The structure of the actin filament uncapping complex mediated by twinfilin

Uncapping of actin filaments is essential for driving polymerization and depolymerization dynamics from capping protein–associated filaments; however, the mechanisms of uncapping leading to rapid disassembly are unknown. Here, we elucidated the x-ray crystal structure of the actin/twinfilin/capping protein complex to address the mechanisms of twinfilin uncapping of actin filaments. The twinfilin/capping protein complex binds to two G-actin subunits in an orientation that resembles the actin filament barbed end. This suggests an unanticipated mechanism by which twinfilin disrupts the stable capping of actin filaments by inducing a G-actin conformation in the two terminal actin subunits. Furthermore, twinfilin disorders critical actin-capping protein interactions, which will assist in the dissociation of capping protein, and may promote filament uncapping through a second mechanism involving V-1 competition for an actin-binding surface on capping protein. The extensive interactions with capping protein indicate that the evolutionary conserved role of twinfilin is to uncap actin filaments

Meerkat close calls encode group-specific signatures, but receivers fail to discriminate

A great deal of variation is known to underlie the vocalisations of animals. Calls can for example vary among individuals or between social and behavioural contexts. Calls also have the potential to vary between groups. Many group living animals are known to produce stereotyped group-specific calls and such group signatures are thought to play a role in territory defence or indeed mate choice. Group signatures are generally found in long-distance call variants that work to maintain contact between group members, sometimes referred to as “contact calls”. Cooperatively breeding, territorial meerkats (Suricata suricatta) also use contact calls, potentially to maintain social organization during foraging. However, these contact calls are generally quieter, than long distance calls in other species, and better described as “close calls”. We investigated whether these similar call types also possess group-specific signatures and whether any such variation is used by receivers. We recorded close calls from 71 individuals belonging to 10 different meerkat groups. We found that such close calls do indeed possess group signatures, but that this underlying variation does not appear to be used by receivers, possibly because meerkats use other sensory systems to identify non-group members. We stress the importance of conducting playback experiments when investigating group-specific vocal signatures and use our results as a basis for predicting which animals may rely on group information encoded within close calls

The effects of recruitment to direct predator cues on predator responses in meerkats

Behavioral responses of animals to direct predator cues (DPCs; e.g., urine) are common and may improve their survival. We investigated wild meerkat (Suricata suricatta) responses to DPCs by taking an experimental approach. When meerkats encounter a DPC they often recruit group members by emitting a call type, which causes the group members to interrupt foraging and approach the caller. The aim of this study was to identify the qualities of olfactory predator cues, which affect the strength of response by meerkats, and determine the benefits of responses to such cues. Experimental exposure to dog (Canis lupus) urine as a DPC revealed that the recruited individuals increased vigilance to fresh urine in comparison to older urine, whereas a higher quantity of urine did not induce such an effect. Both freshness and higher quantities increased the proportion of group members recruited. These results indicate that recruitment might play a crucial role in correctly assessing the current level of danger and that recruiting might facilitate group decision making. To test the prediction that the reaction to a DPC enhances early predator response, we presented a DPC of a predator and a control cue of a herbivore, and each time simultaneously moved a full-mounted caracal (Caracal caracal) in the vicinity of the group. Meerkats responded earlier to the caracal when the DPC was presented, indicating that the response to a DPC facilitates predator response and that they use information from the cue that reliably reflects the risk in the current momen

Trace element studies on Karachi populations Part V: Blood lead levels in normal healthy adults and grammar school children

Blood lead levels of healthy Karachi population were estimated. Mean levels for males, females, soldiers and school children were 34.4, 31.8, 29.9 and 38.2 micrograms/dl respectively. About 93% cases of either sex had elevated lead levels, of whom 30% males and 10% females had levels above the safety limits (40 micrograms/dl). Soldiers living in relatively pollution free area though had levels lower than the rest of the population but 91% had levels over 25 micrograms/dl and only two had acceptable levels. Ninety-two percent children showed levels above 25 micrograms/dl with a large number having levels over 40 micrograms/dl. A very small percentage had normal levels. Pollution by traffic exhaust was assumed to be the principal cause for these high levels

Estimating flexibility preferences to resolve temporal scheduling conflicts in activity-based modelling

This paper presents a novel activity-based demand model that combines an optimisation framework for continuous temporal scheduling decisions (i.e. activity timings and durations) with traditional discrete choice models for non-temporal choice dimensions (i.e. activity participation, number and type of tours, and destinations). The central idea of our approach is that individuals resolve temporal scheduling conflicts that arise from overlapping activities, e.g. needing to work and desiring to shop at the same time, in order to maximise their daily utility. Flexibility parameters capture behavioural preferences that penalise deviations from desired timings. This framework has three advantages over existing activity-based modelling approaches: (i) the time conflicts between different temporal scheduling decisions including the activity sequence are treated jointly; (ii) flexibility parameters follow a utility maximisation approach; and (iii) the framework can be used to estimate and simulate a city-scale case study in reasonable time. We introduce an estimation routine that allows flexibility parameters to be estimated using real-world observations as well as a simulation routine to efficiently resolve temporal conflicts using an optimisation model. The framework is applied to the full-time workers of a synthetic population for the city of Lausanne, Switzerland. We validate the model results against reported schedules. The results demonstrate the capabilities of our approach to reproduce empirical observations in a real-world case study

Adaptation in anaesthesia team coordination in response to a simulated critical event and its relationship to clinical performance

Background Recent studies in anaesthesia and intensive care indicate that a team's ability to adapt its coordination activities to changing situational demands is crucial for effective teamwork and thus, safe patient care. This study addresses the relationship between adaptation of team coordination and markers of clinical performance in response to a critical event, particularly regarding which types of coordination activities are used and which team member engages in those coordination activities. Methods Video recordings of 15 two-person anaesthesia teams (anaesthesia trainee plus anaesthesia nurse) performing a simulated induction of general anaesthesia were coded, using a structured observation system for coordination activities. The simulation involved a critical event—asystole during laryngoscopy. Clinical performance was assessed using two separate reaction times related to the critical event. Results Analyses of variance revealed a significant effect of the critical event on team coordination: after the occurrence of the asystole, team members adapted their coordination activities by spending more time on information management—a specific type of coordination activity (F1,28=15.17, P=0.001). No significant effect was found for task management. The increase in information management was related to faster decisions regarding how to respond to the critical event, but only for trainees and not for nurses. Conclusions Our findings support the claim that adaptation of coordination activities is related to improved team performance in healthcare. Moreover, adaptation and its relationship to team performance were found to vary with regard to type of coordination activities and team membe

The predictive value of segmentation metrics on dosimetry in organs at risk of the brain.

BACKGROUND Fully automatic medical image segmentation has been a long pursuit in radiotherapy (RT). Recent developments involving deep learning show promising results yielding consistent and time efficient contours. In order to train and validate these systems, several geometric based metrics, such as Dice Similarity Coefficient (DSC), Hausdorff, and other related metrics are currently the standard in automated medical image segmentation challenges. However, the relevance of these metrics in RT is questionable. The quality of automated segmentation results needs to reflect clinical relevant treatment outcomes, such as dosimetry and related tumor control and toxicity. In this study, we present results investigating the correlation between popular geometric segmentation metrics and dose parameters for Organs-At-Risk (OAR) in brain tumor patients, and investigate properties that might be predictive for dose changes in brain radiotherapy. METHODS A retrospective database of glioblastoma multiforme patients was stratified for planning difficulty, from which 12 cases were selected and reference sets of OARs and radiation targets were defined. In order to assess the relation between segmentation quality -as measured by standard segmentation assessment metrics- and quality of RT plans, clinically realistic, yet alternative contours for each OAR of the selected cases were obtained through three methods: (i) Manual contours by two additional human raters. (ii) Realistic manual manipulations of reference contours. (iii) Through deep learning based segmentation results. On the reference structure set a reference plan was generated that was re-optimized for each corresponding alternative contour set. The correlation between segmentation metrics, and dosimetric changes was obtained and analyzed for each OAR, by means of the mean dose and maximum dose to 1% of the volume (Dmax 1%). Furthermore, we conducted specific experiments to investigate the dosimetric effect of alternative OAR contours with respect to the proximity to the target, size, particular shape and relative location to the target. RESULTS We found a low correlation between the DSC, reflecting the alternative OAR contours, and dosimetric changes. The Pearson correlation coefficient between the mean OAR dose effect and the Dice was -0.11. For Dmax 1%, we found a correlation of -0.13. Similar low correlations were found for 22 other segmentation metrics. The organ based analysis showed that there is a better correlation for the larger OARs (i.e. brainstem and eyes) as for the smaller OARs (i.e. optic nerves and chiasm). Furthermore, we found that proximity to the target does not make contour variations more susceptible to the dose effect. However, the direction of the contour variation with respect to the relative location of the target seems to have a strong correlation with the dose effect. CONCLUSIONS This study shows a low correlation between segmentation metrics and dosimetric changes for OARs in brain tumor patients. Results suggest that the current metrics for image segmentation in RT, as well as deep learning systems employing such metrics, need to be revisited towards clinically oriented metrics that better reflect how segmentation quality affects dose distribution and related tumor control and toxicity

Outcome and patterns of failure after postoperative intensity modulated radiotherapy for locally advanced or high-risk oral cavity squamous cell carcinoma

Background To determine the outcome and patterns of failure in oral cavity cancer (OCC) patients after postoperative intensity modulated radiotherapy (IMRT) with concomitant systemic therapy. Methods All patients with locally advanced (AJCC stage III/IV) or high-risk OCC (AJCC stage II) who underwent postoperative IMRT at our institution between December 2006 and July 2010 were retrospectively analyzed. The primary endpoint was locoregional recurrence-free survival (LRRFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), acute and late toxicities. Results Overall 53 patients were analyzed. Twenty-three patients (43%) underwent concomitant chemotherapy with cisplatin, two patients with carboplatin (4%) and four patients were treated with the monoclonal antibody cetuximab (8%). At a median follow-up of 2.3 (range, 1.1–4.6) years the 3-year LRRFS, DMFS and OS estimates were 79%, 90%, and 73% respectively. Twelve patients experienced a locoregional recurrence. Eight patients, 5 of which had both a flap reconstruction and extracapsular extension (ECE), showed an unusual multifocal pattern of recurrence. Ten locoregional recurrences occurred marginally or outside of the high-risk target volumes. Acute toxicity grades of 2 (27%) and 3 (66%) and late toxicity grades of 2 (34%) and 3 (11%) were observed. Conclusion LRRFS after postoperative IMRT is satisfying and toxicity is acceptable. The majority of locoregional recurrences occurred marginally or outside of the high-risk target volumes. Improvement of high-risk target volume definition especially in patients with flap reconstruction and ECE might transfer into better locoregional control