Discovery of TUG-770: a highly potent free fatty acid receptor 1 (FFA1/GPR40) agonist for treatment of type 2 diabetes

Free fatty acid receptor 1 (FFA1 or GPR40) enhances glucose-stimulated insulin secretion from pancreatic β-cells and currently attracts high interest as a new target for the treatment of type 2 diabetes. We here report the discovery of a highly potent FFA1 agonist with favorable physicochemical and pharmacokinetic properties. The compound efficiently normalizes glucose tolerance in diet-induced obese mice, an effect that is fully sustained after 29 days of chronic dosing

Measuring the effect of whalewatching boats on minke whale behavioural budget using a multivariate hidden Markov model

Human disturbances of wildlife, such as tourism, can alter the activities of targeted individuals. Repeated behavioural disruptions can have long-term consequences on individual's vital rates. To manage these sub-lethal impacts, we need to understand how activity disruptions can influence variation in individual's vital rates. This study informs the mechanistic links between whalewatching boat exposure and behavioural variation and vital rates for Mysticetes. We compared Minke whale Balaenoptera acutorostrata behaviour on a feeding ground in the presence and absence of whalewatching boats in Iceland, using individual focal follows. Activity states were inferred from movement metric data and multi-state models were used to estimate the relative proportion of different activity states. Spatially explicit mark-recapture models were used to estimate the seasonal exposure rate of individual whales to whalewatching activities. Whalewatching interactions disrupted the foraging behaviour of Minke whales, causing a decrease in proportion of time whales spent foraging. The cumulative exposure was sufficiently large to cause changes in the animal's seasonal behavioural budget. Minke whales are capital breeders, so a decrease in foraging success on feeding grounds due to whalewatching could lead to a decrease in energy available for lactation on breeding grounds, which could have negative effects on calf survival

Mineralization of an Axially Aligned Collagenous Matrix: A Morphological Study

Bone can be described as a highly ordered composite of type I collagen integrated with an inorganic mineral phase. In vitro models of bone mineralization using collagenous substrates have been reported in the literature. This study reports an in vitro system of mineralized reconstituted collagen fibers, with aligned fibrillar substructure. The collagen fibers were mineralized in a double diffusion chamber saturated with respect to calcium and phosphate. The morphology and ultrastructure of the mineral precipitate were evaluated as a function of the pH of the incubating media. Brushite crystal was observed at acidic pH. Large rectangular crystals formed at pH 5.15 and appear to associate with the collagen fibers. At neutral and alkaline pHs, hydroxyapatite crystals were observed in association with the collagen fibers . Spherical aggregates of hydroxyapatite crystals were seen at neutral and alkaline pHs, but these structures were reduced in size when formed on collagen at alkaline pH. On close examination these spherical structures were found to be hollow when viewed in cross section. The crystals precipitated within the interior of the collagen fiber at neutral and alkaline pHs were comparable in both size and shape to crystals observed in mineralized turkey tendon and skeletal tissues. These preliminary observations indicate that with further refinement the reconstituted collagen fibers may prove useful in model systems for the study of collagen mediated mineralization in vitro. In addition, mineralization of collagenous matrices may lead to the development of biomaterials for bone repair and replacement

Computing Lyapunov spectra with continuous Gram-Schmidt orthonormalization

We present a straightforward and reliable continuous method for computing the full or a partial Lyapunov spectrum associated with a dynamical system specified by a set of differential equations. We do this by introducing a stability parameter beta>0 and augmenting the dynamical system with an orthonormal k-dimensional frame and a Lyapunov vector such that the frame is continuously Gram-Schmidt orthonormalized and at most linear growth of the dynamical variables is involved. We prove that the method is strongly stable when beta > -lambda_k where lambda_k is the k'th Lyapunov exponent in descending order and we show through examples how the method is implemented. It extends many previous results.Comment: 14 pages, 10 PS figures, ioplppt.sty, iopl12.sty, epsfig.sty 44 k

The ensemble of random Markov matrices

The ensemble of random Markov matrices is introduced as a set of Markov or stochastic matrices with the maximal Shannon entropy. The statistical properties of the stationary distribution pi, the average entropy growth rate $h$ and the second largest eigenvalue nu across the ensemble are studied. It is shown and heuristically proven that the entropy growth-rate and second largest eigenvalue of Markov matrices scale in average with dimension of matrices d as h ~ log(O(d)) and nu ~ d^(-1/2), respectively, yielding the asymptotic relation h tau_c ~ 1/2 between entropy h and correlation decay time tau_c = -1/log|nu| . Additionally, the correlation between h and and tau_c is analysed and is decreasing with increasing dimension d.Comment: 12 pages, 6 figur

Schematics of a Water Balloon Launcher Design and Reproducible Water-Balloon-Filling Procedures Used for a Middle School Summer Science Camp

We recently held a Science Summer Camp for middle school students, designed to infuse young people with increased excitement for STEM (Science, Technology, Engineering, and Math) subjects. Our efforts, which received nationally-syndicated news coverage,1 included the invention of a versatile water balloon launcher. This document contains: (1) detailed construction schematics and user operation guidelines for our balloon launcher; (2) data and instructions for reproducibly filling water balloons to specific volumes and weights, within used by students during the summer camp

Non-integrability of the mixmaster universe

We comment on an analysis by Contopoulos et al. which demonstrates that the governing six-dimensional Einstein equations for the mixmaster space-time metric pass the ARS or reduced Painlev\'{e} test. We note that this is the case irrespective of the value, $I$, of the generating Hamiltonian which is a constant of motion. For $I < 0$ we find numerous closed orbits with two unstable eigenvalues strongly indicating that there cannot exist two additional first integrals apart from the Hamiltonian and thus that the system, at least for this case, is very likely not integrable. In addition, we present numerical evidence that the average Lyapunov exponent nevertheless vanishes. The model is thus a very interesting example of a Hamiltonian dynamical system, which is likely non-integrable yet passes the reduced Painlev\'{e} test.Comment: 11 pages LaTeX in J.Phys.A style (ioplppt.sty) + 6 PostScript figures compressed and uuencoded with uufiles. Revised version to appear in J Phys.

A numerical study of infinitely renormalizable area-preserving maps

It has been shown in (Gaidashev et al, 2010) and (Gaidashev et al, 2011) that infinitely renormalizable area-preserving maps admit invariant Cantor sets with a maximal Lyapunov exponent equal to zero. Furthermore, the dynamics on these Cantor sets for any two infinitely renormalizable maps is conjugated by a transformation that extends to a differentiable function whose derivative is Holder continuous of exponent alpha>0. In this paper we investigate numerically the specific value of alpha. We also present numerical evidence that the normalized derivative cocycle with the base dynamics in the Cantor set is ergodic. Finally, we compute renormalization eigenvalues to a high accuracy to support a conjecture that the renormalization spectrum is real

Failure Mechanisms of Ni-H2 and Li-Ion Batteries Under Hypervelocity Impacts

Lithium-Ion (Li-Ion) batteries have yielded significant performance advantages for many industries, including the aerospace industry, and have been selected to replace nickel hydrogen (Ni-H2) batteries for the International Space Station (ISS) program to meet the energy storage demands. As the ISS uses its vast solar arrays to generate its power, the solar arrays meet their sunlit power demands and supply excess power to battery packs for power delivery on the sun obscured phase of the approximate 90 minute low Earth orbit. These large battery packs are located on the exterior of the ISS, and as such, the battery packs are exposed to external environment threats like naturally occurring meteoroids and artificial orbital debris (MMOD). While the risks from these solid particle environments has been known and addressed to an acceptable risk of failure through shield design, it is not possible to completely eliminate the risk of loss of these assets on orbit due to MMOD, and as such, failure consequences to the ISS have been considered

Investigation of MMOD Impact on STS-115 Shuttle Payload Bay Door Radiator

The Orbiter radiator system consists of eight individual 4.6 m x 3.2 m panels located with four on each payload bay door. Forward panels #1 and #2 are 2.3 cm thick while the aft panels #3 and #4 have a smaller overall thickness of 1.3 cm. The honeycomb radiator panels consist of 0.028 cm thick Aluminum 2024-T81 facesheets and Al5056-H39 cores. The face-sheets are topped with 0.005 in. (0.127 mm) silver-Teflon tape. The radiators are located on the inside of the shuttle payload bay doors, which are closed during ascent and reentry, limiting damage to the on-orbit portion of the mission. Post-flight inspections at the Kennedy Space Center (KSC) following the STS-115 mission revealed a large micrometeoroid/orbital debris (MMOD) impact near the hinge line on the #4 starboard payload bay door radiator panel. The features of this impact make it the largest ever recorded on an orbiter payload bay door radiator. The general location of the damage site and the adjacent radiator panels can be seen in Figure 2. Initial measurements of the defect indicated that the hole in the facesheet was 0.108 in. (2.74 mm) in diameter. Figure 3 shows an image of the front side damage. Subsequent observations revealed exit damage on the rear facesheet. Impact damage features on the rear facesheet included a 0.03 in. diameter hole (0.76 mm), a approx.0.05 in. tall bulge (approx.1.3 mm), and a larger approx.0.2 in. tall bulge (approx.5.1 mm) that exhibited a crack over 0.27 in. (6.8 mm) long. A large approx.1 in. (25 mm) diameter region of the honeycomb core was also damaged. Refer to Figure 4 for an image of the backside damage to the panel. No damage was found on thermal blankets or payload bay door structure under the radiator panel. Figure 5 shows the front facesheet with the thermal tape removed. Ultrasound examination indicated a maximum facesheet debond extent of approximately 1 in. (25 mm) from the entry hole. X-ray examinations revealed damage to an estimated 31 honeycomb cells with an extent of 0.85 in. x 1.1 in. (21.6 x 27.9 mm). Pieces of the radiator at and surrounding the impact site were recovered during the repair procedures at KSC. They included the thermal tape, front facesheet, honeycomb core, and rear facesheet. These articles were examined at JSC using a scanning electron microscope (SEM) with an energy dispersive x-ray spectrometer (EDS). Figure 6 shows SEM images of the entry hole in the facesheet. The asymmetric height of the lip may be attributed to projectile shape and impact angle. Numerous instances of a glass-fiber organic matrix composite were observed in the facesheet tape sample. The fibers were approximately 10 micrometers in diameter and variable lengths. EDS analysis indicated a composition of Mg, Ca, Al, Si, and O. Figures 7 and 8 present images of the fiber bundles, which were believed to be circuit board material based on similarity in fiber diameter, orientation, consistency, and composition. A test program was initiated in an attempt to simulate the observed damage to the radiator facesheet and honeycomb. Twelve test shots were performed using projectiles cut from a 1.6 mm thick fiberglass circuit board substrate panel. Results from test HITF07017, shown in figures 9 and 10, correlates with the observed impact features reasonably well. The test was performed at 4.14 km/sec with an impact angle of 45 degrees using a cylindrical projectile with a diameter and length of 1.25 mm. The fiberglass circuit board material had a density of 1.65 g/cu cm, giving a projectile mass of 2.53 mg. An analysis was performed using the Bumper code to estimate the probability of impact to the shuttle from a 1.25 mm diameter particle. Table 1 shows a 1.6% chance (impact odds = 1 in 62) of a 1.25 mm or larger MMOD impact on the radiators of the vehicle during a typical ISS mission. There is a 0.4% chance (impact odds = 1 in 260) that a 1.25 mm or larger MMOD particle would impact the RCC wing leading edge and nose cap during a typical miion. Figure 11 illustrates the vulnerable areas of the wing leading edge reinforced carbon-carbon (RCC), an area of the vehicle that is very sensitive to impact damage. The highlighted red, orange, yellow, and light green areas would be expected to experience critical damage if impacted by an OD particle such as the one that hit the RH4 radiator panel on STS-115