Redox modulation of stress resilience by Crocus sativus L. for potential neuroprotective and anti-neuroinflammatory applications in brain disorders: From molecular basis to therapy.

Recent evidence demonstrates that Crocus sativus L. (saffron) counteracts oxidative stress, mitochondrial dysfunction and neuroinflammation, closely linked to initiation and progression of major brain pathologies. Interestingly, saffron constituents such as crocin, crocetin and safranal can exert antioxidant or toxic effects depending on their endogenous concentration. According to the hormesis principles, at low dose they act as antioxidants in a wide range of brain diseases by upregulating Nrf2 signaling pathway and the expression of vitagenes, such as NAD(P)H-quinone oxidoreductase (NQO1), glutathione transferase (GT), heme oxygenase-1 (HO-1), sirtuin-1 (Sirt1) and thioredoxin (Trx) system. Importantly, neuronal dysregulation of Nrf2 pathway can be a prominent cause of selective susceptibility, under neuroinflammatory conditions, due to the high vulnerability of brain cells to oxidative stress. Here we discuss natural inducers from saffron targeting Nrf2/vitagene pathway for development of new therapeutical strategies to suppress oxidative stress and neuroinflammation and consequently cognitive dysfunction. In this review we also focus on the hormetic effect of saffron active constituents, summarizing their neuroprotective and anti-neuroinflammatory properties, as well as pharmacological perspectives in brain disorders.

Mechanism of translation control of the alternative Drosophila melanogaster Voltage Dependent Anion-selective Channel 1 mRNAs.

The eukaryotic porin, also called the Voltage Dependent Anion-selective Channel (VDAC), is the main pore-forming protein of the outer mitochondrial membrane. In Drosophila melanogaster, a cluster of genes evolutionarily linked to VDAC is present on chromosome 2L. The main VDAC isoform, called VDAC1 (Porin1), is expressed from the first gene of the cluster. The porin1 gene produces two splice variants, 1A-VDAC and 1B-VDAC, with the same coding sequence but different 5' untranslated regions (UTRs). Here, we studied the influence of the two 5' UTRs, 1A-5' UTR and 1B-5' UTR, on transcription and translation of VDAC1 mRNAs. In porin-less yeast cells, transformation with a construct carrying 1A-VDAC results in the expression of the corresponding protein and in complementation of a defective cell phenotype, whereas the 1B-VDAC sequence actively represses VDAC expression. Identical results were obtained using constructs containing the two 5' UTRs upstream of the GFP reporter. A short region of 15 nucleotides in the 1B-5' UTR should be able to pair with an exposed helix of 18S ribosomal RNA (rRNA), and this interaction could be involved in the translational repression. Our data suggest that contacts between the 5' UTR and 18S rRNA sequences could modulate the translation of Drosophila 1B-VDAC mRNA. The evolutionary significance of this finding is discussed.

Verb learning in children with SLI: frequency and spacing effects.

PURPOSE: This study explored the effect of frequency (number of presentations), and spacing (period between presentations) on verb learning in children with specific language impairment (SLI). Children learn words more efficiently when presentations are frequent and appropriately spaced, and this study investigated whether children with SLI likewise benefit. Given that these children demonstrate greater frequency dependence and rapid forgetting of recently acquired words, an investigation of frequency and spacing in this population is especially warranted. METHOD: Twenty-four children with SLI (mean age 5;6 [years;months]) and 24 language-matched control children (mean age 3;4) were taught novel verbs during play sessions. In a repeated measures design, 4 experimental conditions combined frequency (12 or 18 presentations) and spacing (all presentations in 1 session, or spread over 4 days). Comprehension and production probes were administered after the final session and 1 week later. RESULTS: Although the children with SLI benefited significantly from frequent and widely spaced presentations, there were no significant effect in the control group. The language-impaired children showed rapid forgetting. CONCLUSIONS: The frequency and spacing of presentations crucially affect the verb learning of children with SLI. A training regimen characterized by appropriately spaced intervals and moderate repetition will optimally benefit lexical learning.

The role of pronouns in young children's acquisition of the English transitive construction.

Two studies investigating the linguistic representations underlying English-speaking 2 1/2-year-olds' production of transitive utterances are reported. The first study was a training study in which half the children heard utterances with full nouns as agent and patient, and half the children heard utterances with both pronouns (i.e., He's [verb]-ing it) and also full nouns. In subsequent testing, only children who had been trained with pronouns and nouns were able to produce a transitive utterance creatively with a nonce verb. The second study reported an analogous set of findings, but in comprehension. Together, the results of these 2 studies suggest that English-speaking children build many of their early linguistic constructions around certain specific lexical or morphological items and patterns, perhaps especially around particular pronoun configurations.

Chimpanzees know what conspecifics do and do not see.

We report a series of experiments on social problem solving in chimpanzees, Pan troglodytes. In each experiment a subordinate and a dominant individual were put into competition over two pieces of food. In all experiments dominants obtained virtually all of the foods to which they had good visual and physical access. However, subordinates were successful quite often in three situations in which they had better visual access to the food than the dominant, for example, when the food was positioned so that only the subordinate (and not the dominant) could see it. In some cases, the subordinate might have been monitoring the behaviour of the dominant directly and simply avoided the food that the dominant was moving towards (which just happened to be the one it could see). In other cases, however, we ruled out this possibility by giving subordinates a small headstart and forcing them to make their choice (to go to the food that both competitors could see, or the food that only they could see) before the dominant was released into the area. Together with other recent studies, the present investigation suggests that chimpanzees know what conspecifics can and cannot see, and, furthermore, that they use this knowledge to devise effective social-cognitive strategies in naturally occurring food competition situations. Copyright 2000 The Association for the Study of Animal Behaviour.

The item-based nature of children's early syntactic development.

Recent research using both naturalistic and experimental methods has found that the vast majority of young children's early language is organized around concrete, item-based linguistic schemas. From this beginning, children then construct more abstract and adult-like linguistic constructions, but only gradually and in piecemeal fashion. These new data present significant problems for nativist accounts of children's language development that use adult-like linguistic categories, structures and formal grammars as analytical tools. Instead, the best account of these data is provided by a usage-based model in which children imitatively learn concrete linguistic expressions from the language they hear around them, and then - using their general cognitive and social-cognitive skills - categorize, schematize and creatively combine these individually learned expressions and structures.

Do young children have adult syntactic competence?

Many developmental psycholinguists assume that young children have adult syntactic competence, this assumption being operationalized in the use of adult-like grammars to describe young children's language. This "continuity assumption" has never had strong empirical support, but recently a number of new findings have emerged - both from systematic analyses of children's spontaneous speech and from controlled experiments - that contradict it directly. In general, the key finding is that most of children's early linguistic competence is item based, and therefore their language development proceeds in a piecemeal fashion with virtually no evidence of any system-wide syntactic categories, schemas, or parameters. For a variety of reasons, these findings are not easily explained in terms of the development of children's skills of linguistic performance, pragmatics, or other "external" factors. The framework of an alternative, usage-based theory of child language acquisition - relying explicitly on new models from Cognitive-Functional Linguistics - is presented.

Factors affecting young children's use of pronouns as referring expressions.

Most studies of children's use of pronouns have focused either on the morphology of personal pronouns or on the anaphoric use of pronouns by older children. The current two studies investigated factors affecting children's choice of pronouns as referring expressions-in contrast with their use of full nouns and null references. In the first study it was found that 2.5- and 3.5-year-old children did not use pronouns differentially whether the adult (a) modeled a pronoun or a noun for the target object or (b) did or did not witness the target event (although there was evidence that they did notice and take account of the adult's witnessing in other ways). In the second study it was found that children of this same age (a) do not use pronouns to avoid unfamiliar or difficult nouns but (b) do use pronouns differently depending on the immediately preceding discourse of the experimenter (whether they were asked a specific question such as "What did X do?" or a general question such as "What happened?"). In the case of specific questions, children prefer to use a null reference but use some pronouns as well (almost never using full nouns); in the case of the generic questions, children use pronouns even more often (and use nouns more as well). This finding was corroborated by some new analyses of children's use of pronouns in specific discourse situations in previously published studies. These findings suggest that children's choice of pronouns as referring expressions in early language development is influenced more by the immediately preceding discourse than other kinds of factors.

Chimpanzees, Pan troglodytes, follow gaze direction geometrically.

Two experiments on chimpanzee gaze following are reported. In the first, chimpanzee subjects watched as a human experimenter looked around various types of barriers. The subjects looked around each of the barriers more when the human had done so than in a control condition (in which the human looked in another direction). In the second experiment, chimpanzees watched as a human looked towards the back of their cage. As they turned to follow the human's gaze a distractor object was presented. The chimpanzees looked at the distractor while still following the human's gaze to the back of the cage. These two experiments effectively disconfirm the low-level model of chimpanzee gaze following in which it is claimed that upon seeing another animate being's gaze direction chimpanzees simply turn in that direction and look around for something interesting. Rather, they support the hypothesis that chimpanzees follow the gaze direction of other animate beings geometrically to specific locations, in much the same way as human infants. The degree to which chimpanzees have a mentalistic interpretation of the gaze and/or visual experience of others is still an open question. Copyright 1999 The Association for the Study of Animal Behaviour.

A nonverbal false belief task: the performance of children and great apes.

A nonverbal task of false belief understanding was given to 4- and 5-year-old children (N = 28) and to two species of great ape: chimpanzees and orangutans (N = 7). The task was embedded in a series of finding games in which an adult (the hider) hid a reward in one of two identical containers, and another adult (the communicator) observed the hiding process and attempted to help the participant by placing a marker on the container that she believed to hold the reward. An initial series of control trials ensured that participants were able to use the marker to locate the reward, follow the reward in both visible and invisible displacements, and ignore the marker when they knew it to be incorrect. In the crucial false belief trials, the communicator watched the hiding process and then left the area, at which time the hider switched the locations of the containers. When the communicator returned, she marked the container at the location where she had seen the reward hidden, which was incorrect. The hider then gave the subject the opportunity to find the sticker. Successful performance required participants to reason as follows: the communicator placed the marker where she saw the reward hidden; the container that was at that location is now at the other location; so the reward is at the other location. Children were also given a verbal false belief task in the context of this same hiding game. The two main results of the study were: (1) children's performance on the verbal and nonverbal false belief tasks were highly correlated (and both fit very closely with age norms from previous studies), and (2) no ape succeeded in the nonverbal false belief task even though they succeeded in all of the control trials indicating mastery of the general task demands.

Young children learn to produce passives with nonce verbs.

Younger and older children (mean ages = 2 years 11 months and 3 years 5 months) learned 2 nonce verbs in a full passive or active transitive construction. When asked patient-focused questions encouraging passive-voice replies (e.g., "What happened to the ball?") or agent-focused questions encouraging active-voice replies (e.g., "What did Elmo do?"), children used a variety of strategies to meet the demands of the questions, usually without changing the construction in which the verb occurred. In Study 2 in which passive and active constructions were primed, 40% of the almost 3-year-old children used an active-introduced verb in a passive construction and 35% used a passive-introduced verb in an active transitive construction when discourse demands encouraged them to do so. Thus, before their 3rd birthdays, some children have an understanding of the passive and active transitive constructions general enough to support productive usages with newly learned verbs.

Young children's overgeneralizations with fixed transitivity verbs.

The present study examined English-speaking children's tendency to make argument structure overgeneralization errors (e.g., I disappeared it). Children were exposed to several English verbs of fixed transitivity (exclusively intransitive or exclusively transitive) and then asked questions that encouraged them to overgeneralize usage of the verbs. Seventy-two children (24 in each of three age groups: 3, 4/5, and 8 years of age) experienced four actions performed by puppets. Each action had two verbs of similar meaning associated with it in the context of the experimental action: one more familiar to young children and one less familiar. Children at all ages were more likely to overgeneralize usage of verbs that were less familiar to them, supporting the hypothesis that children's usage of verbs in particular construction types becomes entrenched over time. As children solidly learn the transitivity status of particular verbs, they become more reluctant to use those verbs in other argument structure constructions.

Social cognition, joint attention, and communicative competence from 9 to 15 months of age.

At around 1 year of age, human infants display a number of new behaviors that seem to indicate a newly emerging understanding of other persons as intentional beings whose attention to outside objects may be shared, followed into, and directed in various ways. These behaviors have mostly been studied separately. In the current study, we investigated the most important of these behaviors together as they emerged in a single group of 24 infants between 9 and 15 months of age. At each of seven monthly visits, we measured joint attentional engagement, gaze and point following, imitation of two different kinds of actions on objects, imperative and declarative gestures, and comprehension and production of language. We also measured several nonsocial-cognitive skills as a point of comparison. We report two studies. The focus of the first study was the initial emergence of infants' social-cognitive skills and how these skills are related to one another developmentally. We found a reliable pattern of emergence: Infants progressed from sharing to following to directing others' attention and behavior. The nonsocial skills did not emerge predictably in this developmental sequence. Furthermore, correlational analyses showed that the ages of emergence of all pairs of the social-cognitive skills or their components were inter-related. The focus of the second study was the social interaction of infants and their mothers, especially with regard to their skills of joint attentional engagement (including mothers' use of language to follow into or direct infants' attention) and how these skills related to infants' early communicative competence. Our measures of communicative competence included not only language production, as in previous studies, but also language comprehension and gesture production. It was found that two measures--the amount of time infants spent in joint engagement with their mothers and the degree to which mothers used language that followed into their infant's focus of attention--predicted infants' earliest skills of gestural and linguistic communication. Results of the two studies are discussed in terms of their implications for theories of social-cognitive development, for theories of language development, and for theories of the process by means of which human children become fully participating members of the cultural activities and processes into which they are born.

Five primate species follow the visual gaze of conspecifics.

Individuals from five primate species were tested experimentally for their ability to follow the visual gaze of conspecifics to an outside object. Subjects were from captive social groups of chimpanzees, Pan troglodytes, sooty mangabeys, Cercocebus atys torquatus, rhesus macaques, Macaca mulatta, stumptail macaques, M. arctoides, and pigtail macaques, M. nemestrina. Experimental trials consisted of an experimenter inducing one individual to look at food being displayed, and then observing the reaction of another individual (the subject) that was looking at that individual (not the food). Control trials consisted of an experimenter displaying the food in an identical manner when the subject was alone. Individuals from all species reliably followed the gaze of conspecifics, looking to the food about 80% of the time in experimental trials, compared with about 20% of the time in control trials. Results are discussed in terms of both the proximate mechanisms that might be involved and the adaptive functions that might be served by gaze-following. Copyright 1998 The Association for the Study of Animal Behaviour. Copyright 1998 The Association for the Study of Animal Behaviour.

Distinguishing intentional from accidental actions in orangutans (Pongo pygmaeus), chimpanzees (Pan troglodytes), and human children (Homo sapiens).

This study investigates the understanding of others' intentions in 2- and 3-year-old children, chimpanzees (Pan troglodytes), and orangutans (Pongo pygmaeus). During training, subjects learned to use a discriminative cue to select a baited box. During testing, the experimenter placed a marker on top of the baited box to inform the subject of the reward's location. However, the experimenter also accidentally dropped the marker on top of an unbaited box, so that during any given trial the experimenter marked 2 boxes, 1 intentionally and 1 accidentally. All 3 species preferentially selected the box the experimenter had marked intentionally (especially during the initial trials), with 3-year-old children presenting the most robust results. These findings suggest that subjects understood something about the experimenter's intentions. The authors speculate that understanding of others' intentions may precede the understanding of others' beliefs both at the ontogenetic and phylogenetic levels.

Acquiring the transitive construction in English: the role of animacy and pronouns.

Twenty-four children between 2;5 and 3;1 were taught two nonce verbs. Each verb was used multiple times by an adult experimenter to refer to a highly transitive action involving a mostly animate agent (including the child herself) and a patient of varying animacy. One of the verbs was modelled in the Two-Participants condition in which the experimenter said: 'Look. Big Bird is dopping the boat'. The other verb was modelled in the No-Participant condition in which the experimenter named the Two-Participants but did not use them as arguments of the novel verb: 'Look what Big Bird is doing to the boat. It's called keefing'. It was found that whereas many children produced transitive sentences with the Two-Participants verb, only children close to 3;0 produced transitive sentences with the No-Participant verb. This age is somewhat younger than previous studies in which young children were asked to produce transitive sentences with two lexical nouns for the two animate participants. Also, re-analyses of previously published studies in which children learned novel verbs in sentence frames without arguments found that the few transitive sentences produced by children under 2;6 involved either I or me as subject. One hypothesis is thus that as young children in the third year of life begin to construct a more abstract and verb-general transitive construction, this construction initially contains only certain types of participants expressed in only certain kinds of linguistic forms.

Chimpanzee gaze following in an object-choice task.

Many primate species reliably track and follow the visual gaze of conspecifics and humans, even to locations above and behind the subject. However, it is not clear whether primates follow a human's gaze to find hidden food under one of two containers in an object-choice task. In a series of experiments six adult female chimpanzees followed a human's gaze (head and eye direction) to a distal location in space above and behind them, and checked back to the human's face when they did not find anything interesting or unusual. This study also assessed whether these same subjects would also use the human's gaze in an object-choice task with three types of occluders: barriers, tubes, and bowls. Barriers and tubes permitted the experimenter to see their contents (i.e., food) whereas bowls did not. Chimpanzees used the human's gaze direction to choose the tube or barrier containing food but they did not use the human's gaze to decide between bowls. Our findings allowed us to discard both simple orientation and understanding seeing-knowing in others as the explanations for gaze following in chimpanzees. However, they did not allow us to conclusively choose between orientation combined with foraging tendencies and understanding seeing in others. One interesting possibility raised by these results is that studies in which the human cannot see the reward at the time of subject choice may potentially be underestimating chimpanzees' social knowledge.

Primate causal understanding in the physical and psychological domains.

Evidence for primates' understanding of causality is presented and discussed. Understanding causality requires the organism to understand not just that two events are associated with one another in space and time, but also that there is some `mediating force' that binds the two events to one another which may be used to predict or control those events (e.g. a physical force such as gravity or a psychological force such as an intention). In the physical domain, studies of tool use indicate that capuchin monkeys do not have a causal understanding of the functioning of tools in terms of the physical forces involved, but rather they learn to associate aspects of their own behavior with the results it produces. Apes show some possible signs of understanding the causal relations involved in tool use in the sense that they may employ various forms of foresight in approaching novel tasks, perhaps involving an understanding of physical forces-although not to the extent of human children. In the psychological domain, nonhuman primates understand conspecifics as animate beings that generate their own behavior and, thus, they appreciate that to manipulate conspecifics communicative signals, and not physical activities, are required. However, there is very little evidence that nonhuman primates of any species understand others as psychological beings with intentions and other psychological states that mediate their behavioral interactions with the world-as human children begin to do sometime during their second year of life. More research, using a wider range of problem-solving situations, is needed if we are to become more precise in our understanding of how primates understand the causal structure of the world around them.

Young children's productivity with word order and verb morphology.

Four studies examined English-speaking children's productivity with word order and verb morphology. Two- and 3-year-olds were taught novel transitive verbs with experimentally controlled argument structures. The younger children neither used nor comprehended word order with these verbs; older children comprehended and used word order correctly to mark agents and patients of the novel verbs. Children as young as 2 years 1 month added -ing but not -ed to verb stems; older children were productive with both inflections. These studies demonstrate that the present progressive inflection is used productively before the regular past tense marker and suggest that productivity with word order may be independent of developments in verb morphology. The findings are discussed in terms of M. Tomasello's (1992a) Verb Island hypothesis and M. Rispoli's (1991) notion of the mosaic acquisition of grammatical relations.

Differential productivity in young children's use of nouns and verbs.

A fundamental question of child language acquisition is children's productivity with newly learned forms. The current study addressed this question experimentally with children just beginning to combine words. Ten children between 1;6 and 1;11 were taught four new words, two nouns and two verbs, over multiple sessions. All four words were modelled in minimal syntactic contexts. The experimenter gave children multiple opportunities to produce the words and made attempts to elicit morphological endings (plural for nouns, past tense for verbs). Overall, children combined the novel nouns productively with already known words much more often than they did the novel verbs-by many orders of magnitude. Several children also pluralized a newly learned noun, whereas none of them formed a past tense with a newly learned verb. A follow-up study using a slightly different methodology confirmed the finding of limited syntactic productivity with verbs. Hypotheses accounting for this asymmetry in the early use of nouns and verbs are discussed.