Zebrafish studies identify serotonin receptors mediating antiepileptic activity in Dravet syndrome.

Dravet syndrome is a life-threatening early-onset epilepsy not well controlled by antiepileptic drugs. Drugs that modulate serotonin (5-HT) signalling, including clemizole, locaserin, trazodone and fenfluramine, have recently emerged as potential treatment options for Dravet syndrome. To investigate the serotonin receptors that could moderate this antiepileptic activity, we designed and synthesized 28 novel analogues of clemizole, obtained receptor binding affinity profiles, and performed in vivo screening in a scn1lab mutant zebrafish (Danio rerio) model which recapitulates critical clinical features of Dravet syndrome. We discovered three clemizole analogues with 5-HT receptor binding that exert powerful antiepileptic activity. Based on structure-activity relationships and medicinal chemistry-based analysis, we then screened an additional set of known 5-HT receptor specific drug candidates. Integrating our in vitro and in vivo data implicates 5-HT2B receptors as a critical mediator in the mechanism of seizure suppression observed in Dravet syndrome patients treated with 5-HT modulating drugs

The Effect of Short and Long Recovery Periods on the Contribution of Oxidative Processes to Energy Expenditure During Multiple Bouts of Supramaximal Exercise

The Effect of Short and Long Recovery Periods on the Contribution of Oxidative Processes to Energy Expenditure During Multiple Bouts of Supramaximal Exercise Olson, E. (undergraduate), Christensen, K., Jajtner, A., Copeland, J., Unthank, M., and Mitchell, J. Exercise Physiology Lab, Texas Christian University, Ft. Worth, TX. The contribution of oxidative energy production to multiple sprint exercises is of interest due to implications for the training needs of people engaging in anaerobic activities. PURPOSE: The purpose of this study was to examine the effect of short and long active recovery durations on oxidative and anaerobic contributions to energy output during maximal intensity cycle ergometry. METHODS: Six male subjects, including well-trained endurance athletes and well-trained strength athletes, completed the study. After a VO2max test on the bicycle ergometer, each subject completed two conditions: a short recovery condition (SRC) and a long recovery condition (LRC). The SRC consisted of 10, 10-sec. supramaximal sprints with 30-sec. recovery periods. The LRC consisted of 10, 10-sec supramaximal sprints with 3-min. recovery periods. The load applied to the ergometer was 1.2 g/kg and the RPM during the sprints varied based on the maximal output. During recovery, no load was applied and subjects maintained a cadence of 80 RPM. Oxygen uptake was measured during the entirety of both conditions and peak power and total work were calculated from two, 5-sec RPM averages generated during the sprints. Blood samples were taken pre-exercise, after sprints 4, 7, and 10, and 3 minutes post-exercise. RESULTS: Peak power and total work were significantly greater (p \u3c 0.05) in the LRC (1091.3 + 88.7 W and 1363.6 + 34.6 kg-m) compared to the SRC (915.3 + 109.2 W and 1161.6 + 33.9 kg-m). In addition, peak power decayed by 21.7% over the 10 sprints in the SRC compared to no decay in the LRC. Oxygen uptake averaged 28.3 + 0.9 ml/kg/min for the entirety of the LRC; whereas, in the SRC there was a large increase in oxygen uptake during the second sprint that remained elevated and averaged 47 + 1.5 ml/kg/min for the remaining 8 sprints. There was no difference in blood lactate concentrations between conditions. CONCLUSION: The heightened aerobic response and the lower work and power outputs seen in the SRC are suggestive of a decrement in both anaerobic glycolysis and phosphocreatine (PCr) activity as successive sprints were completed. After repeated bouts of explosive exercise with short rest periods, oxidative processes play a more important role in energy production, most likely due to fatigue occurring in the anaerobic energy producing systems. These findings point to the need for enhancing the aerobic capacity of athletes engaging in consecutive high intensity bouts of exercise when rest intervals are short

Direct spectroscopic evidence for mixed-valence Tl in the low carrier-density superconductor Pb1-xTIxTe

Upon doping with Tl the narrow band-gap semiconductor PbTe exhibits anomalously high-temperature superconductivity despite a very low carrier-density as well as signatures of the Kondo effect despite an absence of magnetic moments. These phenomena have been explained by invoking 2e fluctuations of the valence of the Tl dopants, but a direct measurement of the mixed valency implied by such a mechanism has not been reported to date. In this work we present the unambiguous observation of multiple valences of Tl in Tl-doped PbTe via photoemission spectroscopy measurements. It is shown via a quantitative analysis that the suppression of the carrier density in compositions exhibiting superconductivity and Kondo-like behavior can be accounted for by mixed valency, thus arguing against a self-compensation scenario proposed elsewhere for this material and strengthening the case for valence fluctuation models. In addition to the identification of Tl+ and Tl3+ a possible third intermediate local charge-density is suggested by full fits to the data, the origins of which are also discussed but remain unclear

Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma.

Infiltrating low grade gliomas (LGGs) are heterogeneous in their behavior and the strategies used for clinical management are highly variable. A key factor in clinical decision-making is that patients with mutations in the isocitrate dehydrogenase 1 and 2 (IDH1/2) oncogenes are more likely to have a favorable outcome and be sensitive to treatment. Because of their relatively long overall median survival, more aggressive treatments are typically reserved for patients that have undergone malignant progression (MP) to an anaplastic glioma or secondary glioblastoma (GBM). In the current study, ex vivo metabolic profiles of image-guided tissue samples obtained from patients with newly diagnosed and recurrent LGG were investigated using proton high-resolution magic angle spinning spectroscopy (1H HR-MAS). Distinct spectral profiles were observed for lesions with IDH-mutated genotypes, between astrocytoma and oligodendroglioma histologies, as well as for tumors that had undergone MP. Levels of 2-hydroxyglutarate (2HG) were correlated with increased mitotic activity, axonal disruption, vascular neoplasia, and with several brain metabolites including the choline species, glutamate, glutathione, and GABA. The information obtained in this study may be used to develop strategies for in vivo characterization of infiltrative glioma, in order to improve disease stratification and to assist in monitoring response to therapy

Another exact inflationary solution

A new closed-form inflationary solution is given for a hyperbolic interaction potential. The method used to arrive at this solution is outlined as it appears possible to generate additional sets of equations which satisfy the model. In addition a new form of decaying cosmological constant is presented.Comment: 10 pages, 0 figure

Calibration of myocardial T2 and T1 against iron concentration.

BACKGROUND: The assessment of myocardial iron using T2* cardiovascular magnetic resonance (CMR) has been validated and calibrated, and is in clinical use. However, there is very limited data assessing the relaxation parameters T1 and T2 for measurement of human myocardial iron. METHODS: Twelve hearts were examined from transfusion-dependent patients: 11 with end-stage heart failure, either following death (n=7) or cardiac transplantation (n=4), and 1 heart from a patient who died from a stroke with no cardiac iron loading. Ex-vivo R1 and R2 measurements (R1=1/T1 and R2=1/T2) at 1.5 Tesla were compared with myocardial iron concentration measured using inductively coupled plasma atomic emission spectroscopy. RESULTS: From a single myocardial slice in formalin which was repeatedly examined, a modest decrease in T2 was observed with time, from mean (± SD) 23.7 ± 0.93 ms at baseline (13 days after death and formalin fixation) to 18.5 ± 1.41 ms at day 566 (p<0.001). Raw T2 values were therefore adjusted to correct for this fall over time. Myocardial R2 was correlated with iron concentration [Fe] (R2 0.566, p<0.001), but the correlation was stronger between LnR2 and Ln[Fe] (R2 0.790, p<0.001). The relation was [Fe] = 5081•(T2)-2.22 between T2 (ms) and myocardial iron (mg/g dry weight). Analysis of T1 proved challenging with a dichotomous distribution of T1, with very short T1 (mean 72.3 ± 25.8 ms) that was independent of iron concentration in all hearts stored in formalin for greater than 12 months. In the remaining hearts stored for <10 weeks prior to scanning, LnR1 and iron concentration were correlated but with marked scatter (R2 0.517, p<0.001). A linear relationship was present between T1 and T2 in the hearts stored for a short period (R2 0.657, p<0.001). CONCLUSION: Myocardial T2 correlates well with myocardial iron concentration, which raises the possibility that T2 may provide additive information to T2* for patients with myocardial siderosis. However, ex-vivo T1 measurements are less reliable due to the severe chemical effects of formalin on T1 shortening, and therefore T1 calibration may only be practical from in-vivo human studies