Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells

Only 40% of patients with advanced ovarian cancer survive more than 5 years. We have previously shown that pitavastatin induces regression of ovarian cancer xenografts in mice. To evaluate whether the response of ovarian cancer cells to pitavastatin is potentiated by farnesyl diphosphate synthase inhibitors or geranylgeraniol transferase I inhibitors, we evaluated combinations of pitavastatin with zoledronic acid, risedronate and GGTI-2133 in a panel of ovarian cancer cells. Pitavastatin (IC50 = 0.6-14 μM), zoledronic acid (IC50 = 21-57 μM), risedronate (IC50 > 100 μM) or GGTI-2133 (IC50 > 25 μM) inhibited the growth of ovarian cancer cell cultures. Combinations of pitavastatin with zoledronic acid displayed additive or synergistic effects in cell growth assays in 10 of 11 cell lines evaluated as well as in trypan blue exclusion, cellular ATP or caspase 3/7, 8 and 9 assays. Pitavastatin reduced levels of GGT-IIβ and the membrane localization of several small GTPases and this was potentiated by zoledronic acid. siRNA to GGT-Iβ and GGT-IIβ used in combination, but not when used individually, significantly increased the sensitivity of cells to pitavastatin. These data suggest that zoledronic acid, a drug already in clinical use, may be usefully combined with pitavastatin in the treatment of ovarian cancer

Estimation of Actuation System Parameters for Lower Limb Prostheses

This paper provides guidelines to estimate the kinematics, energy and torque requirements for lower limb prosthetic actuation systems during daily living activities. These parameters are estimated based on human biomechanical data from different sources to consider the variability due to the assumptions and errors in the analysis and data collection. The results showed that the powered actuation source is important at the ankle joint in the stance phase during level ground walking while it is more important at knee joint during stair ascending. These estimated parameters can be used as guidelines to design and select proper actuation systems

Effect of Different Prosthetic Knees/feet on the Roll-Over Shape

Roll-over shape (ROS) of knee-ankle-foot (KAF) is a scientific method which has been used to compare performance and design of the different prosthetic foot. In the current study, however, we aimed to understand the influence of the prosthetic components (i.e. knee and foot) on the knee-ankle-foot roll-over shape in a unilateral transfemoral amputee. We performed a case study based on series of experiments with repeated measures on single amputee wearing two different commercially available microprocessor prosthetic knees, during two weeks adaptation period to understand the influence of the prosthetic knee/foot using KAF ROS as an objective measure during level ground walking. The kinematics of the center of pressure (COP), lateral knee and ankle markers were collected and processed to obtain ROS and the results were used to fit a circular shape arc to obtain radius of curvature (ROC). The results indicated that the prosthetic knees have influenced ROC outcomes. The analysis of variance (ANOVA) and post hoc test of the normalized radius of curvature showed the mean of ROC were significantly different between Rheo3 knee, Orion2 and Orion2 with Echelon foot. The amputee reflected his comfort with Rheo3 plus College park foot and Orion with Echelon foot. A conclusion is drawn that multiple comfort zones may exists based on amputee’s ROS metrics. This finding suggests that the design of prosthetic knee should not be considered as a single component but rather as part of a whole system with different comfort zones

Self-similarity of fluid residence time statistics in a turbulent round jet

Fluid residence time is a key concept in the understanding and design of chemically reacting flows. In order to investigate how turbulent mixing affects the residence time distribution within a flow, this study examines statistics of fluid residence time from a direct numerical simulation (DNS) of a statistically stationary turbulent round jet with a jet Reynolds number of 7290. The residence time distribution in the flow is characterised by solving transport equations for the residence time of the jet fluid and for the jet fluid mass fraction. The product of the jet fluid residence time and the jet fluid mass fraction, referred to as the mass-weighted stream age, gives a quantity that has stationary statistics in the turbulent jet. Based on the observation that the statistics of the mass fraction and velocity are self-similar downstream of an initial development region, the transport equation for the jet fluid residence time is used to derive a model describing a self-similar profile for the mean of the mass-weighted stream age. The self-similar profile predicted is dependent on, but different from, the self-similar profiles for the mass fraction and the axial velocity. The DNS data confirm that the first four moments and the shape of the one-point probability density function of mass-weighted stream age are indeed self-similar, and that the model derived for the mean mass-weighted stream-age profile provides a useful approximation. Using the self-similar form of the moments and probability density functions presented it is therefore possible to estimate the local residence time distribution in a wide range of practical situations in which fluid is introduced by a high-Reynolds-number jet of fluid

Investigation into Energy Efficiency and Regeneration in an Electric Prosthetic Knee

Powered lower limb prosthesis are facing energy and efficiency challenges. This article presents an investigation into reducing the energy losses and increasing the efficiencies of energy regeneration for a powered prosthetic knee during level ground walking. The results showed that the regeneration and overall system efficiencies would dramatically increase if the negative mechanical load in the braking quadrants are within the regenerative zone of the motor. This approach reduced the energy losses in the stance and swing phases and increased the possibility of harvesting more negative mechanical energy during level ground walking

Ecological and methodological drivers of species' distribution and phenology responses to climate change

Climate change is shifting species’ distribution and phenology. Ecological traits, such as mobility or reproductive mode, explain variation in observed rates of shift for some taxa. However, estimates of relationships between traits and climate responses could be influenced by how responses are measured. We compiled a global data set of 651 published marine species’ responses to climate change, from 47 papers on distribution shifts and 32 papers on phenology change. We assessed the relative importance of two classes of predictors of the rate of change, ecological traits of the responding taxa and methodological approaches for quantifying biological responses. Methodological differences explained 22% of the variation in range shifts, more than the 7.8% of the variation explained by ecological traits. For phenology change, methodological approaches accounted for 4% of the variation in measurements, whereas 8% of the variation was explained by ecological traits. Our ability to predict responses from traits was hindered by poor representation of species from the tropics, where temperature isotherms are moving most rapidly. Thus, the mean rate of distribution change may be underestimated by this and other global syntheses. Our analyses indicate that methodological approaches should be explicitly considered when designing, analysing and comparing results among studies. To improve climate impact studies, we recommend that (1) reanalyses of existing time series state how the existing data sets may limit the inferences about possible climate responses; (2) qualitative comparisons of species’ responses across different studies be limited to studies with similar methodological approaches; (3) meta-analyses of climate responses include methodological attributes as covariates; and (4) that new time series be designed to include the detection of early warnings of change or ecologically relevant change. Greater consideration of methodological attributes will improve the accuracy of analyses that seek to quantify the role of climate change in species’ distribution and phenology changes

A rare duplication on chromosome 16p11.2 is identified in patients with psychosis in Alzheimer's disease

Epidemiological and genetic studies suggest that schizophrenia and autism may share genetic links. Besides common single nucleotide polymorphisms, recent data suggest that some rare copy number variants (CNVs) are risk factors for both disorders. Because we have previously found that schizophrenia and psychosis in Alzheimer's disease (AD+P) share some genetic risk, we investigated whether CNVs reported in schizophrenia and autism are also linked to AD+P. We searched for CNVs associated with AD+P in 7 recurrent CNV regions that have been previously identified across autism and schizophrenia, using the Illumina HumanOmni1-Quad BeadChip. A chromosome 16p11.2 duplication CNV (chr16: 29,554,843-30,105,652) was identified in 2 of 440 AD+P subjects, but not in 136 AD subjects without psychosis, or in 593 AD subjects with intermediate psychosis status, or in 855 non-AD individuals. The frequency of this duplication CNV in AD+P (0.46%) was similar to that reported previously in schizophrenia (0.46%). This duplication CNV was further validated using the NanoString nCounter CNV Custom CodeSets. The 16p11.2 duplication has been associated with developmental delay, intellectual disability, behavioral problems, autism, schizophrenia (SCZ), and bipolar disorder. These two AD+P patients had no personal of, nor any identified family history of, SCZ, bipolar disorder and autism. To the best of our knowledge, our case report is the first suggestion that 16p11.2 duplication is also linked to AD+P. Although rare, this CNV may have an important role in the development of psychosis

Deceptive body movements reverse spatial cueing in soccer

This article has been made available through the Brunel Open Access Publishing Fund.The purpose of the experiments was to analyse the spatial cueing effects of the movements of soccer players executing normal and deceptive (step-over) turns with the ball. Stimuli comprised normal resolution or point-light video clips of soccer players dribbling a football towards the observer then turning right or left with the ball. Clips were curtailed before or on the turn (-160, -80, 0 or +80 ms) to examine the time course of direction prediction and spatial cueing effects. Participants were divided into higher-skilled (HS) and lower-skilled (LS) groups according to soccer experience. In experiment 1, accuracy on full video clips was higher than on point-light but results followed the same overall pattern. Both HS and LS groups correctly identified direction on normal moves at all occlusion levels. For deceptive moves, LS participants were significantly worse than chance and HS participants were somewhat more accurate but nevertheless substantially impaired. In experiment 2, point-light clips were used to cue a lateral target. HS and LS groups showed faster reaction times to targets that were congruent with the direction of normal turns, and to targets incongruent with the direction of deceptive turns. The reversed cueing by deceptive moves coincided with earlier kinematic events than cueing by normal moves. It is concluded that the body kinematics of soccer players generate spatial cueing effects when viewed from an opponent's perspective. This could create a reaction time advantage when anticipating the direction of a normal move. A deceptive move is designed to turn this cueing advantage into a disadvantage. Acting on the basis of advance information, the presence of deceptive moves primes responses in the wrong direction, which may be only partly mitigated by delaying a response until veridical cues emerge

Microservice Transition and its Granularity Problem: A Systematic Mapping Study

Microservices have gained wide recognition and acceptance in software industries as an emerging architectural style for autonomic, scalable, and more reliable computing. The transition to microservices has been highly motivated by the need for better alignment of technical design decisions with improving value potentials of architectures. Despite microservices' popularity, research still lacks disciplined understanding of transition and consensus on the principles and activities underlying "micro-ing" architectures. In this paper, we report on a systematic mapping study that consolidates various views, approaches and activities that commonly assist in the transition to microservices. The study aims to provide a better understanding of the transition; it also contributes a working definition of the transition and technical activities underlying it. We term the transition and technical activities leading to microservice architectures as microservitization. We then shed light on a fundamental problem of microservitization: microservice granularity and reasoning about its adaptation as first-class entities. This study reviews state-of-the-art and -practice related to reasoning about microservice granularity; it reviews modelling approaches, aspects considered, guidelines and processes used to reason about microservice granularity. This study identifies opportunities for future research and development related to reasoning about microservice granularity.Comment: 36 pages including references, 6 figures, and 3 table

Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer

Pre-clinical and retrospective studies of patients using statins to reduce plasma cholesterol have suggested that statins may be useful to treat cancer. However, prospective clinical trials have yet to demonstrate significant efficacy. We have previously shown that this is in part because a hydrophobic statin with a long half-life is necessary. Pitavastatin, the only statin with this profile, has not undergone clinical evaluation in oncology. The target of pitavastatin, hydroxymethylglutarate coenzyme-A reductase (HMGCR), was found to be over-expressed in all ovarian cancer cell lines examined and upregulated by mutated TP53, a gene commonly altered in ovarian cancer. Pitavastatin-induced apoptosis was blocked by geranylgeraniol and mevalonate, products of the HMGCR pathway, confirming that pitavastatin causes cell death through inhibition of HMGCR. Solvent extracts of human and mouse food were also able to block pitavastatin-induced apoptosis, suggesting diet might influence the outcome of clinical trials. When nude mice were maintained on a diet lacking geranylgeraniol, oral pitavastatin caused regression of Ovcar-4 tumour xenografts. However, when the animal diet was supplemented with geranylgeraniol, pitavastatin failed to prevent tumour growth. This suggests that a diet containing geranylgeraniol can limit the anti-tumour activity of pitavastatin and diet should be controlled in clinical trials of statins