Molecular basis of the selective binding of MDMA enantiomers to the Alpha4Beta2 nicotinic receptor subtype: synthesis, pharmacological evaluation and mechanistic studies

The α4β2 nicotinic acetylcholine receptor (nAChR) is a molecular target of 3,4-methylenedioxymethamphetamine (MDMA), a synthetic drug also known as ecstasy, and it modulates the MDMA-mediated reinforcing properties. However, the enantioselective preference of the α4β2 nAChR subtype still remains unknown. Since the two enantiomers exhibit different pharmacological profiles and stereoselective metabolism, the aim of this study is to assess a possible difference in the interaction of the MDMA enantiomers with this nAChR subtype. To this end, we report a novel simple, yet highly efficient enantioselective synthesis of the MDMA enantiomers, in which the key step is the diastereoselective reduction of imides derived from optically pure tert-butylsulfinamide. The enantioselective binding to the receptor is examined using [3H]epibatidine in a radioligand assay. Even though the two enantiomers induced a concentration-dependent binding displacement, (S)-MDMA has an inhibition constant 13-fold higher than (R)-MDMA, which shows a Hill's coefficient not significantly different from unity, implying a competitive interaction. Furthermore, when NGF-differentiated PC12 cells were pretreated with the compounds, a significant increase in binding of [3H]epibatidine was found for (R)-MDMA, indicating up-regulation of heteromeric nAChR in the cell surface. Finally, docking and molecular dynamics studies have been used to identify the binding mode of the two enantiomers, which provides a structural basis to justify the differences in affinity from the differential interactions played by the substituents at the stereogenic center of MDMA. The results provide a basis to explore the distinct psychostimulant profiles of the MDMA enantiomers mediated by the α4β2 nAChR subtype

TOI-2196 b : Rare planet in the hot Neptune desert transiting a G-type star

Funding: C.M.P., M.F., I.G., and J.K. gratefully acknowledge the support of the Swedish National Space Agency (DNR 65/19, 174/18, 177/19, 2020-00104). L.M.S and D.G. gratefully acknowledge financial support from the CRT foundation under Grant No. 2018.2323 “Gaseous or rocky? Unveiling the nature of small worlds”. P.K. acknowledges support from grant LTT-20015. E.G. acknowledge the support of the Thüringer Ministerium für Wirtschaft, Wissenschaft und Digitale Gesellschaft. J.S.J. gratefully acknowledges support by FONDECYT grant 1201371 and from the ANID BASAL projects ACE210002 and FB210003. H.J.D. acknowledges support from the Spanish Research Agency of the Ministry of Science and Innovation (AEI-MICINN) under grant PID2019-107061GBC66, DOI: 10.13039/501100011033. D.D. acknowledges support from the TESS Guest Investigator Program grants 80NSSC21K0108 and 80NSSC22K0185. M.E. acknowledges the support of the DFG priority program SPP 1992 "Exploring the Diversity of Extrasolar Planets" (HA 3279/12-1). K.W.F.L. was supported by Deutsche Forschungsgemeinschaft grants RA714/14-1 within the DFG Schwerpunkt SPP 1992, Exploring the Diversity of Extrasolar Planets. N.N. acknowledges support from JSPS KAKENHI Grant Number JP18H05439, JST CREST Grant Number JPMJCR1761. M.S.I.P. is funded by NSF.The hot Neptune desert is a region hosting a small number of short-period Neptunes in the radius-instellation diagram. Highly irradiated planets are usually either small (R ≲ 2 R⊕) and rocky or they are gas giants with radii of ≳1 RJ. Here, we report on the intermediate-sized planet TOI-2196 b (TIC 372172128.01) on a 1.2 day orbit around a G-type star (V = 12.0, [Fe/H] = 0.14 dex) discovered by the Transiting Exoplanet Survey Satellite in sector 27. We collected 41 radial velocity measurements with the HARPS spectrograph to confirm the planetary nature of the transit signal and to determine the mass. The radius of TOI-2196 b is 3.51 ± 0.15 R⊕, which, combined with the mass of 26.0 ± 1.3 M⊕, results in a bulk density of 3.31−0.43+0.51 g cm−3. Hence, the radius implies that this planet is a sub-Neptune, although the density is twice than that of Neptune. A significant trend in the HARPS radial velocity measurements points to the presence of a distant companion with a lower limit on the period and mass of 220 days and 0.65 MJ, respectively, assuming zero eccentricity. The short period of planet b implies a high equilibrium temperature of 1860 ± 20 K, for zero albedo and isotropic emission. This places the planet in the hot Neptune desert, joining a group of very few planets in this parameter space discovered in recent years. These planets suggest that the hot Neptune desert may be divided in two parts for planets with equilibrium temperatures of ≳1800 K: a hot sub-Neptune desert devoid of planets with radii of ≈ 1.8−3 R⊕ and a sub-Jovian desert for radii of ≈5−12 R⊕. More planets in this parameter space are needed to further investigate this finding. Planetary interior structure models of TOI-2196 b are consistent with a H/He atmosphere mass fraction between 0.4% and 3%, with a mean value of 0.7% on top of a rocky interior. We estimated the amount of mass this planet might have lost at a young age and we find that while the mass loss could have been significant, the planet had not changed in terms of character: it was born as a small volatile-rich planet and it remains one at present.Publisher PDFPeer reviewe

Two warm Neptunes transiting HIP 9618 revealed by TESS and Cheops

peer reviewedHIP 9618 (HD 12572, TOI-1471, TIC 306263608) is a bright (G = 9.0 mag) solar analogue. TESS photometry revealed the star to have two candidate planets with radii of 3.9 ± 0.044 R (HIP 9618 b) and 3.343 ± 0.039 R (HIP 9618 c). While the 20.77291 d period of HIP 9618 b was measured unambiguously, HIP 9618 c showed only two transits separated by a 680-d gap in the time series, leaving many possibilities for the period. To solve this issue, CHEOPS performed targeted photometry of period aliases to attempt to recover the true period of planet c, and successfully determined the true period to be 52.56349 d. High-resolution spectroscopy with HARPS-N, SOPHIE, and CAFE revealed a mass of 10.0 ± 3.1M for HIP 9618 b, which, according to our interior structure models, corresponds to a 6.8 ± 1.4 per cent gas fraction. HIP 9618 c appears to have a lower mass than HIP 9618 b, with a 3-sigma upper limit of 50 d, opening the door for the atmospheric characterization of warm (Teq < 750 K) sub-Neptunes

The relationship between vigilance capacity and physical exercise: A mixed-effects multistudy analysis

A substantial body of work has depicted a positive association between physical exercise and cognition, although the key factors driving that link are still a matter of scientific debate. Here, we aimed to contribute further to that topic by pooling the data from seven studies (N=361) conducted by our research group to examine whether cardiovascular fitness (VO2), sport type participation (externally-paced [e.g., football or basketball] and self-paced [e.g., triathlon or track and field athletes] vs. sedentary), or both, are crucial factors to explain the association between the regular practice of exercise and vigilance capacity. We controlled for relevant variables such as age and the method of VO2 estimation. The Psychomotor Vigilance Task was used to measure vigilance performance by means of reaction time (RT). The results showed that externally-paced sport practice (e.g., football) resulted in significantly shorter RT compared to self-paced sport (e.g., triathlon) and sedentary condition, depicting larger effects in children and adolescents than in adults. Further analyses revealed no significant effect of cardiovascular fitness and self-paced sport practice, in comparison to the sedentary condition, on RT. Our data point to the relevance of considering the type of sport practice over and above the level of cardiovascular fitness as crucial factor to explain the positive association between the regular practice of exercise and vigilance capacity

Molecular basis of the selective binding of MDMA enantiomers to the Alpha4Beta2 nicotinic receptor subtype: synthesis, pharmacological evaluation and mechanistic studies

The α4β2 nicotinic acetylcholine receptor (nAChR) is a molecular target of 3,4-methylenedioxymethamphetamine (MDMA), a synthetic drug also known as ecstasy, and it modulates the MDMA-mediated reinforcing properties. However, the enantioselective preference of the α4β2 nAChR subtype still remains unknown. Since the two enantiomers exhibit different pharmacological profiles and stereoselective metabolism, the aim of this study is to assess a possible difference in the interaction of the MDMA enantiomers with this nAChR subtype. To this end, we report a novel simple, yet highly efficient enantioselective synthesis of the MDMA enantiomers, in which the key step is the diastereoselective reduction of imides derived from optically pure tert-butylsulfinamide. The enantioselective binding to the receptor is examined using [3H]epibatidine in a radioligand assay. Even though the two enantiomers induced a concentration-dependent binding displacement, (S)-MDMA has an inhibition constant 13-fold higher than (R)-MDMA, which shows a Hill's coefficient not significantly different from unity, implying a competitive interaction. Furthermore, when NGF-differentiated PC12 cells were pretreated with the compounds, a significant increase in binding of [3H]epibatidine was found for (R)-MDMA, indicating up-regulation of heteromeric nAChR in the cell surface. Finally, docking and molecular dynamics studies have been used to identify the binding mode of the two enantiomers, which provides a structural basis to justify the differences in affinity from the differential interactions played by the substituents at the stereogenic centre of MDMA. The results provide a basis to explore the distinct psychostimulant profiles of the MDMA enantiomers mediated by the α4β2 nAChR subtype

Molecular basis of the selective binding of MDMA enantiomers to the Alpha4Beta2 nicotinic receptor subtype: synthesis, pharmacological evaluation and mechanistic studies

The α4β2 nicotinic acetylcholine receptor (nAChR) is a molecular target of 3,4-methylenedioxymethamphetamine (MDMA), a synthetic drug also known as ecstasy, and it modulates the MDMA-mediated reinforcing properties. However, the enantioselective preference of the α4β2 nAChR subtype still remains unknown. Since the two enantiomers exhibit different pharmacological profiles and stereoselective metabolism, the aim of this study is to assess a possible difference in the interaction of the MDMA enantiomers with this nAChR subtype. To this end, we report a novel simple, yet highly efficient enantioselective synthesis of the MDMA enantiomers, in which the key step is the diastereoselective reduction of imides derived from optically pure tert-butylsulfinamide. The enantioselective binding to the receptor is examined using [3H]epibatidine in a radioligand assay. Even though the two enantiomers induced a concentration-dependent binding displacement, (S)-MDMA has an inhibition constant 13-fold higher than (R)-MDMA, which shows a Hill's coefficient not significantly different from unity, implying a competitive interaction. Furthermore, when NGF-differentiated PC12 cells were pretreated with the compounds, a significant increase in binding of [3H]epibatidine was found for (R)-MDMA, indicating up-regulation of heteromeric nAChR in the cell surface. Finally, docking and molecular dynamics studies have been used to identify the binding mode of the two enantiomers, which provides a structural basis to justify the differences in affinity from the differential interactions played by the substituents at the stereogenic center of MDMA. The results provide a basis to explore the distinct psychostimulant profiles of the MDMA enantiomers mediated by the α4β2 nAChR subtype

Use of Telemedicine for Post-discharge Assessment of the Surgical Wound: International Cohort Study, and Systematic Review with Meta-analysis

Objective: This study aimed to determine whether remote wound reviews using telemedicine can be safely upscaled, and if standardised assessment tools are needed. Summary background data: Surgical site infection is the most common complication of surgery worldwide, and frequently occurs after hospital discharge. Evidence to support implementation of telemedicine during postoperative recovery will be an essential component of pandemic recovery. Methods: The primary outcome of this study was surgical site infection reported up to 30-days after surgery (SSI), comparing rates reported using telemedicine (telephone and/or video assessment) to those with in-person review. The first part of this study analysed primary data from an international cohort study of adult patients undergoing abdominal surgery who were discharged from hospital before 30-days after surgery. The second part combined this data with the results of a systematic review to perform a meta-analysis of all available data conducted in accordance with PRIMSA guidelines (PROSPERO:192596). Results: The cohort study included 15,358 patients from 66 countries (8069 high, 4448 middle, 1744 low income). Of these, 6907 (45.0%) were followed up using telemedicine. The SSI rate reported using telemedicine was slightly lower than with in-person follow-up (13.4% vs. 11.1%, P&lt;0.001), which persisted after risk adjustment in a mixed-effects model (adjusted odds ratio: 0.73, 95% confidence interval 0.63-0.84, P&lt;0.001). This association was consistent across sensitivity and subgroup analyses, including a propensity-score matched model. In nine eligible non-randomised studies identified, a pooled mean of 64% of patients underwent telemedicine follow-up. Upon meta-analysis, the SSI rate reported was lower with telemedicine (odds ratio: 0.67, 0.47-0.94) than in-person (reference) follow-up (I2=0.45, P=0.12), although there a high risk of bias in included studies. Conclusions: Use of telemedicine to assess the surgical wound post-discharge is feasible, but risks underreporting of SSI. Standardised tools for remote assessment of SSI must be evaluated and adopted as telemedicine is upscaled globally