Thirty-two untrained men [mean (SD) age 22.5 (5.8) years, height 178.3 (7.2) cm, body mass 77.8 (11.9) kg] participated in an 8-week progressive resistance-training program to investigate the "strength-endurance continuum". Subjects were divided into four groups: a low repetition group (Low Rep, n = 9) performing 3-5 repetitions maximum (RM) for four sets of each exercise with 3 min rest between sets and exercises, an intermediate repetition group (Int Rep, n = 11) performing 9-11 RM for three sets with 2 min rest, a high repetition group (High Rep, n = 7) performing 20-28 RM for two sets with 1 min rest, and a non-exercising control group (Con, n = 5). Three exercises (leg press, squat, and knee extension) were performed 2 days/week for the first 4 weeks and 3 days/week for the final 4 weeks. Maximal strength [one repetition maximum, 1RM), local muscular endurance (maximal number of repetitions performed with 60% of 1RM), and various cardiorespiratory parameters (e.g., maximum oxygen consumption, pulmonary ventilation, maximal aerobic power, time to exhaustion) were assessed at the beginning and end of the study. In addition, pre- and post-training muscle biopsy samples were analyzed for fiber-type composition, cross-sectional area, myosin heavy chain (MHC) content, and capillarization. Maximal strength improved significantly more for the Low Rep group compared to the other training groups, and the maximal number of repetitions at 60% 1RM improved the most for the High Rep group. In addition, maximal aerobic power and time to exhaustion significantly increased at the end of the study for only the High Rep group. All three major fiber types (types I, IIA, and IIB) hypertrophied for the Low Rep and Int Rep groups, whereas no significant increases were demonstrated for either the High Rep or Con groups. However, the percentage of type IIB fibers decreased, with a concomitant increase in IIAB fibers for all three resistance-trained groups. These fiber-type conversions were supported by a significant decrease in MHCIIb accompanied by a significant increase in MHCIIa. No significant changes in fiber-type composition were found in the control samples. Although all three training regimens resulted in similar fiber-type transformations (IIB to IIA), the low to intermediate repetition resistance-training programs induced a greater hypertrophic effect compared to the high repetition regimen. The High Rep group, however, appeared better adapted for submaximal, prolonged contractions, with significant increases after training in aerobic power and time to exhaustion. Thus, low and intermediate RM training appears to induce similar muscular adaptations, at least after short-term training in previously untrained subjects. Overall, however, these data demonstrate that both physical performance and the associated physiological adaptations are linked to the intensity and number of repetitions performed, and thus lend support to the "strength-endurance continuum".

This study presents data collected over the past 10 years on the muscle fiber type composition of the vastus lateralis muscle of young men and women. Biopsies were taken from the vastus lateralis muscle of 55 women (21.2+/-2.2 yr) and 95 men (21.5+/-2.4 yr) who had volunteered to participate in various research projects. Six fiber types (I, IC, IIC, IIA, IIAB, and IIB) were classified using mATPase histochemistry, and cross-sectional area was measured for the major fiber types (I, IIA, and IIB). Myosin heavy chain (MHC) content was determined electrophoretically on all of the samples from the men and on 26 samples from the women. With the exception of fiber Type IC, no significant differences were found between men and women for muscle fiber type distribution. The vastus lateralis muscle of both the men and women contained approximately 41% I, 1% IC, 1% IIC, 31% IIA, 6% IIAB, and 20% IIB. However, the cross-sectional area of all three major fiber types was larger for the men compared to the women. In addition, the Type IIA fibers were the largest for the men, whereas the Type I fibers tended to be the largest for the women. Therefore, gender differences were found with regard to the area occupied by each specific fiber type: IIA>I>IIB for the men and I>IIA>IIB for the women. These data establish normative values for the mATPase-based fiber type distribution and sizes in untrained young men and women.

Steroids may rapidly alter neuronal function and behavior through poorly characterized, direct actions on neuronal membranes. The membrane-bound receptors mediating these behavioral responses have not been identified. [3H]Corticosterone labels a population of specific, high-affinity recognition sites (dissociation constant = 0.51 nanomolar) in synaptic membranes from an amphibian brain. These binding sites were localized by receptor autoradiography in the neuropil, outside the regions of perikarya. The affinities of corticoids for this [3H]corticosterone binding site were linearly related to their potencies in rapidly suppressing male reproductive behavior. Thus, it appears that brain membranes contain a corticosteroid receptor that could participate in the regulation of behavior.

We have compared the potencies of structurally distinct channel blockers at recombinant NR1/NR2A, NR1/NR2B, NR1/NR2C and NR1/NR2D receptors. The IC 50 values varied with stereochemistry and subunit composition, suggesting that it may be possible to design subunit-selective channel blockers. For dizocilpine (MK-801), the differential potency of MK-801 stereoisomers determined at recombinant NMDA receptors was confirmed at native receptors in vitro and in vivo. Since the proton sensor is tightly linked both structurally and functionally to channel gating, we examined whether blocking molecules that interact in the channel pore with the gating machinery can differentially sense protonation of the receptor. Blockers capable of remaining trapped in the pore during agonist unbinding showed the strongest dependence on extracellular pH, appearing more potent at acidic pH values that promote channel closure. Determination of pK a values for channel blockers suggests that the ionization of ketamine but not of other blockers can influence its pH-dependent potency. Kinetic modelling and single channel studies suggest that the pH-dependent block of NR1/NR2A by (−)MK-801 but not (+)MK-801 reflects an increase in the MK-801 association rate even though protons reduce channel open probability and thus MK-801 access to its binding site. Allosteric modulators that alter pH sensitivity alter the potency of MK-801, supporting the interpretation that the pH sensitivity of MK-801 binding reflects the changes at the proton sensor rather than a secondary effect of pH. These data suggest a tight coupling between the proton sensor and the ion channel gate as well as unique subunit-specific mechanisms of channel block.

Palmyrolide A (1) is a new neuroactive macrolide isolated from a marine cyanobacterial assemblage composed of Leptolyngbya cf. and Oscillatoria spp. collected from Palmyra Atoll. It features a rare N-methyl enamide and an intriguing t-butyl branch; the latter renders the adjacent lactone ester bond resistant to hydrolysis. Consistent with its significant suppression of calcium influx in cerebrocortical neurons (IC 50 =3.70 µM), palmyrolide A (1) showed relatively potent sodium channel blocking activity in neuro-2a cells (IC 50 =5.2 µM), without appreciable cytotoxicity.Suppression and/or activation of spontaneous Ca 2+ oscillations of murine cerebrocortical neurons1 has proven to be an extremely sensitive screening method for the discovery of new neurotoxins, including the recently reported cyanobacterial metabolites hoiamide A,2a alotamide A,2b and palmyramide A.2c In the case of hoiamide A, further pharmacological characterization found it to be a partial agonist at neurotoxin site 2 of voltage-gated sodium channels (VGSCs).2aPrimary cultures of cerebrocortical neurons allow the detection of two distinct actions when cells are loaded with the Ca 2+ sensitive fluorescent dye, fluo-3.1 First, those metabolites that trigger Ca 2+ influx can be easily revealed by monitoring for this ion using a Fluorometric Imaging Plate Reader (FLIPR). Secondly, because these cultures display spontaneous Ca 2+ oscillations, they provide a robust screening system for the discovery of small molecule ion wgerwick@ucsd.edu. Supporting Information Available: Experimental, full NMR data of 1, 2 and 4 (all stereoisomers), bioassay data, and taxonomic characterization. This material is available free of charge via the Internet at http://pubs.acs.org. (Table 1 and SI) was an intense singlet at δ0.86 (nine protons), which could be attributed to three isochronous methyl groups comprising a t-butyl moiety.8 Also present were the methyl doublets at δ0.90 and δ1.21, as well as the N-methyl singlet at δ3.04. The 1 H NMR of 1 was completed by a deshielded methine proton at δ4.88 and a terminal 1,2-disubstituted vinylic system represented by protons at δ5.27 (dt) and δ6.47 (d). The presence of a t-butyl moiety was supported in the 13 C NMR spectrum of 1 by a very intense resonance at δ26.1, as well as a quaternary carbon at δ35.2. Additionally, the deshielded carbons at δ117.3 and δ130.6 were in agreement with a 1,2-disubstituted double bond, whereas the carbonyls at δ172.9 and δ175.3 indicated a total of two ester or/and amide functionalities. As detailed below, extensive analysis of these 1 H and 13 C NMR resonances using HSQC, HMBC, COSY and NOESY led us to deduce the planar structure of 1. NIH Public AccessThe intense singlet at δ0.86 (H9, H10, H11) showed HMBC correlations with the quaternary carbon C8 (δ35.2), oxymethine C7 (δ76.9), and methylene carbon C6 (δ35.6) ( Figure 1A). This last carbon was found by HSQC to bear the diastereotopic proton resonances H6a (δ1.38) and H6b (δ1.66), which according to the COSY spectrum, participa...