Fuzzy associative memory for humanoid robot joint control

Traditional approaches to joint control required accurate modelling of the system dynamic of the plant in question. Fuzzy Associative Memory (FAM) control schemes allow adequate control without a model of the system to be controlled. This paper presents a FAM based joint controller implemented on a humanoid robot. An empirically tuned PI velocity control loop is augmented with this feed forward FAM, with considerable reduction in joint position error achieved online and with minimal additional computational overhead

Maternal exposure to dibutyl phthalate (Dbp) or diethylstilbestrol (des) leads to long-term changes in hypothalamic gene expression and sexual behavior

Xenobiotic exposure during pregnancy and lactation has been linked to perinatal changes in male reproductive outcomes and other endocrine parameters. This pilot study wished to assess whether brief maternal exposure of rats to xenobiotics dibutyl phthalate (DBP) or diethylstilbestrol (DES) might also cause long-term changes in hypothalamic gene expression or in reproductive behavior of the resulting offspring. Time-mated female Sprague Dawley rats were given either DBP (500 mg/kg body weight, every second day from GD14.5 to PND6), DES (125 µg/kg body weight at GD14.5 and GD16.5 only), or vehicle (n = 8–12 per group) and mild endocrine disruption was confirmed by monitoring postnatal anogenital distance. Hypothalamic RNA from male and female offspring at PND10, PND24 and PND90 was analyzed by qRT-PCR for expression of aromatase, oxytocin, vasopressin, ER-alpha, ER-beta, kisspeptin, and GnRH genes. Reproductive behavior was monitored in male and female offspring from PND60 to PND90. Particularly, DES treatment led to significant changes in hypothalamic gene expression, which for the oxytocin gene was still evident at PND90, as well as in sexual behavior. In conclusion, maternal xenobiotic exposure may not only alter endocrine systems in offspring but, by impacting on brain development at a critical time, can have long-term effects on male or female sexual behavior

Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K

SummaryBRAF is an attractive target for melanoma drug development. However, resistance to BRAF inhibitors is a significant clinical challenge. We describe a model of resistance to BRAF inhibitors developed by chronic treatment of BRAFV600E melanoma cells with the BRAF inhibitor SB-590885; these cells are cross-resistant to other BRAF-selective inhibitors. Resistance involves flexible switching among the three RAF isoforms, underscoring the ability of melanoma cells to adapt to pharmacological challenges. IGF-1R/PI3K signaling was enhanced in resistant melanomas, and combined treatment with IGF-1R/PI3K and MEK inhibitors induced death of BRAF inhibitor-resistant cells. Increased IGF-1R and pAKT levels in a post-relapse human tumor sample are consistent with a role for IGF-1R/PI3K-dependent survival in the development of resistance to BRAF inhibitors

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Phase 3, Randomized, 20-Month Study of the Efficacy and Safety of Bimatoprost Implant in Patients with Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 2)

Objective- To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10 and 15 µg bimatoprost implant in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Methods- This randomized, 20-month, multicenter, masked, parallel-group, phase 3 trial enrolled 528 patients with OAG or OHT and an open iridocorneal angle inferiorly in the study eye. Study eyes were administered 10 or 15 µg bimatoprost implant on day 1, week 16, and week 32, or twice-daily topical timolol maleate 0.5%. Primary endpoints were IOP and IOP change from baseline through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD). Results- Both 10 and 15 µg bimatoprost implant met the primary endpoint of noninferiority to timolol in IOP lowering through 12 weeks. Mean IOP reductions from baseline ranged from 6.2–7.4, 6.5–7.8, and 6.1–6.7 mmHg through week 12 in the 10 µg implant, 15 µg implant, and timolol groups, respectively. IOP lowering was similar after the second and third implant administrations. Probabilities of requiring no IOP-lowering treatment for 1 year after the third administration were 77.5% (10 µg implant) and 79.0% (15 µg implant). The most common TEAE was conjunctival hyperemia, typically temporally associated with the administration procedure. Corneal TEAEs of interest (primarily corneal endothelial cell loss, corneal edema, and corneal touch) were more frequent with the 15 than the 10 µg implant and generally were reported after repeated administrations. Loss in mean CECD from baseline to month 20 was ~ 5% in 10 µg implant-treated eyes and ~ 1% in topical timolol-treated eyes. Visual field progression (change in the mean deviation from baseline) was reduced in the 10 µg implant group compared with the timolol group. Conclusions- The results corroborated the previous phase 3 study of the bimatoprost implant. The bimatoprost implant met the primary endpoint and effectively lowered IOP. The majority of patients required no additional treatment for 12 months after the third administration. The benefit-risk assessment favored the 10 over the 15 µg implant. Studies evaluating other administration regimens with reduced risk of corneal events are ongoing. The bimatoprost implant has the potential to improve adherence and reduce treatment burden in glaucoma

Design and Construction of a Humanoid Robot Platform for Walking Gait Research

The desire to one day see a robot assistant cleaning our houses or walking our dogs has led to an increased interest into humanoid robotics research, and more specifically humanoid locomotion. At present, due to the high cost of robot platforms, there are only a small number of labs in the world conducting meaningful research on full sized humanoid robots. The existence of a low-cost humanoid platform would pave the way for greater involvement and development in the field of humanoid locomotion. This thesis describes the complete design and construction of an affordable humanoid robot platform for walking gait research, from the mechanical structure and actuator selection, right through to the required electronics and power storage implementation. The software required to operate the robot is discussed, from low-level feedback control through to high-level motion planning. The distributed nature of computational resources employed on this robot is outlined, along with the interaction with the robots sensors and actuators. A position based control methodology is proposed and implemented using traditional feedback loops on the robot. Control parameters were initially hand-tuned but subsequently improved via the implementation of an off-line evolutionary algorithm. Shortcomings in the mechanical design limited the success of this control scheme, with significant positional error observed in all joints whilst executing a walking gait. Actuator non-linearities as well as significant flexion in the underlying structure contributed to this positional error. To compensate, a series of adaptive control techniques were in turn amalgamated with the initial control loop in an attempt to learn the system dynamics of the robot and provide adequate compensatory signals. These additional control schemes realised a slightly improved level of accuracy in simulation in the joint control space but not enough to compensate for the robots significant mechanical flexion. Extensive hand tuning of algorithm parameters and excessive memory requirements prevented their implementation on the real robot. This robot competed at two international robot competitions with acceptable results. In 2002, the robot competed in the Humanoid League of RoboCup02, in Fukuoka, Japan. The robot was the largest competing humanoid by a considerable margin and it achieved a ranking of 7th in both the freestyle and walking distance category, out of the ten humanoids competing. In 2005 the robot competed in the RoboCup competition, this time in Osaka, reaching the semi-finals of the penalty shootout for robots over 650 mm in height. The final robot was capable of rudimentary walking and other simple movements such as penalty shootout soccer skills, validating the structures ability to withstand the forces required to execute a walking gait

Clinical implications of melanin expression in melanoma and molecular drivers of cutaneous squamous cell tumours

© 2013 Dr. Damien KeeMelanomas are derived from melanocytes – highly specialized pigment-producing cells residing in the basal layers of the skin. The majority of melanomas continue to produce melanin, presenting a potential disease specific biomarker, so far largely unexplored. This thesis begins by examining how melanin might be exploited as a melanoma specific target for molecular based imaging. The novel fluorinated, melanin-binding radiopharmaceutical, MEL050, is tested as a PET-tracer in ten patients with advanced melanoma. We establish MEL050 safety, and detail metabolism, radiopharmacokinetics and normal biodistribution. Diagnostic parameters are compared with a gold-standard of FDG PET/CT. Excellent specificity of 100% but more variable sensitivity is demonstrated. Overall sensitivity was 47%. In a subset of five patients who underwent resection of all known disease sites, histological assessment of tumour melanin correlated with MEL050 PET signal: 100% for melanotic tumours but 0% for amelanotic tumours. These findings suggested a high frequency of amelanotic metastases – an aspect of melanoma not well detailed in the literature. In order to validate melanin as a suitable target for melanoma imaging, but also to determine if changes in its expression may reflect clinically meaningful differences in underlying biology, we next examined melanoma melanin in two distinct clinical cohorts. In the first, amelanosis was evaluated in tumours from 253 patients with primary melanoma. 20% were macroscopically amelanotic. These tumours had a higher Breslow thickness (p < 0.001), were more likely to be ulcerated (p = 0.002), have increased mitoses (p < 0.001) and be BRAF wild-type (p < 0.001). In a multivariate survival analysis, amelanosis was associated with worse disease free survival (HR 2.3, p = 0.031) and disease specific survival (HR 2.5, p = 0.033). The second cohort examined patients with more advanced melanoma. 142 patients with stage IIIa melanoma had sentinel node tumours examined for novel markers of melanin and Ki-67. 45% of tumours were amelanotic by H&E and mean Ki-67 score was 29%. Sentinel node tumour melanin outperformed existing prognostic factors, however, contrary to in primary tumours, persistent melanin was associated with worse disease free (HR 2.1, p = 0.002) and disease specific survival (HR 3.6, p = 0.009). Furthermore, in matched biopsies from primary, regional and distant metastatic sites, the frequency of amelanosis was shown to increase with disease progression – although bidirectional phenotype switching was also observed. Finally, an interaction between molecular targeted therapies and cutaneous squamous cells in a subset of melanoma patients was explored. Using mass-spectrometric genotyping, mutations in cutaneous squamous cell tumours developing in RAF-inhibitor treated patients were compared with similar tumours developing spontaneously or in patients requiring immunosuppression. Treatment related tumours were enriched for RAS mutations (OR 8.0, p = 0.007) supporting a hypothesized proliferative interaction between RAF-inhibitors and RAS primed cells. Amalgamated findings suggest dynamic changes in melanogenesis make melanin an unsuitable target for diagnostic imaging. Clinicopathological and prognostic associations of amelanosis in the context of known regulatory pathways support a distinct phenotype worthy of further clinical exploration and biological characterization. Confirmation of a clinical interaction between RAF inhibitors and RAS activated cells provides strategies for anticipating and managing treatment related toxicities

Evolving a locus based gait for a humanoid robot

This paper describes a process for evolving a stable humanoid walking gait that is based around parameterised loci of motion. The parameters of the loci are chosen by an evolutionary process based on the criteria that the robot's ZMP (zero moment point) follows a desirable path. The paper illustrates the evolution of a straight line walking gait. The gait has been tested on a 1.2 m tall humanoid robot (GuRoo). The results, apart form illustrating a successful walk, illustrate the effectiveness of the ZMP path criterion in not only ensuring a stable walk, but also in achieving efficient use of the actuators