des -Formylflustrabromine (dFBr; 1), perhaps the first selective positive allosteric modulator of α4β2 neuronal nicotinic acetylcholine (nACh) receptors, was deconstructed to determine which structural features contribute to its actions on receptors expressed in Xenopus ooycytes using 2-electrode voltage clamp techniques. Although the intact structure of 1 was found optimal, several deconstructed analogs retained activity. Neither the 6-bromo substituent nor the entire 2-position chain is required for activity. In particular, reduction of the olefinic side chain of 1, as seen with 6, not only resulted in retention of activity/potency but in enhanced selectivity for α4β2 versus α7 nACh receptors. Pharmacophoric features for the allosteric modulation of α4β2 nACh receptors by 1 were identified.

This study reports an online temperature correction method for determining tissue oxygen partial pressure (P t O 2 ) in the striatum and a novel simultaneous measurement of brain P t O 2 and temperature (T brain ) in conjunction with global oxygen consumption (VO 2 ) in non-sedated and non-anesthetized freely moving Arctic ground squirrels (AGS, Spermophilus parryii). This method fills an important research gap-the lack of a suitable method for physiologic studies of tissue P O2 in hibernating or other cool-blooded species. P t O 2 in AGS brain during euthermy (21.22 ± 2.06 mm Hg) is significantly higher (P=0.016) than during hibernation (13.21 ± 0.46 mm Hg) suggests brain oxygenation in the striatum is normoxic during euthermy and hypoxic during hibernation. These results in P t O 2 are different from blood oxygen partial pressure (PaO 2 ) in AGS, which are significantly lower during euthermy than during hibernation and are actually hypoxic during euthermy and normoxic during hibernation in our previous study. This intriguing difference between the P O2 of brain tissue and blood during these two physiological states suggests that regional mechanisms in the brain play a role in maintaining tissue oxygenation and protect against hypoxia during hibernation.

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The present study examined the physiological mechanisms of the responses of brain tissue oxygen partial pressure (P t O 2 ), brain temperature (T brain ), global oxygen consumption V̇o 2 , and respiratory frequency (f R ) to hypoxia in non-sedated and non-anesthetized arctic ground squirrels (Spermophilus parryii, AGS) and rats. We found that 1) in contrast to oxygen partial pressure in blood (P a O 2 ), the baseline value of P t O 2 in summer euthermic AGS is significantly higher than in rats; 2) both P t O 2 and P a O 2 are dramatically reduced by inspired 8% O 2 in AGS and rats, but AGS have a greater capacity in P t O 2 to cope with environmental hypoxia; 3) metabolic rate before, during, and after hypoxic exposure is consistently lower in AGS than in rats; 4) the respiratory responding patterns to hypoxia in the two species differ in that f R decreases in AGS but increases in rats. These results suggest that 1) AGS have special mechanisms to maintain higher P t O 2 and lower P a O 2 , and these levels in AGS represent a typical pattern of adaptation of heterothermic species to and a brain protection from hypoxia; 2) AGS brain responds to hypoxia through greater decreases in P t O 2 and decreased f R and ventilation. In contrast, rat brain responds to hypoxia by less reduction in P t O 2 and increased f R and ventilation.

Introduction-Kinesin-1 motor is a molecular walking machine constructed with amino acids. The understanding of how those structural elements play their mechanical roles is the key to the understanding of kinesin-1 mechanism. Methods-Using molecular dynamics simulations, we investigate the role of a helix structure, a4 (also called switch-II helix), of kinesin-1's motor domain in its processive movement along microtubule. Results-Through the analysis of the structure and the interactions between a4 and the surrounding residues in different nucleotide-binding states, we find that, mechanically, this helix functions as a shaft for kinesin-1's motor-domain rotation and, structurally, it is an amphipathic helix ensuring its shaft functioning. The hydrophobic side of a4 consists strictly of hydrophobic residues, making it behave like a lubricated surface in contact with the core b-sheet of kinesin-1's motor domain. The opposite hydrophilic side of a4 leans firmly against microtubule with charged residues locating at both ends to facilitate its positioning onto the intra-tubulin groove. Conclusions-The special structural feature of a4 makes for an effective reduction of the conformational work in kinesin-1's force generation process.