Tmc1 point mutation affects Ca2+ sensitivity and block by dihydrostreptomycin of the mechanoelectrical transducer current of mouse outer hair cells

The transduction of sound into electrical signals depends on mechanically sensitive ion channels in the stereociliary bundle. The molecular composition of this mechanoelectrical transducer (MET) channel is not yet known. Transmembrane channel-like protein isoforms 1 (TMC1) and 2 (TMC2) have been proposed to form part of the MET channel, although their exact roles are still unclear. Using Beethoven (Tmc1Bth/Bth) mice, which have an M412K point mutation in TMC1 that adds a positive charge, we found that Ca2+ permeability and conductance of the MET channel of outer hair cells (OHCs) were reduced. Tmc1Bth/Bth OHCs were also less sensitive to block by the permeant MET channel blocker dihydrostreptomycin, whether applied extracellularly or intracellularly. These findings suggest that the amino acid that is mutated in Bth is situated at or near the negatively charged binding site for dihydrostreptomycin within the permeation pore of the channel. We also found that the Ca2+ dependence of the operating range of the MET channel was altered by the M412K mutation. Depolarization did not increase the resting open probability of the MET current of Tmc1Bth/Bth OHCs, whereas raising the intracellular concentration of the Ca2+ chelator BAPTA caused smaller increases in resting open probability in Bth mutant OHCs than in wild-type control cells. We propose that these observations can be explained by the reduced Ca2+ permeability of the mutated MET channel indirectly causing the Ca2+ sensor for adaptation, at or near the intracellular face of the MET channel, to become more sensitive to Ca2+ influx as a compensatory mechanism

Do public relations professionals understand corporate governance issues well enough to advise companies on stakeholder relationship management?

The King Reports on Governance for South Africa are internationally respected for proposing integrated reporting in a triple bottom-line business context to improve corporate governance. The most recent report, King III, views stakeholder relationship management as a key tenet of corporate governance. The question that begs answering is whether Public relations professionals (PRPs) understand the principles of corporate governance well-enough to inform and guide organizations on the management of stakeholder relationships to ensure organizational sustainability. The views of senior PRPs at selected top performing companies were elicited on their practice of stakeholder relationship management in line with corporate governance principles. It was found that their knowledge on corporate governance was limited, although the importance thereof was recognized; six role functions are fulfilled in managing stakeholder relationships on a strategic or managerial level; these role functions are aligned with the King III principles on stakeholder relationship. The following three were of particular importance: developing corporate strategy, giving advice to senior management and managing crisis communication. Different terminologies were used to build relations with stakeholders and different approaches were used to profile stakeholders. It is recommended that organizations leverage the proven public relations function on strategic and managerial level in support of their corporate governance efforts. In turn, PRPs are encouraged to ensure a deep knowledge on corporate governance issues when counseling senior management on building stakeholder relationships to ensure organizational sustainability.http://www.journals.elsevier.com/public-relations-review/hb201

In silico synchronization reveals regulators of nuclear ruptures in lamin A/C deficient model cells

The nuclear lamina is a critical regulator of nuclear structure and function. Nuclei from laminopathy patient cells experience repetitive disruptions of the nuclear envelope, causing transient intermingling of nuclear and cytoplasmic components. The exact causes and consequences of these events are not fully understood, but their stochastic occurrence complicates in-depth analyses. To resolve this, we have established a method that enables quantitative investigation of spontaneous nuclear ruptures, based on co-expression of a rmly bound nuclear reference marker and a uorescent protein that shuttles between the nucleus and cytoplasm during ruptures. Minimally invasive imaging of both reporters, combined with automated tracking and in silico synchronization of individual rupture events, allowed extracting information on rupture frequency and recovery kinetics. Using this approach, we found that rupture frequency correlates inversely with lamin A/C levels, and can be reduced in genome- edited LMNA knockout cells by blocking actomyosin contractility or inhibiting the acetyl-transferase protein NAT10. Nuclear signal recovery followed a kinetic that is co-determined by the severity of the rupture event, and could be prolonged by knockdown of the ESCRT-III complex component CHMP4B. In conclusion, our approach reveals regulators of nuclear rupture induction and repair, which may have critical roles in disease development

External validation of a prediction model and decision tree for sickness absence due to mental disorders

Purpose: A previously developed prediction model and decision tree were externally validated for their ability to identify occupational health survey participants at increased risk of long-term sickness absence (LTSA) due to mental disorders. Methods: The study population consisted of N = 3415 employees in mobility services who were invited in 2016 for an occupational health survey, consisting of an online questionnaire measuring the health status and working conditions, followed by a preventive consultation with an occupational health provider (OHP). The survey variables of the previously developed prediction model and decision tree were used for predicting mental LTSA (no = 0, yes = 1) at 1-year follow-up. Discrimination between survey participants with and without mental LTSA was investigated with the area under the receiver operating characteristic curve (AUC). Results: A total of n = 1736 (51%) non-sick-listed employees participated in the survey and 51 (3%) of them had mental LTSA during follow-up. The prediction model discriminated (AUC = 0.700; 95% CI 0.628–0.773) between participants with and without mental LTSA during follow-up. Discrimination by the decision tree (AUC = 0.671; 95% CI 0.589–0.753) did not differ significantly (p = 0.62) from discrimination by the prediction model. Conclusion: At external validation, the prediction model and the decision tree both poorly identified occupational health survey participants at increased risk of mental LTSA. OHPs could use the decision tree to determine if mental LTSA risk factors should be explored in the preventive consultation which follows after completing the survey questionnaire

Development of Prediction Models for Sickness Absence Due to Mental Disorders in the General Working Population

PurposeThis study investigated if and how occupational health survey variables can be used to identify workers at risk of long-term sickness absence (LTSA) due to mental disorders.MethodsCohort study including 53,833 non-sicklisted participants in occupational health surveys between 2010 and 2013. Twenty-seven survey variables were included in a backward stepwise logistic regression analysis with mental LTSA at 1-year follow-up as outcome variable. The same variables were also used for decision tree analysis. Discrimination between participants with and without mental LTSA during follow-up was investigated by using the area under the receiver operating characteristic curve (AUC); the AUC was internally validated in 100 bootstrap samples.Results30,857 (57%) participants had complete data for analysis; 450 (1.5%) participants had mental LTSA during follow-up. Discrimination by an 11-predictor logistic regression model (gender, marital status, economic sector, years employed at the company, role clarity, cognitive demands, learning opportunities, co-worker support, social support from family/friends, work satisfaction, and distress) was AUC = 0.713 (95% CI 0.692-0.732). A 3-node decision tree (distress, gender, work satisfaction, and work pace) also discriminated between participants with and without mental LTSA at follow-up (AUC = 0.709; 95% CI 0.615-0.804).ConclusionsAn 11-predictor regression model and a 3-node decision tree equally well identified workers at risk of mental LTSA. The decision tree provides better insight into the mental LTSA risk groups and is easier to use in occupational health care practice

Estimating the cumulative effects of the nature-based tourism in a coastal dolphin population from southern Kenya

Due to the growth of nature-based tourism worldwide, behavioural studies are needed to assess the impact of this industry on wildlife populations and understand their short-term effect. Tourism impact on dolphin populations remain poorly documented in developing countries. This study investigates the effects of nature-based tourism on the behaviour of the Indo-Pacific bottlenose dolphins (Tursiops aduncus) in southern Kenya. We used Markov chain models to estimate transition probabilities between behavioural states in the presence and absence of tourist boats, and assess the overall behavioural budgets. Based on these data and the tourism intensity in the area, we quantified the potential tourist boat disturbance over the period 2006-2013. Our results demonstrated that tourist boat interactions affected dolphins' behavioural budgets, with a significant decrease in the overall amount of time travelling and an increase in diving. The average duration of travelling and resting decreased significantly in the presence of boats. Although the cumulative tourism exposure was not significant for the dolphin population at their current levels, these impacts should be taken into consideration with the potential tourism growth in the area. This is particularly important if tourism reaches periods of high intensity, as we have shown that these periods could have a significant impact for the species, particularly where home-range and core areas are highly overlap by this activity. Understanding the effect of human disturbance variations from previous years may help to predict the consequences on dolphin populations, towards achieving a more ecological and economic sustainability of the activity

Modelling of Multi-Agent Systems: Experiences with Membrane Computing and Future Challenges

Formal modelling of Multi-Agent Systems (MAS) is a challenging task due to high complexity, interaction, parallelism and continuous change of roles and organisation between agents. In this paper we record our research experience on formal modelling of MAS. We review our research throughout the last decade, by describing the problems we have encountered and the decisions we have made towards resolving them and providing solutions. Much of this work involved membrane computing and classes of P Systems, such as Tissue and Population P Systems, targeted to the modelling of MAS whose dynamic structure is a prominent characteristic. More particularly, social insects (such as colonies of ants, bees, etc.), biology inspired swarms and systems with emergent behaviour are indicative examples for which we developed formal MAS models. Here, we aim to review our work and disseminate our findings to fellow researchers who might face similar challenges and, furthermore, to discuss important issues for advancing research on the application of membrane computing in MAS modelling.Comment: In Proceedings AMCA-POP 2010, arXiv:1008.314

Temporal development of the humoral immune response to surface antigens of Moraxella catarrhalis in young infants

The primary Moraxella catarrha/is-specific humoral immune response, and its association with nasopharyngeal colonization, was studied in a cohort of infants from birth to 2 years of age. Results indicated that the levels of antigen-specific IgG, IgA and IgM showed extensive inter-individual variability over time, with IgM and IgA levels to all 9 recombinant domains, from 7 different OMPs, being relatively low throughout the study period. In contrast, the level of antigen-specific IgG was significantly higher for the recombinant domains Hag(385-863), MID764-913, MID962-1200, UspA1(557-704) and UspA2(165-318) in cord blood compared to 6 months of age (P <= 0.001). This was a most likely a consequence of maternal transmission of antigen-specific IgG to newborn babies, possibly indicating a future role for these 3 surface antigens in the development of an effective humoral immune response to M. catarrhalis. Finally, at 2 years of age, the levels of antigen-specific IgG still remained far below that obtained from cord blood samples, indicating that the immune response to M. catarrhalis has not matured at 2 years of age. We provide evidence that a humoral antibody response to OMPs UspA1,UspA2 and Hag/MID may play a role in the immune response to community acquired M. catarrhalis colonization events. (C) 2011 Elsevier Ltd. All rights reserved

3D Protein structure prediction with genetic tabu search algorithm

Abstract Background Protein structure prediction (PSP) has important applications in different fields, such as drug design, disease prediction, and so on. In protein structure prediction, there are two important issues. The first one is the design of the structure model and the second one is the design of the optimization technology. Because of the complexity of the realistic protein structure, the structure model adopted in this paper is a simplified model, which is called off-lattice AB model. After the structure model is assumed, optimization technology is needed for searching the best conformation of a protein sequence based on the assumed structure model. However, PSP is an NP-hard problem even if the simplest model is assumed. Thus, many algorithms have been developed to solve the global optimization problem. In this paper, a hybrid algorithm, which combines genetic algorithm (GA) and tabu search (TS) algorithm, is developed to complete this task. Results In order to develop an efficient optimization algorithm, several improved strategies are developed for the proposed genetic tabu search algorithm. The combined use of these strategies can improve the efficiency of the algorithm. In these strategies, tabu search introduced into the crossover and mutation operators can improve the local search capability, the adoption of variable population size strategy can maintain the diversity of the population, and the ranking selection strategy can improve the possibility of an individual with low energy value entering into next generation. Experiments are performed with Fibonacci sequences and real protein sequences. Experimental results show that the lowest energy obtained by the proposed GATS algorithm is lower than that obtained by previous methods. Conclusions The hybrid algorithm has the advantages from both genetic algorithm and tabu search algorithm. It makes use of the advantage of multiple search points in genetic algorithm, and can overcome poor hill-climbing capability in the conventional genetic algorithm by using the flexible memory functions of TS. Compared with some previous algorithms, GATS algorithm has better performance in global optimization and can predict 3D protein structure more effectively