FUNCTIONS OF DEADENYLATION FACTORS IN MRNA DECAY AND MRNA PROCESSING BODY FORMATION

Most newly synthesized messenger RNAs possess a 5’ cap and a 3’ poly(A) tail. The process of poly(A) tail shortening, also termed deadenylation, is important for post-transcriptional gene regulation, because deadenylation not only leads to mRNA translational inhibition but also is the first step of major mRNA degradation. Translationally inhibited mRNAs can be stored and/or degraded in dynamic cytoplasmic foci termed mRNA processing bodies, or P bodies, which are conserved in eukaryotes. To shed new light on the mechanisms of P body formation and P body functions, I focused on the link between deadenylation factors and P bodies. I found that the two major deadenylation complexes, Pan3-Pan2 and Ccr4-Caf1, can both be enriched in P bodies. The deadenylase activity of the Ccr4-Caf1 complex is prerequisite for P body formation. Pan3, but not the deadenylase Pan2, is essential for P body formation. While the C-terminal domain of Pan3 is important for interaction with Pan2, Pan3 N-terminal domain is important for Pan3 to form cytoplasmic foci colocalizing with P bodies and to promote mRNA decay. Interestingly, Pan3 N-terminal domain may be phosphorylated to regulate Pan3 localization and functions. Aside from the functions of the two deadenylation complexes in P bodies, I also studied all reported human P body proteins as a whole using bioinformatics. This effort not only has generated a comprehensive picture of the functions of and interactions among human P body proteins, but also has predicted proteins that may regulate P body formation and/or functions. In summary, my study has established a direct link between mRNA deadenylation and P body formation and has also led to new hypotheses to guide future research on how P body dynamics are controlled.

The processing of human pro-tumor necrosis factor

Human pro-TNF-$\alpha$ is a 26 kd type II transmembrane protein, and it is the precursor of 17 kd mature TNF. Pro-TNF release mature from its extracellular domain by proteolytic cleavage between resideu Ava ($-$1) and Val (+1). Both forms of TNF are biologically active and the native form of mature TNF is a bell-shaped trimer. The structure of pro-TNF was studied both in intact cell system and in an in vitro translation system by chemical crosslinking. We found that human pro-TNF protein exist as a trimer in intact cells (LPS-induced THP-1 cells and TNF cDNA transfected COS-3 cells) and this trimeric structure is assembled intracellularly, possibly in the ER. By analysis several deletion mutants, we observed a correlation between expression of pro-TNF cytotoxicity in a juxtacrine fashion and detection of the trimer, suggesting the trimeric structure is very important for its biologic activity. With a series of deletion mutants in the linking domain, we found that the small deletion did not block the cleavage and large deletion did regardless of the presence or absence of the native cleavage site, suggesting that the length of the residues between the plasma membrane and the base of the trimer determines the rate of the cleavage, possibly by blocking the accessibility of the cleavage enzyme to its action site. Our data also suggest that the native cleavage site is not sufficient for the release of mature TNF and alternative cleavage site(s) exists. ^

Effects of anxiety on decision making and visual search behaviour in complex sport situations

Introduction Current empirical findings indicate that the efficiency of decision making (both for experts and near-experts) in simple situations is reduced under increased stress (Wilson, 2008). Explaining the phenomenon, the Attentional Control Theory (ACT, Eysenck et al., 2007) postulates an impairment of attentional processes resulting in a less efficient processing of visual information. From a practitioner’s perspective, it would be highly relevant to know whether this phenomenon can also be found in complex sport situations like in the game of football. Consequently, in the present study, decision making of football players was examined under regular vs. increased anxiety conditions. Methods 22 participants (11 experts and 11 near-experts) viewed 24 complex football situations (counterbalanced) in two anxiety conditions from the perspective of the last defender. They had to decide as fast and accurate as possible on the next action of the player in possession (options: shot on goal, dribble or pass to a designated team member) for equal numbers of trials in a near and far distance condition (based on the position of the player in possession). Anxiety was manipulated via a competitive environment, false feedback as well as ego threats. Decision time and accuracy, gaze behaviour (e.g., fixation duration on different locations) as well as state anxiety and mental effort were used as dependent variables and analysed with 2 (expertise) x 2 (distance) x 2 (anxiety) ANOVAs with repeated measures on the last two factors. Besides expertise differences, it was hypothesised that, based on ACT, increased anxiety reduces performance efficiency and impairs gaze behaviour. Results and Discussion Anxiety was manipulated successfully, indicated by higher ratings of state anxiety, F(1, 20) = 13.13, p < .01, ηp2 = .40. Besides expertise differences in decision making – experts responded faster, F(1, 20) = 11.32, p < .01, ηp2 = .36, and more accurate, F(1,20) = 23.93, p < .01, ηp2 = .55, than near-experts – decision time, F(1, 20) = 9.29, p < .01, ηp2 = .32, and mental effort, F(1, 20) = 7.33, p = .01, ηp2 = .27, increased for both groups in the high anxiety condition. This result confirms the ACT assumption that processing efficiency is reduced when being anxious. Replicating earlier findings, a significant expertise by distance interaction could be observed, F(1, 18) = 18.53, p < .01, ηp2 = .51), with experts fixating longer on the player in possession or the ball in the near distance and longer on other opponents, teammates and free space in the far distance condition. This shows that experts are able to adjust their gaze behaviour to affordances of displayed playing patterns. Additionally, a three way interaction was found, F(1, 18) = 7.37 p = .01, ηp2 = .29, revealing that experts utilised a reduced number of fixations in the far distance condition when being anxious indicating a reduced ability to pick up visual information. Since especially the visual search behaviour of experts was impaired, the ACT prediction that particularly top-down processes are affected by anxiety could be confirmed. Taken together, the results show that sports performance is negatively influenced by anxiety since longer response times, higher mental effort and inefficient visual search behaviour were observed. From a practitioner’s perspective, this finding might suggest preferring (implicit) perceptual cognitive training; however, this recommendation needs to be empirically supported in intervention studies. References: Eysenck, M. W., Derakshan, N., Santos, R., & Calvo, M. G. (2007). Anxiety and cognitive performance: Attentional control theory. Emotion, 7, 336-353. Wilson, M. (2008). From processing efficiency to attentional control: A mechanistic account of the anxiety-performance relationship. Int. Review of Sport and Exercise Psychology, 1, 184-201.

Effects of anxiety on decision making and visual search behaviour in complex sport situations

Based on the Attentional Control Theory (ACT; Eysenck et al., 2007), performance efficiency is decreased in high-anxiety situations because worrying thoughts compete for attentional resources. A repeated-measures design (high/low state anxiety and high/low perceptual task demands) was used to test ACT explanations. Complex football situations were displayed to expert and non-expert football players in a decision making task in a controlled laboratory setting. Ratings of state anxiety and pupil diameter measures were used to check anxiety manipulations. Dependent variables were verbal response time and accuracy, mental effort ratings and visual search behavior (e.g., visual search rate). Results confirmed that an anxiety increase, indicated by higher state-anxiety ratings and larger pupil diameters, reduced processing efficiency for both groups (higher response times and mental effort ratings). Moreover, high task demands reduced the ability to shift attention between different locations for the expert group in the high anxiety condition only. Since particularly experts, who were expected to use more top-down strategies to guide visual attention under high perceptual task demands, showed less attentional shifts in the high compared to the low anxiety condition, as predicted by ACT, anxiety seems to impair the shifting function by interrupting the balance between top-down and bottom-up processes.

Visual hallucinations in the psychosis spectrum and comparative information from neurodegenerative disorders and eye disease

Much of the research on visual hallucinations (VHs) has been conducted in the context of eye disease and neurodegenerative conditions, but little is known about these phenomena in psychiatric and nonclinical populations. The purpose of this article is to bring together current knowledge regarding VHs in the psychosis phenotype and contrast this data with the literature drawn from neurodegenerative disorders and eye disease. The evidence challenges the traditional views that VHs are atypical or uncommon in psychosis. The weighted mean for VHs is 27% in schizophrenia, 15% in affective psychosis, and 7.3% in the general community. VHs are linked to a more severe psychopathological profile and less favorable outcome in psychosis and neurodegenerative conditions. VHs typically co-occur with auditory hallucinations, suggesting a common etiological cause. VHs in psychosis are also remarkably complex, negative in content, and are interpreted to have personal relevance. The cognitive mechanisms of VHs in psychosis have rarely been investigated, but existing studies point to source-monitoring deficits and distortions in top-down mechanisms, although evidence for visual processing deficits, which feature strongly in the organic literature, is lacking. Brain imaging studies point to the activation of visual cortex during hallucinations on a background of structural and connectivity changes within wider brain networks. The relationship between VHs in psychosis, eye disease, and neurodegeneration remains unclear, although the pattern of similarities and differences described in this review suggests that comparative studies may have potentially important clinical and theoretical implications.

Performance on auditory and visual temporal informationprocessing is related to psychometric intelligence

The present study investigated the relationship between psychometric intelligence and temporal resolution power (TRP) as simultaneously assessed by auditory and visual psychophysical timing tasks. In addition, three different theoretical models of the functional relationship between TRP and psychometric intelligence as assessed by means of the Adaptive Matrices Test (AMT) were developed. To test the validity of these models, structural equation modeling was applied. Empirical data supported a hierarchical model that assumed auditory and visual modality-specific temporal processing at a first level and amodal temporal processing at a second level. This second-order latent variable was substantially correlated with psychometric intelligence. Therefore, the relationship between psychometric intelligence and psychophysical timing performance can be explained best by a hierarchical model of temporal information processing.

Effects of anxiety on decision making and visual search Behaviour in dynamic, time-constrained situations

Einleitung Aktuelle empirische Befunde deuten darauf hin, dass Sportler/innen durch Stress und erhöhte Angst eine reduzierte Effizienz bei der Entscheidungsfindung aufweisen (Wilson, 2008). Erklärt werden kann dieser Befund durch die Attentional-Control-Theory (ACT, Eysenck et al., 2007), die postuliert, dass aufmerksamkeitslenkende Prozesse unter Angst gestört werden. Um diese Annahme für komplexe Situationen im Sport zu prüfen, wurden Fußballspieler unter erhöhten und regulären Druckbedingungen verglichen. Methode Je 11 Experten und Nicht-Experten hatten aus der Perspektive des Abwehrspielers die Aufgabe, in zwei mal 24 Spielsituationen so schnell und korrekt wie möglich verbal anzugeben, welche Aktion der ballführende Spieler (in naher vs. ferner Spielsituation) nach Ausblendung der Szene ausführen wird. Während im ersten Block der Druck nicht erhöht wurde, wurden Druckbedingungen im zweiten Block u.a. durch eine Wettkampfsituation und „falscher“ Ergebnisrückmeldung gesteigert. Entscheidungs- und Blickverhalten (u.a. Anzahl Fixationen), Pupillengröße, Zustandsangst und „Mental Effort“ (Wilson, 2008) wurden erfasst. Neben Expertiseunterschieden wurde erwartet, dass erhöhte Angst die Entscheidungseffizienz sowie das Blickverhalten stört (ACT-Annahme), was mit 2 (Experten/Nicht-Experten) x 2 (nahe/ferne Spielsituation) x 2 (hohe/reguläre Druckbedingung) ANOVAs (? = .05) mit Messwiederholungen auf den letzten beiden Faktoren geprüft wurde. Ergebnisse Druckmanipulationen führten zu höherer Zustandsangst und größeren Pupillendurchmessern. Neben Expertiseunterschieden – Experten antworteten schneller, korrekter und zeigten ein situationsangepasstes visuelles Suchverhalten – wiesen beide Gruppen in Drucksituationen längere Antwortzeiten und höheren Mental Effort auf. Erhöhter Druck führte bei Experten zur Reduktion der Fixationsortwechsel für ferne Spielsituationen. Nicht-Experten differenzierten ihr Suchverhalten weder zwischen Bedingungen noch für Spielsituationen. Diskussion Die Resultate bestätigen die ACT-Annahme, dass Angst und Stress die sportliche Leistung durch längere Reaktionszeiten, höhere kognitive Anstrengung und ein teilweise ineffizientes visuelles Suchverhalten negativ beeinflusst. Eine gestörte Balance zwischen Top-Down und Bottom-Up-Prozessen könnte die Ursache sein (Eysenck et al., 2007). Literatur Eysenck, M. W., Derakshan, N., Santos, R., & Calvo, M. G. (2007). Anxiety and cognitive performance: Attentional control theory. Emotion, 7, 336–353. Wilson, M. (2008). From processing efficiency to attentional control: A mechanistic account of the anxiety-performance relationship. International Review of Sport and Exercise Psychology, 1, 184– 201. 2 Vorträge und Poster

Semantic, perceptual and number space: relations between category width and spatial processing.

Coarse semantic encoding and broad categorization behavior are the hallmarks of the right cerebral hemisphere's contribution to language processing. We correlated 40 healthy subjects' breadth of categorization as assessed with Pettigrew's category width scale with lateral asymmetries in perceptual and representational space. Specifically, we hypothesized broader category width to be associated with larger leftward spatial biases. For the 20 men, but not the 20 women, this hypothesis was confirmed both in a lateralized tachistoscopic task with chimeric faces and a random digit generation task; the higher a male participant's score on category width, the more pronounced were his left-visual field bias in the judgement of chimeric faces and his small-number preference in digit generation ("small" is to the left of "large" in number space). Subjects' category width was unrelated to lateral displacements in a blindfolded tactile-motor rod centering task. These findings indicate that visual-spatial functions of the right hemisphere should not be considered independent of the same hemisphere's contribution to language. Linguistic and spatial cognition may be more tightly interwoven than is currently assumed.

Perception of co-speech gestures in aphasic patients: A visual exploration study during the observation of dyadic conversations.

BACKGROUND Co-speech gestures are part of nonverbal communication during conversations. They either support the verbal message or provide the interlocutor with additional information. Furthermore, they prompt as nonverbal cues the cooperative process of turn taking. In the present study, we investigated the influence of co-speech gestures on the perception of dyadic dialogue in aphasic patients. In particular, we analysed the impact of co-speech gestures on gaze direction (towards speaker or listener) and fixation of body parts. We hypothesized that aphasic patients, who are restricted in verbal comprehension, adapt their visual exploration strategies. METHODS Sixteen aphasic patients and 23 healthy control subjects participated in the study. Visual exploration behaviour was measured by means of a contact-free infrared eye-tracker while subjects were watching videos depicting spontaneous dialogues between two individuals. Cumulative fixation duration and mean fixation duration were calculated for the factors co-speech gesture (present and absent), gaze direction (to the speaker or to the listener), and region of interest (ROI), including hands, face, and body. RESULTS Both aphasic patients and healthy controls mainly fixated the speaker's face. We found a significant co-speech gesture × ROI interaction, indicating that the presence of a co-speech gesture encouraged subjects to look at the speaker. Further, there was a significant gaze direction × ROI × group interaction revealing that aphasic patients showed reduced cumulative fixation duration on the speaker's face compared to healthy controls. CONCLUSION Co-speech gestures guide the observer's attention towards the speaker, the source of semantic input. It is discussed whether an underlying semantic processing deficit or a deficit to integrate audio-visual information may cause aphasic patients to explore less the speaker's face.

Lateralized processing of faces: The role of features, configurations and familiarity

We investigated the lateralized processing of featural and configural information in face recognition in two divided visual field studies. In Experiment 1, participants matched the identity of a cue face containing either featural (scrambled faces) or configural (blurred faces) information with an intact test face presented subsequently either in the right visual field (RVF) or in the left visual field (LVF). Unilateral presentation was controlled by monitoring eye movements. The results show an advantage of the left hemisphere (LH) over the right hemisphere (RH) for featural processing and a specialization of the RH for configural compared to featural processing. In Experiment 2, we focused on configural processing and its relationship to familiarity. Either learned or novel test faces were presented in the LVF or the RVF. Participants recognized learned faces better when presented in the LVF than in the RVF, suggesting that the RH has an advantage in the recognition of learned faces. Because the recognition of familiar faces relies strongly on configural information (Buttle & Raymond, 2003), we argue that the advantage of the RH over the LH in configural processing is a function of familiarity.

Unique Sm core structure of U7 snRNPs: assembly by a specialized SMN complex and the role of a new component, Lsm11, in histone RNA processing.

A set of seven Sm proteins assemble on the Sm-binding site of spliceosomal U snRNAs to form the ring-shaped Sm core. The U7 snRNP involved in histone RNA 3' processing contains a structurally similar but biochemically unique Sm core in which two of these proteins, Sm D1 and D2, are replaced by Lsm10 and by another as yet unknown component. Here we characterize this factor, termed Lsm11, as a novel Sm-like protein with apparently two distinct functions. In vitro studies suggest that its long N-terminal part mediates an important step in histone mRNA 3'-end cleavage, most likely by recruiting a zinc finger protein previously identified as a processing factor. In contrast, the C-terminal part, which comprises two Sm motifs interrupted by an unusually long spacer, is sufficient to assemble with U7, but not U1, snRNA. Assembly of this U7-specific Sm core depends on the noncanonical Sm-binding site of U7 snRNA. Moreover, it is facilitated by a specialized SMN complex that contains Lsm10 and Lsm11 but lacks Sm D1/D2. Thus, the U7-specific Lsm11 protein not only specifies the assembly of the U7 Sm core but also fulfills an important role in U7 snRNP-mediated histone mRNA processing.

Larger visual stimuli are perceived to last longer from time to time: The internal clock is not affected by nontemporal visual stimulus size

Performance on interval timing is often explained by the assumption of an internal clock based on neural counting. According to this account, a neural pacemaker generates pulses, and the number of pulses relating to a physical time interval is recorded by a counter. Thus, the number of accumulated pulses is the internal representation of this interval. Several studies demonstrated that large visual stimuli are perceived to last longer than smaller ones presented for the same duration. The present study was designed to investigate whether nontemporal visual stimulus size directly affects the internal clock. For this purpose, a temporal reproduction task was applied. Sixty participants were randomly assigned to one of two experimental conditions with stimulus size being experimentally varied within either the target or the reproduction interval. A direct effect of nontemporal stimulus size on the pacemaker-counter system should become evident irrespective of whether stimulus size was experimentally varied within the target or the reproduction interval. An effect of nontemporal stimulus size on reproduced duration only occurred when stimulus size was varied during the target interval. This finding clearly argues against the notion that nontemporal visual stimulus size directly affects the internal clock. Furthermore, our findings ruled out a decisional bias as a possible cause of the observed differential effect of stimulus size on reproduced duration. Rather the effect of stimulus size appeared to originate from the memory stage of temporal information processing at which the timing signal from the pacemaker-counter component is encoded in reference memory.

Insights into post-translational processing of beta-galactosidase in an animal model resembling late infantile human G-gangliosidosis

G(M1)-gangliosidosis is a lysosomal storage disorder caused by a deficiency of ss-galactosidase activity. Human GM1-gangliosidosis has been classified into three forms according to the age of clinical onset and specific biochemical parameters. In the present study, a canine model for type II late infantile human GM1-gangliosidosis was investigated 'in vitro' in detail. For a better understanding of the molecular pathogenesis underlying G(M1)-gangliosidosis the study focused on the analysis of the molecular events and subsequent intracellular protein trafficking of beta-galactosidase. In the canine model the genetic defect results in exclusion or inclusion of exon 15 in the mRNA transcripts and to translation of two mutant precursor proteins. Intracellular localization, processing and enzymatic activity of these mutant proteins were investigated. The obtained results suggested that the beta-galactosidase C-terminus encoded by exons 15 and 16 is necessary for correct C-terminal proteolytic processing and enzyme activity but does not affect the correct routing to the lysosomes. Both mutant protein precursors are enzymatically inactive, but are transported to the lysosomes clearly indicating that the amino acid sequences encoded by exons 15 and 16 are necessary for correct folding and association with protective protein/cathepsin A, whereas the routing to the lysosomes is not influenced. Thus, the investigated canine model is an appropriate animal model for the human late infantile form and represents a versatile system to test gene therapeutic approaches for human and canine G(M1)-gangliosidosis.

The Quiet Eye and Information Processing: Facilitation of Stimulus Identification and Response Selection

Background: A prerequisite for high performance in motor tasks is the acquisition of egocentric sensory information that must be translated into motor actions. A phenomenon that supports this process is the Quiet Eye (QE) defined as long final fixation before movement initiation. It is assumed that the QE facilitates information processing, particularly regarding movement parameterization. Aims: The question remains whether this facilitation also holds for the information-processing stage of response selection and – related to perception crucial – stage of stimulus identification. Method: In two experiments with sport science students, performance-enhancing effects of experimentally manipulated QE durations were tested as a function of target position predictability and target visibility, thereby selectively manipulating response selection and stimulus identification demands, respectively. Results: The results support the hypothesis of facilitated information processing through long QE durations since in both experiments performance-enhancing effects of long QE durations were found under increased processing demands only. In Experiment 1, QE duration affected performance only if the target position was not predictable and positional information had to be processed over the QE period. In Experiment 2, in a full vs. no target visibility comparison with saccades to the upcoming target position induced by flicker cues, the functionality of a long QE duration depended on the visual stimulus identification period as soon as the interval falls below a certain threshold. Conclusions: The results corroborate earlier findings that QE efficiency depends on demands put on the visuomotor system, thereby furthering the assumption that the phenomenon supports the processes of sensorimotor integration.