Synthesis of novel nitric oxide (NO)-releasing esters of timolol

A novel class of timolol derivatives with nitric oxide (NO)-donating moieties achieved chemical stability yet under physiologically relevant conditions released timolol and NO. Hindered esters A were designed and synthesized, whose ‘triggered’ release relied on enzymatic hydrolysis of the nitrate ester in A to B, that in turn cyclized to liberate timolol.     

Visual Feedback Dominates the Sense of Agency for Brain-Machine Actions

Recent advances in neuroscience and engineering have led to the development of technologies that permit the control of external devices through real-time decoding of brain activity (brain-machine interfaces; BMI). Though the feeling of controlling bodily movements (sense of agency; SOA) has been well studied and a number of well-defined sensorimotor and cognitive mechanisms have been put forth, very little is known about the SOA for BMI-actions. Using an on-line BMI, and verifying that our subjects achieved a reasonable level of control, we sought to describe the SOA for BMI-mediated actions. Our results demonstrate that discrepancies between decoded neural activity and its resultant real-time sensory feedback are associated with a decrease in the SOA, similar to SOA mechanisms proposed for bodily actions. However, if the feedback discrepancy serves to correct a poorly controlled BMI-action, then the SOA can be high and can increase with increasing discrepancy, demonstrating the dominance of visual feedback on the SOA. Taken together, our results suggest that bodily and BMI-actions rely on common mechanisms of sensorimotor integration for agency judgments, but that visual feedback dominates the SOA in the absence of overt bodily movements or proprioceptive feedback, however erroneous the visual feedback may be.     

Effect of pyrithiamine treatment on potassium ion fluxes in rat cortical slices

The effect of thiamine deficiency on energy-requiring processes in brain tissue was studied by comparing cortical slices prepared from control and pyrithiamine-treated rats. Veratridine was used to stimulate energy metabolism by opening voltage-sensitive sodium channels resulting in enhanced Na+/K+ pumping; subsequent tetrodotoxin addition closed the sodium channels. Pyrithiamine-treated slices showed both lower basal and veratridine-stimulated respiration rates compared to control slices. K+ was released from the tissue upon addition of veratridine and was taken up again upon addition of tetrodotoxin. The movement of K+ was monitored directly with a K+-sensitive electrode as well as by measuring the rubidium diffusion potential. There was no difference between control and pyrithiamine-treated slices in K+ fluxes in response to veratridine and tetrodotoxin. The extent of reuptake of K+ upon tetrodotoxin addition was inversely related to the extracellular Ca2+ concentration and to the incubation temperature. Veratridine resulted in a marked decrease in tissue levels of ATP and creatine phosphate; these levels remained quite low upon tetrodotoxin addition. Despite the different respiration rates, control and pyrithiamine-treated slices showed the same ATP and creatine phosphate levels in response to veratridine and tetrodotoxin.     

The subunit structure of the hemocyanin from the crayfish Jasus edwardsii.

The hemocyanin from the crayfish Jasus edwardsii(=lalandii) has been studied using ultracentrifugation, viscosity, circular dichroism and oxygen binding techniques. Sedimentation velocity experiments at pH 7.0 indicated the presence of principal species with S 20w=16.4 S, and at higher pH the presence of a species with S20,w=5.2S. Sedimentation equilibrium experiments yielded molecular weights of 490 000 and 81 000 respectively, indicating that the larger unit is a hexamer of the monomer unit. However, preliminary experiments with gel filtration and electrophoresis under denaturing conditions indicate that more than one monomer species may be present with molecular weight in the range 76-100 000. Circular dichroism (CD) spectra are presented at pH 7.0,8.6,10.0 and 11.0 for oxy-, deoxy- and apo-hemocyanins. Slight differences were observed in the magnitude of the bands in the presence or absence of Mg++. Oxygen binding studies have been made at pH 6.1,7.0,8.8 and 10.6, in the presence of 0.01 M MgCl2. The extent of cooperative binding was indicated by a maximum value of n=3.7, and a pronounced bohr effect was observed.     

Absorption of isophane (NPH) insulin and its clinical implications.

Absorption of 125I-NPH insulin (125I-isophane insulin) (40 IU/ml) was studied in eight diabetics given 50% and 150% of their normal daily dose of insulin. Insulin absorption correlated with plasma insulin (r = 0.97, p less than 0.001) and blood glucose (r = -0.87, p less than 0.01) concentrations. Absorption was slower at higher doses, so that trebling the insulin dose only doubled the amount absorbed over the first 24 hours. The plasma elimination half time (t12) of insulin was about five minutes. Thus, the disappearance of radiolabelled insulin is a reliable and quantitative index of insulin absorption; subcutaneous degradation, if present, is minimal and constant. Changes in dise of intermediate-acting insulin further increases the large variation in insulin absorption. This implies that minor adjustments of intermediate insulin dosage are probably futile.