The rat model of global anoxia at birth has been used extensively to investigate effects of perinatal hypoxia on central nervous system function. Less research has characterized behavioural phenotypes resulting from birth hypoxia. Experiment 1 examined maternal behaviour (licking/grooming, retrieval) directed toward pups born vaginally (Vag), by caesarean section (CS) or by caesarean section with anoxia (CS+anox). Similar levels of maternal care were observed across all birth groups indicating that the sequelae of birth hypoxia in the rat are not mediated by differential postnatal maternal care. Experiment 2 investigated the effects of birth hypoxia on prepulse inhibition (PPI) and latent inhibition (LI), behaviours with clinical correlates in neurodevelopmental disorders. No differences were found in PPI or LI between Vag, CS or CS+anox groups at adulthood. Intriguingly, however, decreased freezing to the context was observed in CS and CS+anox rats suggesting that caesarean section birth may produce deficits in contextual learning.

The number of species of tapeworms readily available for laboratory control is quite limited. Two species in particular seem best suited for testing the interesting hypothesis propounded by Read, Simmons, Campbell and Rothman (1960). Hymenolepis diminuta, a cestode whose normal definitive host is the wild rat, grows quite well in both albino rats and hamsters, attaining a greater size in the former (Read and Voge, 1954). Hymenolepis citelli, a parasite of ground squirrels, is morphologically very similar to H. diminuta, and while it grows quite well in hamsters, growth and development is very poor in the albino rat (Read and Phifer, 1959). Thus, a knowledge of the characteristics of absorption of amino acids by the two worms, together with a knowledge of the amino acid mixtures characteristic of the intestines of different host species, will perhaps allow direct experimental testing of the hypothesis that these factors are involved in establishment and development of a tapeworm in a particular host species. It is apparent that we still know very little concerning amino acid absorption by Hymenolepis diminuta. The present study was designed to increase our understanding of this phenomenon, especially concerning the absorption of L-methionine by this cestode. Advantage was taken of the more adequate methods described by Read, Simmons and Rothman (1960) to overcome the defects in design of experiments performed by Daugherty (1957a, 1957b) and Daugherty and Foster (1958). In addition it was hoped that such a study would reveal whether the methods employed and the species studied would be suitable in undertaking experimentation designed to answer some fundamental questions concerning the ecological relationship called "parasitism", raised by our present knowledge of amino acid permeation into tapeworms.

Upon disruption of the integrity of the endothelial monolayer, smooth muscle cells (SMC) may be directly exposed to blood flow and their behavior may be modulated by the local hemodynamic environment. Furthermore, modeling studies indicate that in the normal vasculature, underlying SMC are exposed to significant shear stresses due to transmural interstitial flaw. To study the contribution of fluid shear stress to SMC growth and metabolism, cultured human aortic smooth muscle cells (hASMC) were subjected to physiological levels of shear stress using parallel plate flow chambers connected to recirculating flow loops. Fluid shear stress decreased the growth rate of hASMC. The cell number at high shear stress levels was significantly lower compared to low levels of shear stress and this was not a result of cell injury. These findings are consistent with in vivo observations in which it was found that areas of low shear stress were associated with greater intimal hyperplasia. Exposure of SMC to shear stress resulted in a rapid nitric oxide (NO) release which was followed by a sustained nitrite production, independent of the level of shear stress in the range of 5-25 dyn/cm$\sp2$. NO production was calcium dependent and was due to activation of a constitutive nitric oxide synthase (NOS) I. The constitutive expression of NOS in SMC and its concomitant activation by shear stress may play a regulatory role in the blood vessel wall in the absence of endothelium following vascular injury, and may also be important in normal vessel homeostasis. Shear stress differentially mediated the expression of thrombin receptor (TR) and tissue plasminogen activator (tPA) in hASMC. The upregulation of tPA and downregulation of TR mRNA and protein by high shear stress are consistent with the relative paucity of lesions in areas of high shear stress within the vasculature, while the downregulation of tPA and upregulation of TR mRNA by low shear stresses are consistent with the known predilection of low shear stress areas to thrombus formation and to vascular cell proliferation. The finding of a domain within the TR promoter that contains a potential shear responsive element offers new insights into these regulatory events.

Using immunocytochemical and electrophysiological methods, the effects of mutations in the structural gene for a calcium activated potassium channel, slowpoke (slo), in Drosophila melanogaster were studied. Anti-horseradish peroxidase was used to visualize the branching of the nerves innervating the body wall muscles. No differences are observed between slo and normal larvae. Defects in synaptic transmission at the neuromuscular junction were analyzed electrophysiologically. slo mutants show significant reductions in transmitter release. Also, slo mutations paired with hyperexcitable mutants (Shaker, ether a go go) and/or pharmacological agents (4-aminopyridine) significantly decrease the high amounts of transmitter release normally observed in these situations. Significant reductions in transmitter release caused by the slo mutation are only observed at low external calcium concentrations. This decrease in transmitter release may be due to reduced neuronal excitability conferred by the slo mutation.

A mathematical model of the external respiratory system is presented which integrates component models of airway mechanics and gas exchange at the pulmonary capillaries. The respiratory system is lumped into: (1) a conducting zone consisting of a rigid compartment in series with a collapsible segment, and (2) a respiratory zone consisting of respiratory bronchioles and alveolar sacs. Ventilation of the alveolar space is simulated by driving the airway mechanics model with a measured intrapleural pressure waveform obtained experimentally from a volunteer human subject in a clinical Pulmonary Function Laboratory (PFL). Capillary gas transfer is described using a one-dimensional spatially distributed model with transport of gas species between air in the alveoli and blood in the pulmonary capillaries driven by the species partial pressure gradient across the alveolar-capillary barrier. The effects of cyclic fluctuation of airflow upon the gas composition in the partitioned airway compartments, as well as within the pulmonary capillary, are simulated under conditions of tidal breathing, panting, and forced-vital capacity maneuvers. Simulation results compare favorably with experimental data on lung volume variation, air flow at the mouth, and expired $P\sb{CO\sb2}$ obtained during these maneuvers. Model-generated predictions for alveolar gas pressure, variation of gas composition in each airway compartment during breathing and species partial pressure profiles along the pulmonary capillary are calculated and compared with data obtained from a normal subject.

Endothelial cells line all of the vessels of the circulatory system, providing a non-thrombogenic conduit and form the principal barrier to the transport of substances between the blood and the surrounding tissue. The endothelial barrier is particularly important in the brain since neural function depends on the maintenance of a constant cererbro-spinal fluid composition. The changes in macromolecular permeability of brain microvessel (BMECs) and pulmonary artery (CPA-47s) endothelial cells subjected to fluid shear stress and the physiological mediators atrial natriuretic peptide (ANP) and thrombin were studied. Endothelial cells were grown on a permeable polycarbonate membrane and subjected to different biochemicals or shear stress. The permeability properties of the cells were quantitated by measuring the flux of labeled albumin or dextran that passed through the cell monolayer and the permeability coefficient (P) was calculated. The permeability coefficient of albumin for the BMECs (3.3 $\pm$ 0.2) nm/s was over an order of magnitude less than that of the CPA-47s (58 $\pm$ 4) nm/s. Addition of thrombin dramatically increased the permeability of both the cell types in a dose dependent manner and this effect was modulated by cyclic AMP in CPA-47s but not in BMECs. Neither ANP or cyclic GMP significantly altered thrombin's effect in either cell type. Ionophore A23187, or protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), both dramatically increased albumin permeability in both cell types in a dose dependent manner. PMA's effect was reversible over time and was inhibited by the PKC inhibitor H7 but not HA-1004. Shear stress of 1 dyne/cm$\sp2$ did not produce any large scale morphological changes in BMECs but did cause an increase in macromolecular permeability. Shear stress of 10 dynes/cm$\sp2$ induced the brain cells to take on a cobblestone morphology before elongating in the direction of flow. This higher shear stress level also induced an increase in macromolecular permeability that was maximal between 10 and 20 hours and returned to near baseline values after 60 hours in the shear field.

An existing model of the bursting neuron R15 in Aplysia has been modified to incorporate the effects of the neuromodulatory agents serotonin and dopamine upon the conductances of the subthreshold currents $I\sb{R}$ and $I\sb{SI}$. The model duplicates the various forms of behavior exhibited by R15 in vitro in the presence of serotonin or dopamine, implying that the modeled mechanisms are sufficient to evoke the varied behavioral patterns exhibited by R15. The response of the model to extrinsic stimuli is examined. Serotonin enhances the cell's response to current stimuli of either polarity, while dopamine reduces the cell's response. The model demonstrates bistable behavior, indicating that the model's current state of behavior is dependent upon past behavior and/or stimuli. A nullcline and bifurcation analysis upon reduced models explains the mechanism of bursting and the effects of serotonin and dopamine through the existence of saddle-node and Hopf bifurcations.

In social insect colonies workers realize their reproductive potential through rearing the queen's brood. In the primitively eusocial wasp Polistes exclamans (Hymenoptera: Vespidae) castes are not morphologically distinct. This species has an annual colony cycle that begins when mated, hibernated females start colonies in the spring. One foundress becomes the queen while the rest become workers. The worker population grows throughout the year until the appearance of gynes, females that do not work but become foundresses the following spring. Males are also produced by the end of the season, but they die in winter with the workers. While morphological caste differences are absent, caste can be identified using behavioral and physiological parameters. In contrast with other social insects, female caste remains undetermined until adulthood, and even then females switch between castes under the appropriate circumstances. This can be advantageous since high nest predation rates and unpredictable environmental variation, accompanied by frequent queen supersedure are typical. I studied three aspects of the P. exclamans caste system: (i) morphology and physiology in gynes and workers; (ii) seasonal resource allocation into brood and (iii) effects of brood loss on caste determination. Physiological indicators were derived from qualitative and quantitative studies of biochemical components, and from measurements of metabolic rates. I show that differences between castes are mostly quantitative, rather than qualitative. I suggest that lack of physical and qualitative differentiation is what allows caste transitions. Seasonal resource allocation on brood shows that while young, adult females produced throughout the season increase in weight and size, energy reserves lipids peak in May and June. I suggest that this peak in reserves is related to high predation experienced by colonies during that time and that it allows females to reconstruct their nests more efficiently. Finally, I examine effects of loss of brood in late summer and early fall colonies showing that females that do not have the opportunity to care for brood develop gyne-like characters, but that females that have develop worker-like characters. These results show that caste in P. exclamans is plastic, behaviorally and physiologically, allowing individuals to respond to varying environmental and social conditions.

The crystal structure of tropomyosin has been determined by X-ray diffraction analysis at 7A resolution. Tropomyosin is a 400A-long muscle regulatory protein that consists of two parallel 33,000 Dalton alpha helices wound around one another to form a coiled coil and whose amino-acid sequence is characterized by a characteristic heptad repeat pattern. The structure was solved initially at 9A resolution by molecular replacement and refinement of a uniform wire model with a specially designed refinement procedure. Phase information was later derived from a single mercury derivative by single isomorphous replacement (SIR) refinement and used in the construction of an atomic model which was refined at 7A resolution. The model agrees well with the previous low-resolution X-ray structure and with models of tropomyosin in paracrystalline and micro-crystalline forms based on electron microscopy. The overall shape of the molecules, characteristics of the coiled coil and the geometry of interactions of molecules in the crystal are apparent from the structure. The molecules are precipitated by spermine and polymerize head-to-tail to form sheets of nearly parallel filaments, overlapping by about 2/3 of the molecular length in an antiparallel configuration. The relationship of two cysteine residues on each of the molecules was determined unambiguously by solving the structure of a mercury-labeled form of the protein. The shape of the molecule is influenced by local amino-acid sequence variations and crystal packing interactions. The inherent mobility of the molecule in the crystal indicates the importance of considering the flexibility and motions of tropomyosin in models of muscle thin filament regulation and cooperativity. The detailed structure of the head-to-tail overlap region cannot be ascertained from the present model, but will be an important focus of attention for future study. Through amino-acid sequence analysis, an element of quaternary structure, the coiled coil, can be directly predicted. However, tropomyosin is the largest of this class of proteins whose structure has actually been determined by X-ray crystallography.

We have developed a mathematical model of the rabbit atrial myocyte in order to investigate the ionic bases of rate dependent changes in action potential (AP) wave-shape. Postulated mediators of such changes include rate dependencies of ionic currents (incomplete reactivation) and ionic concentration gradients. The model utilizes biophysical data to quantify the specific morphology and electrophysiology of the rabbit atrial cell. Ionic current descriptions incorporate whole-cell voltage-clamp data from enzymatically isolated rabbit cardiomyocytes, and account for the reactivation timecourse of the largest ionic currents. Our model can simulate both the whole-cell voltage-clamp data upon which it is based and the steady-state AP wave-shapes observed over a range of stimulus rates. It also predicts the intracellular $\lbrack Ca\sp{2+}\rbrack\sb{i}$-transient that accompanies the AP, the "premature stimulus" response, and the effect of rapid stimulation on the AP. These responses provide insight into the electrophysiological mediators of atrial refractoriness and arrhythmia.