Underwater shear-based grooming of marine biofouling using a non-contact Bernoulli pad device.

The biofouling removal ability of a shear-based device was tested on two submerged surface types, Garolite G-10 and Intersleek 1100SR. Each surface was groomed at four frequencies along with a control group. The seven-week grooming study was conducted in Narragansett Bay, Rhode Island. The Bernoulli pad device uses confined radial outflow to generate both surface-normal forces to grip the submerged surface and shear stress to groom the surface without contact. An image-processing algorithm was developed and used to assess the effectiveness of the various grooming protocols, along with direct measurements of chlorophyll a per surface area. The image-processing data showed that the grooming resulted in ∼50% cleanliness on the Garolite at the end of the study whereas the Intersleek was continuously restored to nearly its initial clean state. Chlorophyll a data supported these overall conclusions. These results indicate that surface cleanliness can be maintained effectively on Intersleek using frequent shear-based grooming.

Controlling a robotic arm for functional tasks using a wireless head-joystick: A case study of a child with congenital absence of upper and lower limbs.

Children with movement impairments needing assistive devices for activities of daily living often require novel methods for controlling these devices. Body-machine interfaces, which rely on body movements, are particularly well-suited for children as they are non-invasive and have high signal-to-noise ratios. Here, we examined the use of a head-joystick to enable a child with congenital absence of all four limbs to control a seven degree-of-freedom robotic arm. Head movements were measured with a wireless inertial measurement unit and used to control a robotic arm to perform two functional tasks-a drinking task and a block stacking task. The child practiced these tasks over multiple sessions; a control participant performed the same tasks with a manual joystick. Our results showed that the child was able to successfully perform both tasks, with movement times decreasing by ~40-50% over 6-8 sessions of training. The child's performance with the head-joystick was also comparable to the control participant using a manual joystick. These results demonstrate the potential of using head movements for the control of high degree-of-freedom tasks in children with limited movement repertoire.

Age-dependent differences in learning to control a robot arm using a body-machine interface.

Body-machine interfaces, i.e. interfaces that rely on body movements to control external assistive devices, have been proposed as a safe and robust means of achieving movement and mobility; however, how children learn these novel interfaces is poorly understood. Here we characterized the learning of a body-machine interface in young unimpaired adults, two groups of typically developing children (9-year and 12-year olds), and one child with congenital limb deficiency. Participants had to control the end-effector of a robot arm in 2D using movements of the shoulder and torso. Results showed a striking effect of age - children had much greater difficulty in learning the task compared to adults, with a majority of the 9-year old group unable to even complete the task. The 12-year olds also showed poorer task performance compared to adults (as measured by longer movement times and greater path lengths), which were associated with less effective search strategies. The child with congenital limb deficiency showed superior task performance compared to age-matched children, but had qualitatively distinct coordination strategies from the adults. Taken together, these results imply that children have difficulty learning non-intuitive interfaces and that the design of body-machine interfaces should account for these differences in pediatric populations.

PBPK Modeling - A Predictive, Eco-Friendly, Bio-Waiver Tool for Drug Research.

BACKGROUND: The world has witnessed growing complexities in disease scenario influenced by the drastic changes in host-pathogen- environment triadic relation. Pharmaceutical R&Ds are in constant search of novel therapeutic entities to hasten transition of drug molecules from lab bench to patient bedside. Extensive animal studies and human pharmacokinetics are still the "gold standard" in investigational new drug research and bio-equivalency studies. Apart from cost, time and ethical issues on animal experimentation, burning questions arise relating to ecological disturbances, environmental hazards and biodiversity issues. Grave concerns arises when the adverse outcomes of continued studies on one particular disease on environment gives rise to several other pathogenic agents finally complicating the total scenario. Thus Pharma R&Ds face a challenge to develop bio-waiver protocols. Lead optimization, drug candidate selection with favorable pharmacokinetics and pharmacodynamics, toxicity assessment are vital steps in drug development. METHODS: Simulation tools like Gastro Plus™, PK Sim®, SimCyp find applications for the purpose. Advanced technologies like organ-on-a chip or human-on-a chip where a 3D representation of human organs and systems can mimic the related processes and activities, thereby linking them to major features of human biology can be successfully incorporated in the drug development tool box. RESULTS: PBPK provides the State of Art to serve as an optional of animal experimentation. PBPK models can successfully bypass bio-equivalency studies, predict bioavailability, drug interactions and on hyphenation with in vitro-in vivo correlation can be extrapolated to humans thus serving as bio-waiver. CONCLUSION: PBPK can serve as an eco-friendly bio-waiver predictive tool in drug development.

Discovery and Preclinical Evaluation of BMS-711939, an Oxybenzylglycine Based PPARα Selective Agonist.

BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 µM) and PPARδ (EC50 > 100 µM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.

Body-machine interface for control of a screen cursor for a child with congenital absence of upper and lower limbs: a case report.

BACKGROUND: There has been a recent interest in the development of body-machine interfaces which allow individuals with motor impairments to control assistive devices using body movements. METHODS: In this case study, we report findings in the context of the development of such an interface for a 10-year old child with congenital absence of upper and lower limbs. The interface consisted of 4 wireless inertial measurement units (IMUs), which we used to map movements of the upper body to the position of a cursor on a screen. We examined the learning of a task in which the child had to move the cursor to specified targets on the screen as quickly as possible. In addition, we also determined the robustness of the interface by evaluating the child's performance in two different body postures. RESULTS: We found that the child was not only able to learn the task rapidly, but also showed superior performance when compared to typically developing children in the same age range. Moreover, task performance was comparable for the two different body postures, suggesting that the child was able to control the device in different postures without the need for interface recalibration. CONCLUSIONS: These results clearly establish the viability and robustness of the proposed non-invasive body-machine interface for pediatric populations with severe motor limitations.

Computational pharmacokinetics and in vitro-in vivo correlation of anti-diabetic synergistic phyto-composite blend.

Despite tremendous strides in modern medicine stringent control over insulin resistance or restoration of normoglycemia has not yet been achieved. With the growth of molecular biology, omics technologies, docking studies, and in silico pharmacology, modulators of enzymes and receptors affecting the molecular pathogenesis of the disease are being considered as the latest targets for anti-diabetic therapy. Therapeutic molecular targets are now being developed basing on the up or down regulation of different signaling pathways affecting the disease. Phytosynergistic anti-diabetic therapy is in vogue both with classical and non-classical medicinal systems. However its chemo-profiling, structural and pharmacokinetic validation awaits providing recognition to such formulations for international acceptance. Translational health research with its focus on benchside product development and its sequential transition to patient bedside puts the pharma RDs to a challenge to develop bio-waiver protocols. Pharmacokinetic simulation models and establishment of in vitro-in vivo correlation can help to replace in vivo bioavailability studies and provide means of quality control for scale up and post approval modification. This review attempts to bring different shades highlighting phyto-synergy, molecular targeting of antidiabetic agents via different signaling pathways and bio-waiver studies under a single umbrella.

Synthesis and structure-activity relationships of 2-aryl-4-oxazolylmethoxy benzylglycines and 2-aryl-4-thiazolylmethoxy benzylglycines as novel, potent PPARalpha selective activators- PPARalpha and PPARgamma selectivity modulation.

The synthesis and follow-up SAR studies of our development candidate 1 by incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy moieties into the oxybenzylglycine framework of the PPARalpha/gamma dual agonist muraglitazar is described. SAR studies indicate that different substituents on the aryloxazole/thiazole moieties as well as the choice of carbamate substituent on the glycine moiety can significantly modulate the selectivity of PPARalpha versus PPARgamma. Potent, highly selective PPARalpha activators 2a and 2l, as well as PPARalpha activators with significant PPARgamma activity, such as 2s, were identified. The in vivo pharmacology of these compounds in preclinical animal models as well as their ADME profiles are discussed.

Team science of nursing, engineering, statistics, and practitioner in the development of a robotic reflexology device.

The purpose of this article is to share the lessons learned in forming an interdisciplinary team that implements a team science approach to integrative medicine (IM) research. The disciplines of nursing, statistics, and engineering, along with consultants and a reflexology practitioner, formed this university-based team to conceptualize and develop a prototype robotic device for reflexology for breast cancer patients. The nurse investigator contributed the intervention background and access to the population; the statistician guided the team thinking on factors that needed to be controlled for; the engineers provided the expertise in device design and development; consultants facilitated the team's thinking in new directions; and the reflexology practitioner prescribed the protocol. We discuss the contributions and achievements of each discipline, as well as the challenges, and share the team experiences with the intent to help guide the formation of new IM teams that promote a conducive atmosphere for carrying out cutting-edge IM research and advancing the science.

Discovery of an oxybenzylglycine based peroxisome proliferator activated receptor alpha selective agonist 2-((3-((2-(4-chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic acid (BMS-687453).

An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC(50) of 10 nM for human PPARalpha and approximately 410-fold selectivity vs human PPARgamma in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARdelta. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARalpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARalpha in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.

Novel peroxisome proliferator-activated receptor alpha agonists lower low-density lipoprotein and triglycerides, raise high-density lipoprotein, and synergistically increase cholesterol excretion with a liver X receptor agonist.

The first generation peroxisome proliferator-activated receptor (PPAR) alpha agonist gemfibrozil reduces the risk of major cardiovascular events; therefore, more potent PPARalpha agonists for the treatment of cardiovascular diseases have been actively sought. We describe two novel, potent oxybenzylglycine PPARalpha-selective agonists, BMS-687453 [N-[[3-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methyl]-N-(methoxycarbonyl)-glycine] and BMS-711939 N-[[5-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]-2-fluorophenyl]methyl]-N-(methoxycarbonyl)-glycine], that robustly increase apolipoprotein (Apo) A1 and high-density lipoprotein cholesterol in human ApoA1 transgenic mice and lower low-density lipoprotein-cholesterol and triglycerides in fat-fed hamsters. These compounds have much lower potency against mouse PPARalpha than human PPARalpha; therefore, they were tested in PPARalpha-humanized mice that do not express murine PPARalpha but express human PPARalpha selectively in the liver. We developed hepatic gene induction as a novel biomarker for efficacy and demonstrate hepatic gene induction at very low doses of these compounds. BMS-711939 induces fecal cholesterol excretion, which is further increased upon cotreatment with a liver X receptor (LXR) agonist. It is surprising that this synergistic increase upon coadministration is also observed in mice that express PPARalpha in the liver only. BMS-711939 also prevented the LXR agonist-induced elevation of serum triglycerides. Such PPARalpha agonists could be attractive candidates to explore for the treatment of cardiovascular diseases, especially in combination with a suitable LXR agonist.

Comparing the mathematical models of Lighthill to the performance of a biomimetic fish.

The mathematical models for the performance of aquatic animals developed by M Lighthill are compared with the experimental performance of a biomimetic fish. The equations developed by Lighthill are evaluated at steady-state conditions. Equilibrium velocity and mechanical efficiency are calculated using Lighthill's mathematical model and compared with experimental results. In both cases, a pattern is found wherein an optimum combination of tail frequency and amplitude maximizes equilibrium velocity. Differences between the theoretical and experimental results are attributed to mechanical limitations in the drive train.

PPARs as targets for metabolic and cardiovascular diseases.

Peroxisome proliferator-activated receptors (PPARs) alpha, gamma and delta (beta) are ligand-activated transcription factors of the nuclear hormone receptor superfamily which have been shown to play key roles in maintaining glucose and lipid homeostasis. The physiological effects of several marketed drugs for the treatment of dyslipidemia (fenofibrate and gemfibrozil) and diabetes (rosiglitazone and pioglitazone) have now been shown to be mediated through PPARalpha and PPARgamma respectively. Over the past few years our understanding of how PPAR ligands and receptors modulate gene expression has greatly increased; this knowledge is being used to design even more potent and efficacious PPAR ligands for the treatment of diabetes, dyslipidemia, atherosclerosis and obesity. This review is a brief survey of the PPAR field which highlights recent progress, with an emphasis on new ligands with novel PPAR profiles, particularly compounds which are co-agonists of PPAalpha, gamma and beta (delta).

Raising HDL cholesterol without inducing hepatic steatosis and hypertriglyceridemia by a selective LXR modulator.

Liver X receptors (LXRs) are ligand-activated transcription factors that belong to the nuclear receptor superfamily. LXRs activate transcription of a spectrum of genes that regulate reverse cholesterol transport, including the ATP binding cassette transporter A1 (ABCA1), and raise HDL cholesterol (HDL-C) levels. However, LXR agonists also induce genes that stimulate lipogenesis, including the sterol response element binding protein (SREBP1-c) and fatty acid synthetase (FAS). The induction of these genes in the liver cause increased hepatic triglyceride synthesis, hypertriglyceridemia, and hepatic steatosis. As LXR response elements have been identified in these promoters, it is not clear if these two processes can be separated. Herein, we demonstrate that plasma HDL-C elevation and intestinal ABCA1 induction can occur with relatively little induction of FAS and SREBP1-c in mouse liver via a selective LXR modulator GW3965. This is in contrast to the strong induction of hepatic lipogenic genes by the well-characterized LXR agonist T0901317 (T317). Consistent with the in vivo results, GW3965 is a very weak LXR activator compared with T317 in human hepatoma cells. GW3965-liganded LXR recruits selected coactivators less effectively than T317 and may explain in part the tissue selective gene induction. This demonstration that tissue and gene selective modulation is possible with selective LXR modulators has positive implications for the development of this class of antiatherosclerotic agents.

Induction of endogenous genes by peroxisome proliferator activated receptor alpha ligands in a human kidney cell line and in vivo.

The peroxisome proliferator activated receptor alpha (PPARalpha) plays a key role in regulating fatty acid metabolism by regulating expression of genes involved in fatty acid oxidation. To identify endogenous transcripts that could be used as surrogate markers for on-target activity of PPARalpha agonists, we employed a global profiling approach using DNA microarrays. The HK-2 cell line derived from proximal tubules of the human kidney, showed induction of several genes, including pyruvate dehydrogenase kinase 4 (PDK-4) and adipocyte differentiation related protein (ADRP) by PPARalpha ligands. HK-2 cells express detectable levels of PPARalpha and its dimerization partner the retinoid X receptor (RXRalpha) proteins. Induction of PDK-4 in these cells correlates with induction of PDK-4 in the liver of fat-fed hamsters. The magnitude of fibrate induction of PDK-4 in the liver also mirrors the decrease in serum triglyceride levels. Thus, induction of PDK-4 by PPARalpha agonists in the HK-2 cell model closely correlates with its induction in vivo and may represent an early marker for PPARalpha agonist action.

Retinoid X receptor (RXR) agonist-induced antagonism of farnesoid X receptor (FXR) activity due to absence of coactivator recruitment and decreased DNA binding.

The bile salt export pump (BSEP) plays an integral role in lipid homeostasis by regulating the canalicular excretion of bile acids. Induction of BSEP gene expression is mediated by the farnesoid X receptor (FXR), which binds as a heterodimer with the retinoid X receptor (RXR) to the FXR response element (FXRE) located upstream of the BSEP gene. RXR ligands mimic several partner ligands and show additive effects upon coadministration. Using real-time quantitative PCR and cotransfection reporter assays, we demonstrate that the RXR agonist LG100268 antagonizes induction of BSEP expression mediated by endogenous and synthetic FXR ligands, CDCA and GW4064, respectively. Moreover, this antagonism is a general feature of RXR agonists and is attributed to a decrease in binding of FXR/RXR heterodimers to the BSEP-FXRE coupled with the inability of RXR agonists to recruit coactivators to FXR/RXR. Our data suggest that FXR/RXR is a conditionally permissive heterodimer and is the first example of RXR ligand-mediated antagonism of FXR activity. Because FXR agonists lower triglyceride levels, our results suggest a novel role for RXR-mediated antagonism of FXR activity in the development of hypertriglyceridemia observed with RXR agonists in rodents and humans.

Ligand and coactivator recruitment preferences of peroxisome proliferator activated receptor alpha.

The mechanism by which ligands of nuclear receptors show differential effects on gene transcription is not fully understood, but is believed to result in part from the preferential recruitment and/or displacement of coactivators and corepressors. We have explored the interaction of several known ligands and the nuclear receptor (peroxisome proliferator activated receptor alpha, PPARalpha) using scintillation proximity assay (SPA) and the interaction of LXXLL containing peptides derived from three coactivators (SRC-1, CBP and PGC-1) with PPARalpha in the presence of PPARalpha agonist ligands using fluorescence resonance energy transfer (FRET). The EC(50)s of the individual ligands for recruitment showed the same rank order regardless of the coactivator peptide used, with GW2331