter. Recently it has been shown that XR9576 inhibits both P-gp and BCRP transport function similarly to GF120918 (elacridar). This observation prompted us to investigate 5 XR compounds and 25 structurally related derivatives synthesized in our laboratory for their BCRP inhibitory effect. The biological activity data were determined by our new Hoechst 33342 assay that has been transferred from P-gp to BCRP overexpressing cells. 3D-QSAR models (CoMFA and CoMSIA) were generated and validated by the leave-many-out method and the scrambling stability test. The best models yielded an internal predictive squared correlation coefficient higher than 0.8 and contained steric, electrostatic, hydrophobic, and hydrogen bond donor fields. To our knowledge, this is the first 3D-QSAR analysis of BCRP inhibitors. Additionally the biological activity data determined in P-gp overexpressing cells on one side and BCRP overexpressing cells on the other side were compared to identify selective and non-selective inhibitors of P-gp and BCRP. The results may help to get a better insight which structural elements are necessary to direct the interaction of these compounds with P-gp and/or BCRP.

Infants' discrimination of happy and sad music.

Infants can detect information specifying affect in infant- and adult-directed speech, familiar and unfamiliar facial expressions, and in point-light displays of facial expressions. We examined 3-, 5-, 7-, and 9-month-olds' discrimination of musical excerpts judged by adults and preschoolers as happy and sad. In Experiment 1, using an infant-controlled habituation procedure, 3-, 5-, 7-, and 9-month-olds heard three musical excerpts that were rated as either happy or sad. Following habituation, infants were presented with two new musical excerpts from the other affect group. Nine-month-olds discriminated the musical excerpts rated as affectively different. Five- and seven-month-olds discriminated the happy and sad excerpts when they were habituated to sad excerpts but not when they were habituated to happy excerpts. Three-month-olds showed no evidence of discriminating the sad and happy excerpts. In Experiment 2, 5-, 7-, and 9-month-olds were presented with two new musical excerpts from the same affective group as the habituation excerpts. At no age did infants discriminate these novel, yet affectively similar, musical excerpts. In Experiment 3, we examined 5-, 7-, and 9-month-olds' discrimination of individual excerpts rated as affectively similar. Only the 9-month-olds discriminated the affectively similar individual excerpts. Results are discussed in terms of infants' ability to discriminate affect across a variety of events and its relevance for later social-communicative development.

Experimenter Affective Expression and Gaze Following in 7-Month-Olds.

The study of gaze following in infants younger than 12 months of age has emphasized the effects of gesture, type of target, and its position or placement. This experiment extends this literature by examining the effects of adults' affective expression on 7-month-olds' gaze following. The effects of 3 affective expressions-happy, sad, and neutral-on 7-month-olds' frequency of gaze following were examined. The results indicated that infants more frequently followed the gaze of an adult posing a neutral expression than that of an adult posing either a happy or a sad expression. The infants also looked proportionately longer toward the indicated target when the adult's expression was neutral. The results are interpreted in terms of infants' flexibility of attention.

Matching and naming objects by shape or function: age and context effects in preschool children.

Three experiments tested preschoolers' use of abstract principles to classify and label objects by shape or function. Three- and 4-year-olds were instructed to match objects by shape or function. Four-year-olds readily adopted either rule, but 3-year-olds followed only the shape rule. Without a rule, 4-year-olds tended to match by shape unless object function was shown during matching (Experiment 2). Three-year-olds' ability to use a function rule was tested in several conditions (re-presenting functions; reminders to "use the rule"; repeating rule on every trial). None induced consistent function matching (Experiment 3). Supplemental memory and verbal tasks showed that 3-year-olds have trouble using function as an abstract basis of comparison. Naming data, however, show that preschoolers are learning that object labels are based on function. The results show preschoolers' growing flexibility in adopting abstract generalization rules and growing knowledge of conventions for extending words.