Effect of membrane stiffness and cytoskeletal element density on mechanical stimuli within cells: an analysis of the consequences of ageing in cells

A finite element model of a single cell was created and used to investigate the effects of ageing on biophysical stimuli generated within a cell. Major cellular components were incorporated in the model: the membrane, cytoplasm, nucleus, microtubules, actin filaments, intermediate filaments, nuclear lamina, and chromatin. The model used multiple sets of tensegrity structures. Viscoelastic properties were assigned to the continuum components. To corroborate the model, a simulation of Atomic Force Microscopy (AFM) indentation was performed and results showed a force/indentation simulation with the range of experimental results.

Ageing was simulated by both increasing membrane stiffness (thereby modelling membrane peroxidation with age) and decreasing density of cytoskeletal elements (thereby modelling reduced actin density with age). Comparing normal and aged cells under indentation predicts that aged cells have a lower membrane area subjected to high strain compared to young cells, but the difference, surprisingly, is very small and would not be measurable experimentally. Ageing is predicted to have more significant effect on strain deep in the nucleus. These results show that computation of biophysical stimuli within cells are achievable with single-cell computational models whose force/displacement behaviour is within experimentally observed ranges. the models suggest only small, though possibly physiologically-significant, differences in internal biophysical stimuli between normal and aged cells.

Finding exoplanets orbiting young active stars - I. Technique

Stellar activity, such as starspots, can induce radial velocity (RV) variations that can mask or even mimic the RV signature of orbiting exoplanets. For this reason RV exoplanet surveys have been unsuccessful when searching for planets around young, active stars and are therefore failing to explore an important regime which can help to reveal how planets form and migrate. This paper describes a new technique to remove spot signatures from the stellar line-profiles of moderately rotating, active stars (v sin i ranging from 10 to 50 km s(-1)). By doing so it allows planetary RV signals to be uncovered. We used simulated models of a G5V type star with differing dark spots on its surface along with archive data of the known active star HD 49933 to validate our method. The results showed that starspots could be effectively cleaned from the line-profiles so that the stellar RV jitter was reduced by more than 80 per cent. Applying this procedure to the same models and HD 49933 data, but with fake planets injected, enabled the effective removal of starspots so that Jupiter mass planets on short orbital periods were successfully recovered. These results show that this approach can be useful in the search for hot-Jupiter planets that orbit around young, active stars with a v sin i of similar to 10-50 km/s.

Novel GlyT1 inhibitor chemotypes by scaffold hopping. Part 2: Development of a [3.3.0]-based series and other piperidine bioisosteres

This Letter describes the development and SAR of a novel series of GlyT1 inhibitors derived from a scaffold hopping approach, in lieu of an HTS campaign, which provided intellectual property position. Members within this new [3.3.0]​-​based series, e.g. I, displayed excellent GlyT1 potency, selectivity, free fraction, and modest CNS penetration. Moreover, enantioselective GlyT1 inhibition was obsd., within this novel series and a no. of other piperidine bioisosteric cores.

Detection of cardiac arrest using a simplified frequency analysis of the impedance cardiogram recorded from defibrillator pads

An algorithm based only on the impedance cardiogram (ICG) recorded through two defibrillation pads, using the strongest frequency component and amplitude, incorporated into a defibrillator could determine circulatory arrest and reduce delays in starting cardiopulmonary resuscitation (CPR). Frequency analysis of the ICG signal is carried out by integer filters on a sample by sample basis. They are simpler, lighter and more versatile when compared to the FFT. This alternative approach, although less accurate, is preferred due to the limited processing capacity of devices that could compromise real time usability of the FFT. These two techniques were compared across a data set comprising 13 cases of cardiac arrest and 6 normal controls. The best filters were refined on this training set and an algorithm for the detection of cardiac arrest was trained on a wider data set. The algorithm was finally tested on a validation set. The ICG was recorded in 132 cardiac arrest patients (53 training, 79 validation) and 97 controls (47 training, 50 validation): the diagnostic algorithm indicated cardiac arrest with a sensitivity of 81.1% (77.6-84.3) and specificity of 97.1% (96.7-97.4) for the validation set (95% confidence intervals). Automated defibrillators with integrated ICG analysis have the potential to improve emergency care by lay persons enabling more rapid and appropriate initiation of CPR and when combined with ECG analysis they could improve on the detection of cardiac arrest.

Changing the intellectual climate

Calls for more broad-based, integrated, useful knowledge now abound in the world of global environmental change science. They evidence many scientists' desire to help humanity confront the momentous biophysical implications of its own actions. But they also reveal a limited conception of social science and virtually ignore the humanities. They thereby endorse a stunted conception of 'human dimensions' at a time when the challenges posed by global environmental change are increasing in magnitude, scale and scope. Here, we make the case for a richer conception predicated on broader intellectual engagement and identify some preconditions for its practical fulfilment. Interdisciplinary dialogue, we suggest, should engender plural representations of Earth's present and future that are reflective of divergent human values and aspirations. In turn, this might insure publics and decision-makers against overly narrow conceptions of what is possible and desirable as they consider the profound questions raised by global environmental change.

Laughter Type Recognition from Whole Body Motion

Despite the importance of laughter in social interactions it remains little studied in affective computing. Respiratory, auditory, and facial laughter signals have been investigated but laughter-related body movements have received almost no attention. The aim of this study is twofold: first an investigation into observers' perception of laughter states (hilarious, social, awkward, fake, and non-laughter) based on body movements alone, through their categorization of avatars animated with natural and acted motion capture data. Significant differences in torso and limb movements were found between animations perceived as containing laughter and those perceived as nonlaughter. Hilarious laughter also differed from social laughter in the amount of bending of the spine, the amount of shoulder rotation and the amount of hand movement. The body movement features indicative of laughter differed between sitting and standing avatar postures. Based on the positive findings in this perceptual study, the second aim is to investigate the possibility of automatically predicting the distributions of observer's ratings for the laughter states. The findings show that the automated laughter recognition rates approach human rating levels, with the Random Forest method yielding the best performance.

Arene cis-Diol Dehydrogenase-Catalysed Regio- and Stereoselective Oxidation of Arene-, Cycloalkane- and Cycloalkene-cis-diols to Yield Catechols and Chiral α-Ketols

Benzene cis-diol dehydrogenase and naphthalene cis-diol dehydrogenase enzymes, expressed in Pseudomonas putida wild-type and Escherichia coli recombinant strains, were used to investigate regioselectivity and stereoselectivity during dehydrogenations of arene, cyclic alkane and cyclic alkene vicinal cis-diols. The dehydrogenase-catalysed production of enantiopure cis-diols, α-ketols and catechols, using benzene cis-diol dehydrogenase and naphthalene cis-diol dehydrogenase, involved both kinetic resolution and asymmetric synthesis methods. The chemoenzymatic production and applications of catechol bioproducts in synthesis were investigated.

Design guidelines for developing customised serious games for parkinson's disease rehabilitation using bespoke game sensors

The research presented in this paper proposes a set of design guidelines in the context of a Parkinson's Disease (PD) rehabilitation design framework for the development of serious games for the physical therapy of people with PD. The game design guidelines provided in the paper are informed by the study of the literature review and lessons learned from the pilot testing of serious games designed to suit the requirements of rehabilitation of patients with Parkinson's Disease. The proposed PD rehabilitation design framework employed for the games pilot testing utilises a low-cost, customized and off-the-shelf motion capture system (employing commercial game controllers) developed to cater for the unique requirement of the physical therapy of people with PD. Although design guidelines have been proposed before for the design of serious games in health, this is the first research paper to present guidelines for the design of serious games specifically for PD motor rehabilitation.

Heme oxygenase-1: a metabolic nike

SIGNIFICANCE: Heme degradation, which was described more than 30 years ago, is still very actively explored with many novel discoveries on its role in various disease models every year.

RECENT ADVANCES: The heme oxygenases (HO) are metabolic enzymes that utilize NADPH and oxygen to break apart the heme moiety liberating biliverdin (BV), carbon monoxide (CO), and iron. Heme that is derived from hemoproteins can be toxic to the cells and if not removed immediately, it causes cell apoptosis and local inflammation. Elimination of heme from the milieu enables generation of three products that influences numerous metabolic changes in the cell.

CRITICAL ISSUES: CO has profound effects on mitochondria and cellular respiration and other hemoproteins to which it can bind and affect their function, while BV and bilirubin (BR), the substrate and product of BV, reductase, respectively, are potent antioxidants. Sequestration of iron into ferritin and its recycling in the tissues is a part of the homeodynamic processes that control oxidation-reduction in cellular metabolism. Further, heme is an important component of a number of metabolic enzymes, and, therefore, HO-1 plays an important role in the modulation of cellular bioenergetics.

FUTURE DIRECTIONS: In this review, we describe the cross-talk between heme oxygenase-1 (HO-1) and its products with other metabolic pathways. HO-1, which we have labeled Nike, the goddess who personified victory, dictates triumph over pathophysiologic conditions, including diabetes, ischemia, and cancer.

Factors influencing success of clinical genome sequencing across a broad spectrum of disorders

To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.

Robust bimodal person identification using face and speech with limited training data and corruption of both modalities

This paper presents a novel method of audio-visual fusion for person identification where both the speech and facial modalities may be corrupted, and there is a lack of prior knowledge about the corruption. Furthermore, we assume there is a limited amount of training data for each modality (e.g., a short training speech segment and a single training facial image for each person). A new representation and a modified cosine similarity are introduced for combining and comparing bimodal features with limited training data as well as vastly differing data rates and feature sizes. Optimal feature selection and multicondition training are used to reduce the mismatch between training and testing, thereby making the system robust to unknown bimodal corruption. Experiments have been carried out on a bimodal data set created from the SPIDRE and AR databases with variable noise corruption of speech and occlusion in the face images. The new method has demonstrated improved recognition accuracy.

Virtual Thrower Versus Real Goalkeeper: The Influence of Different Visual Conditions on Performance

In order to use virtual reality as a sport analysis tool, we need to be sure that an immersed athlete reacts realistically in a virtual environment. This has been validated for a real handball goalkeeper facing a virtual thrower. However, we currently ignore which visual variables induce a realistic motor behavior of the immersed handball goalkeeper. In this study, we used virtual reality to dissociate the visual information related to the movements of the player from the visual information related to the trajectory of the ball. Thus, the aim is to evaluate the relative influence of these different visual information sources on the goalkeeper's motor behavior. We tested 10 handball goalkeepers who had to predict the final position of the virtual ball in the goal when facing the following: only the throwing action of the attacking player (TA condition), only the resulting ball trajectory (BA condition), and both the throwing action of the attacking player and the resulting ball trajectory (TB condition). Here we show that performance was better in the BA and TB conditions, but contrary to expectations, performance was substantially worse in the TA condition. A significant effect of ball landing zone does, however, suggest that the relative importance between visual information from the player and the ball depends on the targeted zone in the goal. In some cases, body-based cues embedded in the throwing actions may have a minor influence on the ball trajectory and vice versa. Kinematics analysis was then combined with these results to determine why such differences occur depending on the ball landing zone and consequently how it can clarify the role of different sources of visual information on the motor behavior of an athlete immersed in a virtual environment.

Regular medication reviews for children and young people with ADHD

The National Institute for Health and Care Excellence's (2008) guidelines for the diagnosis and management of attention deficit hyperactivity disorder (ADHD) recommend a full clinical and psychological assessment by an appropriately trained clinician; this should include a detailed developmental and psychiatric history. Stimulant medications, which are Schedule II controlled drugs, are the most commonly prescribed medicines in the UK and across the world for the management of ADHD. Children and young people with a diagnosis of ADHD receiving these stimulant medications are required to attend regular review appointments with a consultant child and adolescent psychiatrist or specialist nurse under shared care guidelines with general practices, and it has long been recognized that appropriately educated nurses can assist in the management of ADHD. Owing to the pharmacological action of the stimulant medication on neurotransmission, there is potential for misuse and dependence. A growing body of evidence suggests that adolescents with ADHD can become involved in drug diversion and that the topic should be explored during assessment. The level of misuse of prescribed stimulants is increasing, and adolescents and young people with ADHD may misuse to enhance cognitive function for academic purposes. The following scenario highlights some of the challenges and opportunities for independent nurse prescribers working in child and adolescent mental health services.

Geofencing Components and Existing Models

This paper describes the various Geofencing Components and Existing Models in terms of their Information Security Control Attribute Profiles. The profiles will dictate the security attributes that should accompany each and every Geofencing Model used for Wi-Fi network security control in an organization, thus minimizing the likelihood of malfunctioning security controls. Although it is up to an organization to investigate the best way of implementing information security for itself, by looking at the related models that have been used in the past this paper will present models commonly used to implement information security controls in the organizations. Our findings will highlight the strengths and weaknesses of the various models and present what our experiment and prototype consider as a robust Geofencing Security Model for securing Wi-Fi Networks