Publications

Abstract

Korean has a very complex phonology, with many interacting alternations. In a coronal-/i/ sequence, depending on the type of phonological boundary present, alternations such as palatalization, nasal insertion, nasal assimilation, coda neutralization, and intervocalic voicing can apply. This paper investigates how the phonological patterns of Korean affect processing of morphemes and words. Past research on languages such as English, German, Dutch, and Finnish has shown that listeners exploit syllable structure constraints in processing speech and segmenting it into words. The current study shows that in parsing speech, listeners also use much more complex patterns that relate the surface phonological string to various boundaries.

Abstract

Social interaction relies on the ability to react to communication signals. Although cortical sensory–motor “mirror” networks are thought to play a key role in visual aspects of primate communication, evidence for a similar generic role for auditory–motor interaction in primate nonverbal communication is lacking. We demonstrate that a network of human premotor cortical regions activated during facial movement is also involved in auditory processing of affective nonverbal vocalizations. Within this auditory–motor mirror network, distinct functional subsystems respond preferentially to emotional valence and arousal properties of heard vocalizations. Positive emotional valence enhanced activation in a left posterior inferior frontal region involved in representation of prototypic actions, whereas increasing arousal enhanced activation in presupplementary motor area cortex involved in higher-order motor control. Our findings demonstrate that listening to nonverbal vocalizations can automatically engage preparation of responsive orofacial gestures, an effect that is greatest for positive-valence and high-arousal emotions. The automatic engagement of responsive orofacial gestures by emotional vocalizations suggests that auditory–motor interactions provide a fundamental mechanism for mirroring the emotional states of others during primate social behavior. Motor facilitation by positive vocal emotions suggests a basic neural mechanism for establishing cohesive bonds within primate social groups.

Abstract

An event-related brain potential experiment was carried out to investigate on-line thematic role assignment during sentence–picture matching in patients with Broca's aphasia. Subjects were presented with a picture that was followed by an auditory sentence. The sentence either matched the picture or mismatched the visual information depicted. Sentences differed in complexity, and ranged from simple active semantically irreversible sentences to passive semantically reversible sentences. ERPs were recorded while subjects were engaged in sentence–picture matching. In addition, reaction time and accuracy were measured. Three groups of subjects were tested: Broca patients (N = 10), non-aphasic patients with a right hemisphere (RH) lesion (N = 8), and healthy aged-matched controls (N = 15). The results of this study showed that, in neurologically unimpaired individuals, thematic role assignment in the context of visual information was an immediate process. This in contrast to patients with Broca's aphasia who demonstrated no signs of on-line sensitivity to the picture–sentence mismatches. The syntactic contribution to the thematic role assignment process seemed to be diminished given the reduction and even absence of P600 effects. Nevertheless, Broca patients showed some off-line behavioral sensitivity to the sentence–picture mismatches. The long response latencies of Broca's aphasics make it likely that off-line response strategies were used.

Abstract

An event-related brain potential experiment was carried out to investigate on-line syntactic processing in patients with Broca’s aphasia. Subjects were visually presented with sentences that were either syntactically correct or contained violations of word-category. Three groups of subjects were tested: Broca patients (N=11), non-aphasic patients with a right hemisphere (RH) lesion (N=9), and healthy aged-matched controls (N=15). Both control groups appeared sensitive to the violations of word-category as shown by clear P600/SPS effects. The Broca patients displayed only a very reduced and delayed P600/SPS effect. The results are discussed in the context of a lexicalist parsing model. It is concluded that Broca patients are hindered to detect on-line violations of word-category, if word class information is incomplete or delayed available.

Abstract

This dissertation focuses on syntactic comprehension problems in patients with Broca's aphasia from an electrophysiological perspective. The central objective of this dissertation was to further explore what syntax-related event-related brain potential (ERP) effects can reveal about the nature of the deficit that underlies syntactic comprehension problems in patients with Broca's aphasia. Chapter two to four describe experiments in which event-related brain potentials were recorded while subjects (Broca patients, non-aphasic patients with a right-hemisphere lesion, and healthy elderly controls) were presented with sentences that contained either violations of syntactic constraints or were syntactically correct. Chapter two investigates ERP effects of subject-verb agreement violations in the different subject groups, and seeks to answer the following questions: Do agrammatic comprehenders show sensitivity to subject-verb agreement violations as indicated by a syntax-related ERP effect? In addition, does the severity of the syntactic comprehension impairment in the Broca patients affect the ERP responses? Chapter three describes an investigation of whether Broca patients show sensitivity to violations of word order as indicated by a syntax-related ERP effect, and whether the ERP responses in the Broca patients are affected by the severity of their syntactic comprehension impairment. Chapter four reports on ERP effects of violations of word-category. In addition, also a semantic violation condition was added to track possible dissociations in the sensitivity to semantic and syntactic information in the Broca patients. Chapter five describes the development of a paradigm in which the electrophysiological approach and the classical sentence-picture matching approach are combined. In this chapter, the ERP method is applied to study on-line thematic role assignment in Broca patients during sentence-picture matching. Also the relation between ERP effects and behavioral responses is pursued. Finally, Chapter 6 provides a summary of the main findings of the experiments and a general discussion.

Abstract

In two eye-tracking experiments the role of contrastive pitch accents during the on-line determination of referents was examined. In both experiments, German listeners looked earlier at the picture of a referent belonging to a contrast pair (red scissors, given purple scissors) when instructions to click on it carried a contrastive accent on the color adjective (L + H*) than when the adjective was not accented. In addition to this prosodic facilitation, a general preference to interpret adjectives contrastively was found in Experiment 1: Along with the contrast pair, a noncontrastive referent was displayed (red vase) and listeners looked more often at the contrastive referent than at the noncontrastive referent even when the adjective was not focused. Experiment 2 differed from Experiment 1 in that the first member of the contrast pair (purple scissors) was introduced with a contrastive accent, thereby strengthening the salience of the contrast. In Experiment 2, listeners no longer preferred a contrastive interpretation of adjectives when the accent in a subsequent instruction was not contrastive. In sum, the results support both an early role for prosody in reference determination and an interpretation of contrastive focus that is dependent on preceding prosodic context.

Abstract

Highly proficient German users of English as a second language, and native speakers of American English, listened to nonsense sequences and responded whenever they detected an embedded English word. The responses of both groups were equivalently facilitated by preceding context that both by English and by German phonotactic constraints forced a boundary at word onset (e.g., lecture was easier to detect in moinlecture than in gorklecture, and wish in yarlwish than in plookwish. The American L1 speakers’ responses were strongly facilitated, and the German listeners’ responses almost as strongly facilitated, by contexts that forced a boundary in English but not in German thrarshlecture, glarshwish. The German listeners’ responses were significantly facilitated also by contexts that forced a boundary in German but not in English )moycelecture, loitwish, while L1 listeners were sensitive to acoustic boundary cues in these materials but not to the phonotactic sequences. The pattern of results suggests that proficient L2 listeners can acquire the phonotactic probabilities of an L2 and use them to good effect in segmenting continuous speech, but at the same time they may not be able to prevent interference from L1 constraints in their L2 listening.

Abstract

Recent studies using phoneme detection tasks have shown that spoken-language processing is neither facilitated nor interfered with by optional assimilation, but is inhibited by violation of obligatory assimilation. Interpretation of these results depends on an assessment of their generality, specifically, whether they also obtain when listeners are processing nonnative language. Two separate experiments are presented in which native listeners of German and native listeners of Dutch had to detect a target fricative in legal monosyllabic Dutch nonwords. All of the nonwords were correct realisations in standard Dutch. For German listeners, however, half of the nonwords contained phoneme strings which violate the German fricative assimilation rule. Whereas the Dutch listeners showed no significant effects, German listeners detected the target fricative faster when the German fricative assimilation was violated than when no violation occurred. The results might suggest that violation of assimilation rules does not have to make processing more difficult per se.

Abstract

This study investigates the influence of both phonotactic and acoustic cues on the segmentation of spoken English. Listeners detected embedded English words in nonsense sequences (word spotting). Words aligned with phonotactic boundaries were easier to detect than words without such alignment. Acoustic cues to boundaries could also have signaled word boundaries, especially when word onsets lacked phonotactic alignment. However, only one of several durational boundary cues showed a marginally significant correlation with response times (RTs). The results suggest that word segmentation in English is influenced primarily by phonotactic constraints and only secondarily by acoustic aspects of the speech signal.

Abstract

Previous research has shown that listeners make use of their knowledge of phonotactic constraints to segment speech into individual words. The present study investigates the influence of phonotactics when segmenting a non-native language. German and English listeners detected embedded English words in nonsense sequences. German listeners also had knowledge of English, but English listeners had no knowledge of German. Word onsets were either aligned with a syllable boundary or not, according to the phonotactics of the two languages. Words aligned with either German or English phonotactic boundaries were easier for German listeners to detect than words without such alignment. Responses of English listeners were influenced primarily by English phonotactic alignment. The results suggest that both native and non-native phonotactic constraints influence lexical segmentation of a non-native, but familiar, language.

Abstract

An eye-tracking experiment examined whether prosodic cues can affect the interpretation of grammatical functions in the absence of clear morphological information. German listeners were presented with scenes depicting three potential referents while hearing temporarily ambiguous SVO and OVS sentences. While case marking on the first noun phrase (NP) was ambiguous, clear case marking on the second NP disambiguated sentences towards SVO or OVS. Listeners interpreted caseambiguous NP1s more often as Subject, and thus expected an Object as upcoming argument, only when sentence beginnings carried an SVO-type intonation. This was revealed by more anticipatory eye movements to suitable Patients (Objects) than Agents (Subjects) in the visual scenes. No such preference was found when sentence beginnings had a clearly OVS-type intonation. Prosodic cues were integrated rapidly enough to affect listeners’ interpretation of grammatical function before disambiguating case information was available. We conclude that in addition to manipulating attachment ambiguities, prosody can influence the interpretation of constituent order ambiguities.

Abstract

In a visual-world study, we examined spoken-wordrecognition in Spanish. Spanish listeners followed spoken instructions to click on pictures while their eye movements were monitored. When instructed to click on the picture of a door (puerta), they experienced interference from the picture of a pig (p u e r c o ). The same interference from phonologically related items was observed when the displays contained printed names or a combination of pictures with their names printed underneath, although the effect was strongest for displays with printed names. Implications of the finding that the interference effect can be induced with standard pictorial displays as well as with orthographic displays are discussed.

Abstract

Dichoptic mixtures of equiluminous components of different wavelengths were matched with a binocularly presented "monocular" mixture of appropriate chosen amounts of the same colour components. Stimuli were chosen from the region of 490-630 nm. Although satisfactory colour matches could be obtained, dichoptic mixtures differed from normal mixtures to a considerable extent. Midspectral stimuli tended to be more dominant in the dichoptic mixtures than either short or long wavelength stimuli. An attempt was made to describe the relation between monocular and dichoptic mixtures with one function containing a wavelength variable and an eye dominance parameter.

Abstract

This paper provides a description of body part terminology used in Savosavo, a Papuan language of the Solomon Islands. The first part of the paper lists the known terms and discusses their meanings. This is followed by an analysis of their structural properties. Finally, the paper discusses partonomic relations in Savosavo and argues that it is difficult to structure the body part terminology hierarchically, because there is no linguistic evidence for part–whole relations between body parts.

Abstract

This follow-up study of the European Dexamethasone Study was designed to examine the potential harmful effect of adjunctive dexamethasone treatment on long-term neuropsychological outcome in adults with bacterial meningitis. METHODS: Neurological, audiological, and neuropsychological examinations were performed in adults who survived pneumococcal or meningococcal meningitis. RESULTS: Eighty-seven of 99 (88%) eligible patients were included in the follow-up study; 46 (53%) were treated with dexamethasone and 41 (47%) with placebo. Median time between meningitis and testing was 99 months. Neuropsychological evaluation showed no significant differences between patients treated with dexamethasone and placebo. The proportions of patients with persisting neurological sequelae or hearing loss were similar in the dexamethasone and placebo groups. The overall rate of cognitive dysfunction did not differ significantly between patients and control subjects; however, patients after pneumococcal meningitis had a higher rate of cognitive dysfunction (21 vs 6%; p = 0.05) and experienced more impairment of everyday functioning due to physical problems (p = 0.05) than those after meningococcal meningitis. INTERPRETATION: Treatment with adjunctive dexamethasone is not associated with an increased risk for long-term cognitive impairment. Adults who survive pneumococcal meningitis are at significant risk for long-term neuropsychological abnormalities.

Abstract

Objectives To assess cognitive outcome and quality of life in patients with moderate disability after bacterial meningitis as compared to patients with good recovery. Methods Neuropsychological evaluation was performed in 40 adults after pneumococcal meningitis; 20 patients with moderate disability at discharge on the glasgow outcome scale (GOS score 4) and 20 with good recovery (GOS score 5). Results Patients with GOS score 4 had similar test results as compared to patients with GOS score 5 for the neuropsychological domains ‘intelligence’, ‘memory’ and ‘attention and executive functioning’. Patients with GOS score 4 showed less cognitive slowness than patients with GOS score 5. In a linear regression analysis cognitive speed was related to current intelligence, years of education and time since meningitis. Overall performance on the speed composite score correlated significantly with time since meningitis (−0.62; P<0.001). Therefore, difference between both groups may have been related to a longer time between meningitis and testing for GOS four patients (29 vs. 12 months; P<0.001). Conclusions Patients with moderate disability after bacterial meningitis are not at higher risk for neuropsychological abnormalities than patients with good recovery. In addition, cognitive slowness after bacterial meningitis may be reversible in time.

Abstract

Three experiments examined the time course of phonological encoding in speech production. A new methodology is introduced in which subjects are required to monitor their internal speech production for prespecified target segments and syllables. Experiment 1 demonstrated that word initial target segments are monitored significantly faster than second syllable initial target segments. The addition of a concurrent articulation task (Experiment 1b) had a limited effect on performance, excluding the possibility that subjects are monitoring a subvocal articulation of the carrier word. Moreover, no relationship was observed between the pattern of monitoring latencies and the timing of the targets in subjects′ overt speech. Subjects are not, therefore, monitoring an internal phonetic representation of the carrier word. Experiment 2 used the production monitoring task to replicate the syllable monitoring effect observed in speech perception experiments: responses to targets were faster when they corresponded to the initial syllable of the carrier word than when they did not. We conclude that subjects are monitoring their internal generation of a syllabified phonological representation. Experiment 3 provides more detailed evidence concerning the time course of the generation of this representation by comparing monitoring latencies to targets within, as well as between, syllables. Some amendments to current models of phonological encoding are suggested in light of these results.

Abstract

In 2001, a point mutation in the forkhead box P2 (FOXP2) coding sequence was identified as the basis of an inherited speech and language disorder suffered by members of the family known as "KE." This mini-symposium review focuses on recent findings and research-in-progress, primarily from five laboratories. Each aims at capitalizing on the FOXP2 discovery to build a neurobiological bridge between molecule and phenotype. Below, we describe genetic through behavioral techniques used currently to investigate FoxP2 in birds, rodents, and humans for discovery of the neural bases of vocal learning and language.

Abstract

Field data are drawn from a particular speech community at a certain place and time. The intent of this survey is to enrich understanding of the various socio-cultural contexts in which linguistic and “cognitive” data may have been collected, so that we can explore the role which societal, cultural and contextual factors may play in this material. The questionnaire gives guidelines concerning types of ethnographic information that are important to cross-cultural and cross-linguistic enquiry, and will be especially useful to researchers who do not have specialised training in anthropology.

Abstract

How do languages encode different kinds of movement, and what features do people pay attention to when describing motion events? This document outlines topics concerning the investigation of “enter” and “exit” events. It helps contextualise research tasks that examine this domain (see 'Motion Elicitation' and 'Enter/Exit animation') and gives some pointers about what other questions can be explored.

Abstract

How do languages express ideas of movement, and how do they package features that can be part of motion, such as path and cause? This questionnaire is used to gain a picture of the lexical resources a language draws on for motion expressions. It targets issues of semantic conflation (i.e., what other semantic information besides motion may be encoded in a verb root) and patterns of semantic distribution (i.e., what types of information are encoded in the morphemes that come together to build a description of a motion event). It was originally designed for Australian languages, but has since been used around the world.

Abstract

Contrastive reference, where a speaker presents or identifies one item in explicit contrast to another (I like this book but that one is boring), has special communicative and information structure properties. This can be reflected in rules of demonstrative use. For example, in some languages, terms equivalent to this and that can be used for contrastive reference in almost any spatial context. But other two-term languages stick more closely to “distance rules” for demonstratives, allowing a this-like term in close space only. This task elicits data concerning one context of contrastive reference, focusing on whether (and how) non-proximal demonstratives can be used to distinguish objects within a proximal area. The task runs like a memory game, with the consultant being asked to identify the locations of two or three hidden items arranged within arm’s reach.

Abstract

Pointing gestures are recognised to be a primary manifestation of human social cognition and communicative capacity. The goal of this task is to collect empirical descriptions of pointing practices in different cultural settings.

Abstract

How do languages encode different kinds of movement, and what features do people pay attention to when describing motion events? This task investigates the expression of “enter” and “exit” activities, that is, events involving motion in(to) and motion out (of) container-like items. The researcher first uses particular stimuli (a ball, a cup, rice, etc.) to elicit descriptions of enter/exit events from one consultant, and then asks another consultant to demonstrate the event based on these descriptions. See also the related entries Enter/Exit Animation and Background Questions for Enter/Exit Research.

Abstract

Demonstrative terms (e.g., this and that) are key to understanding how a language constructs and interprets spatial relationships. They are tricky to pin down, typically having functions that do not match “idealized” uses, and that can become invisible in narrow elicitation settings. This questionnaire is designed to identify the range(s) of use of certain spatial demonstrative terms, and help assess the roles played by gesture, access, attention, and addressee knowledge in demonstrative use. The stimuli consist of 25 diagrammed “elicitation settings” to be created by the researcher.

Abstract

The purpose of this paper is to question some of the basic assumpiions concerning motion verbs. In particular, it examines the assumption that "come" and "go" are lexical universals which manifest a universal deictic Opposition. Against the background offive working hypotheses about the nature of'come" and ''go", this study presents a comparative investigation of t wo unrelated languages—Mparntwe Arrernte (Pama-Nyungan, Australian) and Longgu (Oceanic, Austronesian). Although the pragmatic and deictic "suppositional" complexity of"come" and "go" expressions has long been recognized, we argue that in any given language the analysis of these expressions is much more semantically and systemically complex than has been assumed in the literature. Languages vary at the lexical semantic level äs t o what is entailed by these expressions, äs well äs differing äs t o what constitutes the prototype and categorial structure for such expressions. The data also strongly suggest that, ifthere is a lexical universal "go", then this cannof be an inherently deictic expression. However, due to systemic Opposition with "come", non-deictic "go" expressions often take on a deictic Interpretation through pragmatic attribution. Thus, this crosslinguistic investigation of "come" and "go" highlights the need to consider semantics and pragmatics äs modularly separate.

Abstract

Although generally studied in isolation, language and action often co-occur in everyday life. Here we investigated one particular form of simultaneous language and action, namely speech and gestures that speakers use in everyday communication. In a functional magnetic resonance imaging study, we identified the neural networks involved in the integration of semantic information from speech and gestures. Verbal and/or gestural content could be integrated easily or less easily with the content of the preceding part of speech. Premotor areas involved in action observation (Brodmann area [BA] 6) were found to be specifically modulated by action information "mismatching" to a language context. Importantly, an increase in integration load of both verbal and gestural information into prior speech context activated Broca's area and adjacent cortex (BA 45/47). A classical language area, Broca's area, is not only recruited for language-internal processing but also when action observation is integrated with speech. These findings provide direct evidence that action and language processing share a high-level neural integration system.

Abstract

Co-speech gestures embody a form of manual action that is tightly coupled to the language system. As such, the co-occurrence of speech and co-speech gestures is an excellent example of the interplay between language and action. There are, however, other ways in which language and action can be thought of as closely related. In this paper we will give an overview of studies in cognitive neuroscience that examine the neural underpinnings of links between language and action. Topics include neurocognitive studies of motor representations of speech sounds, action-related language, sign language and co-speech gestures. It will be concluded that there is strong evidence on the interaction between speech and gestures in the brain. This interaction however shares general properties with other domains in which there is interplay between language and action.

Abstract

Angelika Wittek untersuchte Zustandsveränderungsverben bei vier- bis sechsjährigen Kindern. Englischsprechende Kinder verstehen bis zum Alter von 8 Jahren diese Verben als Bewegungsverben und ignorieren, daß sie zusätzlich die Information über einen Endzustand im Sinne der Negation des Ausgangszustands beeinhalten. Wittek zeigte, daß entgegen der Erwartung transparente, morphologisch komplexe Formen (wachmachen), in denen die Partikel den Endzustand explizit macht, nicht besser verstanden werden als Simplizia (wecken). Zudem diskutierte sie, inwieweit die Verwendung des Adverbs wieder in restitutiver Lesart Hinweise auf den Erwerb dieser Verben geben kann.

Abstract

Utilization of computer tools in linguistic research has gained importance with the maturation of media frameworks for the handling of digital audio and video. The increased use of these tools in gesture, sign language and multimodal interaction studies has led to stronger requirements on the flexibility, the efficiency and in particular the time accuracy of annotation tools. This paper describes the efforts made to make ELAN a tool that meets these requirements, with special attention to the developments in the area of time accuracy. In subsequent sections an overview will be given of other enhancements in the latest versions of ELAN, that make it a useful tool in multimodality research.

Abstract

A number of serious reasons will convince an increasing amount of researchers to store their relevant material in centers which we will call "language resource archives". They combine the duty of taking care of long-term preservation as well as the task to give access to their material to different user groups. Access here is meant in the sense that an active interaction with the data will be made possible to support the integration of new data, new versions or commentaries of all sort. Modern Language Resource Archives will have to adhere to a number of basic principles to fulfill all requirements and they will have to be involved in federations to create joint language resource domains making it even more simple for the researchers to access the data. This paper makes an attempt to formulate the essential pillars language resource archives have to adhere to.

Abstract

About 5,000 languages are spoken in the world today. More than half of them have less than 10,000 speakers, a quarter of them even fewer than 1,000. The majority of these “small” languages will not live to see the end of this century; some estimates predict that no more than a dozen languages will still be spoken by the turn of the next millennium. This collection of papers approaches the subject of language extinction through five major topics: general aspects of language death, case studies, endangered subsystems, language protection and revitalization, language ecology. In 24 articles, the authors address the causes, manifestations, and consequences of language endangerment and extinction as well as the linguistic and social changes associated with it, drawing examples from a large number of languages.

Abstract

Brain processing depends on the interactions between neuronal groups. Those interactions are governed by the pattern of anatomical connections and by yet unknown mechanisms that modulate the effective strength of a given connection. We found that the mutual influence among neuronal groups depends on the phase relation between rhythmic activities within the groups. Phase relations supporting interactions between the groups preceded those interactions by a few milliseconds, consistent with a mechanistic role. These effects were specific in time, frequency, and space, and we therefore propose that the pattern of synchronization flexibly determines the pattern of neuronal interactions.

Abstract

This auditory lexical decision study shows that cohort entropies, conditional root uniqueness points, and morphological family size all contribute to the dynamics of the auditory comprehension of prefixed words. Three entropy measures calculated for different positions in the stem of Dutch prefixed words revealed facilitation for higher entropies, except at the point of disambiguation, where we observed inhibition. Morphological family size was also facilitatory, but only for prefixed words in which the conditional root uniqueness point coincided with the conventional uniqueness point. For words with early conditional disambiguation, in contrast, only the morphologically related words that were onset-aligned with the target word facilitated lexical decision.

Abstract

Although sign language-using communities exist in all areas of the world, few sign languages have been documented in detail. Sign languages occur in a variety of sociocultural contexts, ranging from sign languages used in closed village communities to officially recognized national sign languages. They may be grouped into language families on historical grounds or may participate in various language contact situations. Systematic cross-linguistic comparison reveals both significant structural similarities and important typological differences between sign languages. Focusing on information from non-Western countries, this article provides an overview of the sign languages of the world.

Abstract

This article reports on several sub-projects of research and development related to the use of Indian Sign Language in educational settings. In many countries around the world, sign languages are now recognised as the legitimate, full-fledged languages of the deaf communities that use them. In India, the development of sign language resources and their application in educational contexts, is still in its initial stages. The work reported on here, is the first principled and comprehensive effort of establishing educational programmes in Indian Sign Language at a national level. Programmes are of several types: a) Indian Sign Language instruction for hearing people; b) sign language teacher training programmes for deaf people; and c) educational materials for use in schools for the Deaf. The conceptual approach used in the programmes for deaf students is known as bilingual education, which emphasises the acquisition of a first language, Indian Sign Language, alongside the acquisition of spoken languages, primarily in their written form.

Abstract

In response to DNA damage or replication stress, the protein kinase ATR is activated and subsequently transduces genotoxic signals to cell cycle control and DNA repair machinery through phosphorylation of a number of downstream substrates. Very little is known about the molecular mechanism by which ATR is activated in response to genotoxic insults. In this report, we demonstrate that protein phosphatase 5 (PP5) is required for the ATR-mediated checkpoint activation. PP5 forms a complex with ATR in a genotoxic stress-inducible manner. Interference with the expression or the activity of PP5 leads to impairment of the ATR-mediated phosphorylation of hRad17 and Chk1 after UV or hydroxyurea treatment. Similar results are obtained in ATM-deficient cells, suggesting that the observed defect in checkpoint signaling is the consequence of impaired functional interaction between ATR and PP5. In cells exposed to UV irradiation, PP5 is required to elicit an appropriate S-phase checkpoint response. In addition, loss of PP5 leads to premature mitosis after hydroxyurea treatment. Interestingly, reduced PP5 activity exerts differential effects on the formation of intranuclear foci by ATR and replication protein A, implicating a functional role for PP5 in a specific stage of the checkpoint signaling pathway. Taken together, our results suggest that PP5 plays a critical role in the ATR-mediated checkpoint activation.

Abstract

Genome-wide association studies using thousands to hundreds of thousands of single nucleotide polymorphism (SNP) markers and region-wide association studies using a dense panel of SNPs are already in use to identify disease susceptibility genes and to predict disease risk in individuals. Because these tasks become increasingly important, three different data sets were provided for the Genetic Analysis Workshop 15, thus allowing examination of various novel and existing data mining methods for both classification and identification of disease susceptibility genes, gene by gene or gene by environment interaction. The approach most often applied in this presentation group was random forests because of its simplicity, elegance, and robustness. It was used for prediction and for screening for interesting SNPs in a first step. The logistic tree with unbiased selection approach appeared to be an interesting alternative to efficiently select interesting SNPs. Machine learning, specifically ensemble methods, might be useful as pre-screening tools for large-scale association studies because they can be less prone to overfitting, can be less computer processor time intensive, can easily include pair-wise and higher-order interactions compared with standard statistical approaches and can also have a high capability for classification. However, improved implementations that are able to deal with hundreds of thousands of SNPs at a time are required.