Inherited PTEN mutations and the prediction of phenotype

AbstractPTEN has been heavily studied due to its role as a tumour suppressor and as a core inhibitory component of the phosphoinositide 3-kinase (PI3K) signalling network. It is a broadly expressed phosphatase which displays complexity and diversity in both its functions and regulation and accordingly, in the laboratory numerous classes of functionally distinct mutations have been generated. Inherited loss of function mutations in the PTEN gene were originally identified in sufferers of Cowden disease, but later shown to associate with more diverse human pathologies, mostly relating to cell and tissue overgrowth, leading to the use of the broader term, PTEN Hamartoma Tumour Syndrome. Recent phenotypic analysis of clinical cohorts of PTEN mutation carriers, combined with laboratory studies of the consequences of these mutations implies that stable catalytically inactive PTEN mutants may lead to the most severe phenotypes, and conversely, that mutants retaining partial function associate more frequently with a milder phenotype, with autism spectrum disorder often being diagnosed. Future work will be needed to confirm and to refine these genotype–phenotype relationships and convert this developing knowledge into improved patient management and potentially treatment with emerging drugs which target the PI3K pathway

Channelrhodopsin2 Mediated Stimulation of Synaptic Potentials at Drosophila Neuromuscular Junctions

The Drosophila larval neuromuscular preparation has proven to be a useful tool for studying synaptic physiology1,2,3. Currently, the only means available to evoke excitatory junctional potentials (EJPs) in this preparation involves the use of suction electrodes. In both research and teaching labs, students often have difficulty maneuvering and manipulating this type of stimulating electrode. In the present work, we show how to remotely stimulate synaptic potentials at the larval NMJ without the use of suction electrodes. By expressing channelrhodopsin2 (ChR2) 4,5,6 in Drosophila motor neurons using the GAL4-UAS system 7, and making minor changes to a basic electrophysiology rig, we were able to reliably evoke EJPs with pulses of blue light. This technique could be of particular use in neurophysiology teaching labs where student rig practice time and resources are limited

Prostate cancer, PI3K, PTEN and prognosis

Loss of function of the PTEN tumour suppressor, resulting in dysregulated activation of the phosphoinositide 3-kinase (PI3K) signalling network, is recognized as one of the most common driving events in prostate cancer development. The observed mechanisms of PTEN loss are diverse, but both homozygous and heterozygous genomic deletions including PTEN are frequent, and often accompanied by loss of detectable protein as assessed by immunohistochemistry (IHC). The occurrence of PTEN loss is highest in aggressive metastatic disease and this has driven the development of PTEN as a prognostic biomarker, either alone or in combination with other factors, to distinguish indolent tumours from those likely to progress. Here, we discuss these factors and the consequences of PTEN loss, in the context of its role as a lipid phosphatase, as well as current efforts to use available inhibitors of specific components of the PI3K/PTEN/TOR signalling network in prostate cancer treatment.</jats:p

Three-dimensional bioprinting of complex cell laden alginate hydrogel structures

Different bioprinting techniques have been used to produce cell-laden alginate hydrogel structures, however these approaches have been limited to 2D or simple three-dimension (3D) structures. In this study, a new extrusion based bioprinting technique was developed to produce more complex alginate hydrogel structures. This was achieved by dividing the alginate hydrogel cross-linking process into three stages: primary calcium ion cross-linking for printability of the gel, secondary calcium cross-linking for rigidity of the alginate hydrogel immediately after printing and tertiary barium ion cross-linking for long-term stability of the alginate hydrogel in culture medium. Simple 3D structures including tubes were first printed to ensure the feasibility of the bioprinting technique and then complex 3D structures such as branched vascular structures were successfully printed. The static stiffness of the alginate hydrogel after printing was 20.18 ± 1.62 KPa which was rigid enough to sustain the integrity of the complex 3D alginate hydrogel structure during the printing. The addition of 60 mM barium chloride was found to significantly extend the stability of the cross-linked alginate hydrogel from 3 d to beyond 11 d without compromising the cellular viability. The results based on cell bioprinting suggested that viability of U87-MG cells was 93 ± 0.9% immediately after bioprinting and cell viability maintained above 88% ± 4.3% in the alginate hydrogel over the period of 11 d

Convergent learning algorithms for potential games with unknown noisy rewards

In this paper, we address the problem of convergence to Nash equilibria in games with rewards that are initially unknown and which must be estimated over time from noisy observations. These games arise in many real-world applications, whenever rewards for actions cannot be prespecified and must be learned on-line. Standard results in game theory, however, do not consider such settings. Specifically, using results from stochastic approximation and differential inclusions, we prove the convergence of variants of fictitious play and adaptive play to Nash equilibria in potential games and weakly acyclic games, respectively. These variants all use a multi-agent version of Q-learning to estimate the reward functions and a novel form of the e-greedy decision rule to select an action. Furthermore, we derive e-greedy decision rules that exploit the sparse interaction structure encoded in two compact graphical representations of games, known as graphical and hypergraphical normal form, to improve the convergence rate of the learning algorithms. The structure captured in these representations naturally occurs in many distributed optimisation and control applications. Finally, we demonstrate the efficacy of the algorithms in a simulated ad hoc wireless sensor network management problem

Spiritual Directors and Clinical Psychologists: A Comparison of Mental Health and Spiritual Values

We surveyed a total of 315 spiritual directors, psychologist members of the Christian Association for Psychological Studies (CAPS), and psychologist members of the American Psychological Association (APA) to determine their respective values on ten mental health themes derived from Jensen and Bergin (1988), and three spirituality scales drawn from the writings of John of the Cross. All three groups endorsed the value of expressing feelings, personal autonomy and maturity, and integrating work and leisure. CAPS psychologists and spiritual directors endorsed more than APA psychologists the values of spirituality, forgiveness, and the three John of the Cross scales. Spiritual directors reported greater endorsement of the self-awareness and growth theme than did psychodynamic psychologists who, in turn, reported greater endorsement than cognitive-behavioral psychologists. The results are examined in light of the pre-Enlightenment paradigm and value system in which spiritual direction and Christian theology are rooted

Burnout and Substance Use in Collegiate Athletic Trainers

CONTEXT: The Smith Cognitive-Affective Model of Athletic Burnout suggests that athletic trainers (ATs) suffering from burnout may engage in substance use as a coping behavior. Increases in self-reported burnout symptoms are often associated with increases in heavy episodic drinking and tobacco use among various health care providers. However, this relationship has not been examined thoroughly. OBJECTIVE: To investigate the prevalence of substance use in ATs and identify relationships between symptoms of burnout and substance use among ATs. DESIGN: Cross-sectional study. SETTING: Web-based survey. PATIENTS OR OTHER PARTICIPANTS: A total of 783 certified ATs working full time in the collegiate or university setting were sampled for this study. Graduate assistant and other part-time ATs were excluded. The survey was distributed via the National Athletic Trainers\u27 Association membership directory e-mail broadcast service. MAIN OUTCOME MEASURE(S): A 100-item online questionnaire consisting of items from previously used scales was used for this study. The survey included the Maslach Burnout Inventory and questions on substance use from the Monitoring the Future study. Multiple regression analyses were performed to analyze the survey data. All independent (Maslach Burnout Inventory subscales) and dependent (use of alcohol, tobacco, and marijuana) variables were mapped to the Smith Cognitive-Affective Model of Athletic Burnout to determine which dimensions of burnout altered the odds of self-reported substance use. RESULTS: Almost half (46.3%) of participants admitted to at least 1 binge-drinking episode. However, the use of cigarettes, smokeless tobacco, marijuana, and energy drinks during the previous month was less pronounced in the sample. Emotional exhaustion (B = .008, P = .023) and personal accomplishment (B = -.016, P = .02) were significantly correlated with binge drinking. Emotional exhaustion (Exp[B] = 1.017, P \u3c .001) was also significantly positively correlated with energy-drink consumption. CONCLUSIONS: Some ATs engaged in heavy episodic drinking. Emotional exhaustion and a decreased sense of personal accomplishment were significantly correlated with this behavior