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

Palliative Medicines for Children – A New Frontier in Paediatric Research

Objectives: This paper seeks to highlight from a UK perspective the current lack of a research evidence base in paediatric palliative care that has resulted in a paucity of available medicines with appropriate formulations (strength and dosage form) to provide symptom management for children with life-limiting illnesses and to raise awareness of this group of “therapeutic orphans”. Currently, clinicians have limited, often unsuitable medication choices for their paediatric palliative care patients, with little hope of moving away from the status quo. / Key findings: Most medicines used in children receiving palliative care are old and off-patent drugs, developed for and tested in an adult population. Many are not available in suitable formulations (dosage form and strength) for administration to children and there are often no age-related profiles of adverse drug reactions or for safe dosing. / Summary: Existing regional paediatric palliative care networks and support organisations should lobby funding bodies and the academic community to support appropriate research for this group of therapeutic orphans. Support must also be provided to pharmaceutical companies in the development of suitable products with appropriate formulations

Fetal growth, birth size and energetic cost of gestation in southern right whales

The cost of reproduction greatly affects a species’ life history strategy. Baleen whales exhibit some of the fastest offspring growth rates in the animal kingdom. We quantified the energetic cost of gestation for southern right whales (Eubalaena australis) by combining whaling catch records of pregnant females with photogrammetry data on southern right whale mothers and calves from two breeding grounds in Argentina and Australia. The relationship between calf birth size and maternal length was determined from repeated measurements of individual females before and after giving birth. Fetal growth was determined from generalized linear models fitted to fetal length data from whaling operations between 1961 and 1967. Fetal length was converted to volume and mass, using the volume-to-length relationship of newborn southern right whales calves, and published tissue composition and energy content estimates. Fetal maintenance costs (heat of gestation) and the energy content of the placenta were predicted from published relationships and added to the fetal growth cost to calculate the total cost of gestation. Our findings showed that fetal growth rates and birth size increased linearly with maternal length, with calves being born at ∼35% maternal length. Fetal length increased curvilinearly through gestation, which resulted in an exponential increase in fetal volume and mass. Consequently, the cost of gestation was very low during the first (0.1% of total cost) and second trimester (4.9%), but increased rapidly during the last trimester (95.0%). The heat of gestation incurred the highest cost for pregnant females (73.8%), followed by fetal growth (21.2%) and the placental energy content (5.0%)

Large-scale 3-D modeling by integration of resistivity models and borehole data through inversion

We present an automatic method for parameterization of a 3-D model of the subsurface, integrating lithological information from boreholes with resistivity models through an inverse optimization, with the objective of further detailing of geological models, or as direct input into groundwater models. The parameter of interest is the clay fraction, expressed as the relative length of clay units in a depth interval. The clay fraction is obtained from lithological logs and the clay fraction from the resistivity is obtained by establishing a simple petrophysical relationship, a translator function, between resistivity and the clay fraction. Through inversion we use the lithological data and the resistivity data to determine the optimum spatially distributed translator function. Applying the translator function we get a 3-D clay fraction model, which holds information from the resistivity data set and the borehole data set in one variable. Finally, we use k-means clustering to generate a 3-D model of the subsurface structures. We apply the procedure to the Norsminde survey in Denmark, integrating approximately 700 boreholes and more than 100 000 resistivity models from an airborne survey in the parameterization of the 3-D model covering 156 km2. The final five-cluster 3-D model differentiates between clay materials and different high-resistivity materials from information held in the resistivity model and borehole observations, respectively

Resonant enhancement of the jump rate in a double-well potential

We study the overdamped dynamics of a Brownian particle in the double-well potential under the influence of an external periodic (AC) force with zero mean. We obtain a dependence of the jump rate on the frequency of the external force. The dependence shows a maximum at a certain driving frequency. We explain the phenomenon as a switching between different time scales of the system: interwell relaxation time (the mean residence time) and the intrawell relaxation time. Dependence of the resonant peak on the system parameters, namely the amplitude of the driving force A and the noise strength (temperature) D has been explored. We observe that the effect is well pronounced when A/D > 1 and if A/D 1 the enhancement of the jump rate can be of the order of magnitude with respect to the Kramers rate.Comment: Published in J. Phys. A: Math. Gen. 37 (2004) 6043-6051; 6 figure

Switching between dynamic states in intermediate-length Josephson junctions

The appearance of zero-field steps (ZFS’s) in the current-voltage characteristics of intermediate-length overlap-geometry Josephson tunnel junctions described by a perturbed sine-Gordon equation (PSGE) is associated with the growth of parametrically excited instabilities of the McCumber background curve (MCB). A linear stability analysis of a McCumber solution of the PSGE in the asymptotic linear region of the MCB and in the absence of magnetic field yields a Hill’s equation which predicts how the number, locations, and widths of the instability regions depend on the junction parameters. A numerical integration of the PSGE in terms of truncated series of time-dependent Fourier spatial modes verifies that the parametrically excited instabilities of the MCB evolve into the fluxon oscillations characteristic of the ZFS’s. An approximate analysis of the Fourier mode equations in the presence of a small magnetic field yields a field-dependent Hill’s equation which predicts that the major effect of such a field is to reduce the widths of the instability regions. Experimental measurements on Nb-NbxOy-Pb junctions of intermediate length, performed at different operating temperatures in order to vary the junction parameters and for various magnetic field values, verify the physical existence of switching from the MCB to the ZFS’s. Good qualitative, and in many cases quantitative, agreement between analytic, numerical, and experimental results is obtained