The singularly perturbed Hodgkin-Huxley equations as a tool for the analysis of repetitive nerve activity

A qualitative analysis of the Hodgkin-Huxley model (Hodgkin and Huxley 1952), which closely mimics the ionic processes at a real nerve membrane, is performed by means of a singular perturbation theory. This was achieved by introducing a perturbation parameter that, if decreased, speeds up the fast variables of the Hodgkin-Huxley equations (membrane potential and sodium activation), whereas it does not affect the slow variables (sodium inactivation and potassium activation). In the most extreme case, if the perturbation parameter is set to zero, the original four-dimensional system degenerates to a system with only two differential equations. This degenerate system is easier to analyze and much more intuitive than the original Hodgkin-Huxley equations. It shows, like the original model, an infinite train of action potentials if stimulated by an input current in a suitable range. Additionally, explanations for the increased sensitivity to depolarizing current steps that precedes an action potential can be found by analysis of the degenerate system. Using the theory of Mishchenko and Rozov (1980) it is shown that the degenerate system does not only represent a simplification of the original Hodgkin-Huxley equations but also gives a valid approximation of the original model at least for stimulating currents that are constant within a suitable range.     

Haptic discrimination of size and texture in squirrel monkeys (Saimiri sciureus)

The present study analyzed haptic abilities of four squirrel monkeys. Using a two-alternative forced-choice procedure, stimuli were presented in a visually opaque box, allowing unrestrained test subjects to grab through a small opening and touch the discriminanda. Difference thresholds were determined by a modified method of limits. In the first experiment we determined size difference thresholds for the discrimination of circular cylinders using standard stimuli differing in diameter from 10 mm to 35 mm. In the second experiment a texture difference threshold was obtained for the discrimination of grooved surfaces (groove width 2-7 mm). The squirrel monkeys achieved a mean size difference threshold of 8% stimulus difference. The linear increase of absolute thresholds as a function of the starting stimulus size showed that haptic size discriminations in squirrel monkeys correspond to Weber's law. Three of the animals achieved a texture difference of 10% stimulus difference, while one monkey showed a distinctively lower haptic acuity. An analysis of the exploratory behavior points to a subject-related difference in the significance of cutaneous and kinesthetic information during size discriminations. Whereas differences in the animals' exploratory behavior did not correlate with the size difference threshold a subject achieved, different thresholds for texture discrimination can be explained by the different exploratory procedures the monkeys used to touch grooved surfaces. The low difference thresholds determined for the squirrel monkeys in the present study point to the significance of unrestrained test conditions for the assessment of the haptic capacity of a species.     

Novel purine and pyrazolo[3,4-d]pyrimidine inhibitors of PI3 kinase-α: Hit to lead studies

Series of purine and pyrazolo[3,4-d]pyrimidine inhibitors of phosphatidylinositol-3-kinases (PI3K) have been prepared. The optimized purine inhibitors show good potency in a PI3K p110α (PI3K-α) fluorescence polarization assay with good selectivity versus PI3K p110γ (PI3K-γ) and the mammalian target of rapamycin (mTOR). The related pyrazolo[3,4-d]pyrimidines show potent PI3K-α and mTOR inhibition with good selectivity versus PI3K-γ. Representative compounds showed activity in a cellular proliferation assay against Caco-2 colorectal, LoVo colorectal and PC3MM2 prostate adenocarcinoma cancer cells. Signaling through the PI3K pathway was confirmed via inhibition of phospho-AKT in MDA-361 cells.     

PKI-179: An orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor

A series of mono-morpholino 1,3,5-triazine derivatives (8a–8q) bearing a 3-oxa-8-azabicyclo[3.2.1]octane were prepared and evaluated for PI3-kinase/mTOR activity. Replacement of one of the bis-morpholines in lead compound 1 (PKI-587) with 3-oxa-8-azabicyclo[3.2.1]octane and reduction of the molecular weight yielded 8m (PKI-179), an orally efficacious dual PI3-kinase/mTOR inhibitor. The in vitro activity, in vivo efficacy, and PK properties of 8m are discussed.     

Aerial visual acuity in harbor seals (<Emphasis Type="Italic">Phoca vitulina</Emphasis>) as a function of luminance

In this study, we measured aerial visual acuity in harbor seals. As a first approach to the hypothesis that harbor seals can obtain acute aerial visual acuity mediated by the interaction of the vertical slit-shaped pupil and the corneal flattening although refractive measurements had revealed aerial myopia, visual acuity was tested as a function of luminance and pupil dilation. We analyzed aerial visual acuity (minimal resolvable stripe width) in three harbor seals in a two-alternative-forced-choice discrimination experiment. Our results further support the hypothesis that harbor seals possess an aerial visual acuity comparable to the acuity in clear waters if the vertical slit pupil does not exceed the zone of corneal flattening in bright light. When the pupil dilates with decreasing luminance, visual acuity decreases which might be due to deflected light from the stronger curved peripheral cornea.     

High olfactory sensitivity for dimethyl sulphide in harbour seals

Productive areas are patchily distributed at sea and represent important feeding grounds for many marine organisms. Although pinnipeds are known to travel on direct routes and return regularly to particular feeding sites, the environmental information seals use to perform this navigation is as yet unknown. As atmospheric dimethyl sulphide (DMS) has been demonstrated to be a reliable indicator for profitable foraging areas, we tested seals for their ability to smell DMS at concentrations typical for the marine environment. Using a go/no-go response paradigm we determined the DMS detection threshold in two harbour seals (Phoca vitulina vitulina). DMS stimuli from 8.05 x 108 to 8 pmol (DMS)m(-3)(air) were tested against a control stimulus using a custom-made olfactometer. DMS-thresholds determined for both seals (20 and 13 pmol m(-3)) indicate that seals can detect ambient concentrations associated with high primary productivity, e.g. in the North Atlantic. Thus, seals possess an extraordinarily high olfactory sensitivity for DMS, which could provide a sensory basis for identifying or orienting to profitable foraging grounds.     

Tactile size discrimination by a California sea lion (Zalophus californianus) using its mystacial vibrissae

The capability of a blindfolded California sea lion (Zalophus californianus) to discriminate diameter differences of circular discs by means of active touch with its mystacial vibrissae was studied. Using a forced choice paradigm the sea lion was required to choose the larger of two simultaneously presented perspex discs. Absolute difference thresholds (D) were determined for 3 standard discs (1.12 cm Ø, 2.52 cm Ø, 8.74 cm Ø) by the psychophysical method of constants. Increasing disc size resulted in an increase in the absolute difference threshold from 0.33 cm for the smallest disc size to 1.55 cm for the largest disc size. The relative difference threshold (Weber fraction) remained approximately constant at a mean value of 0.26. According to a video analysis the sea lion did not move its vibrissae when touching the discs. Instead, it performed precisely controlled lateral head movements, with the touched disc located centrally between the vibrissae of both sides of the muzzle. Since the extent of these head movements was identical at discs to be compared, discs of different size must have led to different degrees of deflection of vibrissae involved in the tactile process, resulting in quantitatively different mechanical stimulations of mechanoreceptors in the follicles. This suggests that the accuracy of the sea lion's size discrimination was determined by the efficiency of two sensory systems: the mechanosensitivity of follicle receptors as well as kinaesthesis.Abbreviations D starting stimulus size - D _i size of the interpolated comparison disc at 75% correct choices - D absolute difference threshold     

Hydrodynamic perception in true seals (Phocidae) and eared seals (Otariidae)

Pinnipeds, that is true seals (Phocidae), eared seals (Otariidae), and walruses (Odobenidae), possess highly developed vibrissal systems for mechanoreception. They can use their vibrissae to detect and discriminate objects by direct touch. At least in Phocidae and Otariidae, the vibrissae can also be used to detect and analyse water movements. Here, we review what is known about this ability, known as hydrodynamic perception, in pinnipeds. Hydrodynamic perception in pinnipeds developed convergently to the hydrodynamic perception with the lateral line system in fish and the sensory hairs in crustaceans. So far two species of pinnipeds, the harbour seal (Phoca vitulina) representing the Phocidae and the California sea lion (Zalophus californianus) representing the Otariidae, have been studied for their ability to detect local water movements (dipole stimuli) and to follow hydrodynamic trails, that is the water movements left behind by objects that have passed by at an earlier point in time. Both species are highly sensitive to dipole stimuli and can follow hydrodynamic trails accurately. In the individuals tested, California sea lions were clearly more sensitive to dipole stimuli than harbour seals, and harbour seals showed a superior trail following ability as compared to California sea lions. Harbour seals have also been shown to derive additional information from hydrodynamic trails, such as motion direction, size and shape of the object that caused the trail (California sea lions have not yet been tested). The peculiar undulated shape of the harbour seals’ vibrissae appears to play a crucial role in trail following, as it suppresses self-generated noise while the animal is swimming.     

Contrast sensitivity in a harbor seal (<Emphasis Type="Italic">Phoca vitulina</Emphasis>)

In this study, the contrast sensitivity function (CSF) of one harbor seal was determined behaviorally in a go-/no-go-experiment at an ambient light of 0.9 lx in air. Contrast sensitivity was assessed as the reciprocal value of the threshold contrast for spatial frequencies varying between 0.03 and 1.5 cycles/deg, which were displayed with contrast ranging from 0.02 to 1 on a TFT monitor with a mean luminance of 3.8 cd/m2. The CSF of the harbor seal shows the general characteristics described for other species with a peak at an intermediate frequency, a low frequency roll-off and a high frequency cut-off towards the harbor seal’s resolution limit determined in a previous study. The position of the CSF’s peak lies at approximately 0.5 cycles/deg and adopts an absolute height of 40. These results compare well with the cat’s CSF assessed at a comparable adaptation light which might reflect similarities in lifestyle and optics.