Quinine blocks 5-HT and 5-HT3 receptor mediated peristalsis in both guinea pig and mouse ileum tissue

Introduction. Quinine is commonly used to treat malaria; however one of the principal side effects is gastrointestinal disturbances (White, 1992). 5-HT3 receptors modulate gut peristalsis (Chetty et al., 2006), and, as quinine has been shown to act as a 5-HT3 receptor antagonist (Thompson and Lummis, 2008) it is possible that these side effects result from actions at gut 5-HT3 receptors. To address this question, we examined the ability of quinine to antagonise 5-HT and 5-HT3 mediated peristalsis in guinea pig and mouse ileum. Methods. Ileum was excised from male guinea pigs (200-300g) and C57BL/6 mice (25-35g) following cervical dislocation. Ileum segments (3-5 cm) were mounted in 50 ml organ baths containing Tryode’s solution at 35-37 °C. Concentration-response curves were constructed for 5-HT and the selective 5-HT3 agonist 2-Me-5-HT (non-cumulative doses). Quinine was pre-applied for 10 min and inhibition measured using agonist concentrations that elicited a submaximal response. Results. Concentration-dependent contractions produced by 5-HT (pEC50 = 5.45 ± 0.17, n = 8) and the selective 5-HT3 agonist 2-Me-5-HT (5.01 ± 0.17, n = 11) were not significantly different (Student’s t-test, t = 0.619, df = 17, p = 0.544) in guinea pig ileum. Increasing concentrations of quinine were able to antagonise the activities of both 5-HT (pIC50 = 5.03 ± 0.2, n = 6) and 2-Me-5HT (pIC50 = 4.59 ± 0.26, n = 4). At mouse ileum, 5-HT (pEC50 = 7.57 ± 0.33, n = 9) was more potent (Student’s t-test, t = 3.6, df = 12, p = 0.004) than 2-Me-5-HT (pEC50 = 5.45 ± 0.58, n = 5). Quinine antagonised both the 5-HT (pIC50 = 4.87 ± 0.31, n = 7) and 2-Me-5-HT-induced (pIC50 = 6.18 ± 1.14, n = 4) contractions. Conclusions. These results support previous electrophysiological studies that identified quinine as an antagonist at recombinant 5-HT3 receptors with IC50 values comparable with those reported here (pIC50 = 4.87, Thompson et al., 2007). Further, we found that quinine completely blocked 5-HT induced contractions in mouse and guinea pig, raising the possibility that quinine targets other 5-HT receptors in the gut (e.g., 5-HT4 receptors) and may influence intestinal function

High-resolution Spectroscopy of Extremely Metal-poor Stars in the Least Evolved Galaxies: Leo IV

We present high-resolution Magellan/MIKE spectroscopy of the brightest star in the ultra-faint dwarf galaxy Leo IV. We measure an iron abundance of [Fe/H] = –3.2, adding to the rapidly growing sample of extremely metal-poor (EMP) stars being identified in Milky Way satellite galaxies. The star is enhanced in the α elements Mg, Ca, and Ti by ~0.3 dex, very similar to the typical Milky Way halo abundance pattern. All of the light and iron-peak elements follow the trends established by EMP halo stars, but the neutron-capture elements Ba and Sr are significantly underabundant. These results are quite similar to those found for stars in the ultra-faint dwarfs Ursa Major II, Coma Berenices, Boötes I, and Hercules, suggesting that the chemical evolution of the lowest-luminosity galaxies may be universal. The abundance pattern we observe is consistent with predictions for nucleosynthesis from a Population III supernova explosion. The extremely low metallicity of this star also supports the idea that a significant fraction (≳10%) of the stars in the faintest dwarfs have metallicities below [Fe/H] = –3.0

Ion-mediated conformational switches

Molecular switches are ubiquitous in Nature and provide the basis of many forms of transport and signalling. Single synthetic molecules that change conformation, and thus function, reversibly in a stimulus-dependent manner are of great interest not only to chemists but society in general; myriad applications exist in storage, display, sensing and medicine. Here we describe recent developments in the area of ion-mediated switching

a-helix mimetics: outwards and upwards

?-Helices are common secondary structural elements forming key parts of the large, generally featureless interfacial regions of many therapeutically-relevant protein–protein interactions (PPIs). The rational design of helix mimetics is an appealing small-molecule strategy for the mediation of aberrant PPIs, however the first generation of scaffolds presented a relatively small number of residues on a single recognition surface. Increasingly, helices involved in PPIs are found to have more complex binding modes, utilizing two or three recognition surfaces, or binding with extended points of contact. To address these unmet needs the design and synthesis of new generations of multi-sided, extended, and supersecondary structures are underway

Atlantic Ocean Heat Transport Enabled by Indo-Pacific Heat Uptake and Mixing

The ocean transports vast amounts of heat around the planet, helping to regulate regional climate. One important component of this heat transport is the movement of warm water from equatorial regions toward the poles, with colder water flowing in return. Here, we introduce a framework relating meridional heat transport to the diabatic processes of surface forcing and turbulent mixing that move heat across temperature classes. Applied to a (1/4)° global ocean model the framework highlights the role of the tropical Indo‐Pacific in the global ocean heat transport. A large fraction of the northward heat transport in the Atlantic is ultimately sourced from heat uptake in the eastern tropical Pacific. Turbulent mixing moves heat from the warm, shallow Indo‐Pacific circulation to the cold deeper‐reaching Atlantic circulation. Our results underscore a renewed focus on the tropical oceans and their role in global circulation pathways

Experiences and satisfaction of children, young people and their parents with alternative mental health models to inpatient settings : a systematic review

Community-based mental health services for children and young people (CYP) can offer alternatives to inpatient settings and treat CYP in less restrictive environments. However, there has been limited implementation of such alternative models, and their efficacy is still inconclusive. Notably, little is known of the experiences of CYP and their parents with these alternative models and their level of satisfaction with the care provided. Therefore, the main aim of this review was to understand those experiences of the accessibility of alternative models to inpatient care, as well as overall CYP/parental satisfaction. A searching strategy of peer-reviewed articles was conducted from January 1990 to December 2018, with updated searches conducted in June 2019. The initial search resulted in 495 articles, of which 19 were included in this review. A narrative synthesis grouped the studies according to emerging themes: alternative models, tele-psychiatry and interventions applied to crisis, and experiences and satisfaction with crisis provision. The identified articles highlighted increased satisfaction in CYP with alternative models in comparison with care as usual. However, the parental experiential data identified high levels of parental burden and a range of complex emotional reactions associated with engagement with crisis services. Furthermore, we identified a number of interventions, telepsychiatric and mobile solutions that may be effective when applied to urgent and emergency care for CYP experiencing a mental health crisis. Lastly, both parental and CYP experiences highlighted a number of perceived barriers associated with help-seeking from crisis services

Evaluation of the Induction of Immune Memory following Infant Immunisation with Serogroup C Neisseria meningitidis Conjugate Vaccines - Exploratory Analyses within a Randomised Controlled Trial

Aim: We measured meningococcal serogroup C (MenC)-specific memory B-cell responses in infants by Enzyme-Linked Immunospot (ELISpot) following different MenC conjugate vaccine schedules to investigate the impact of priming on immune memory. Methods: Infants aged 2 months were randomised to receive 1 or 2 doses of MenC-CRM197 at 3 or 3 and 4 months, 1 dose of MenC-TT at 3 months, or no primary MenC doses. All children received a Haemophilus influenzae type b (Hib)-MenC booster at 12 months. Blood was drawn at 5, 12, 12 months +6 days and 13 months of age. Results: Results were available for 110, 103, 76 and 44 children from each group respectively. Following primary immunisations, and prior to the 12-month booster, there were no significant differences between 1- or 2-dose primed children in the number of MenC memory B-cells detected. One month following the booster, children primed with 1 dose MenC-TT had more memory B-cells than children primed with either 1-dose (p = 0.001) or 2-dose (p<0.0001) MenC-CRM197. There were no differences in MenC memory B-cells detected in children who received 1 or 2 doses of MenC-CRM197 in infancy and un-primed children. Conclusions: MenC-specific memory B-cell production may be more dependent on the type of primary vaccine used than the number of doses administered. Although the mechanistic differences between MenC-CRM197 and MenC-TT priming are unclear, it is possible that structural differences, including the carrier proteins, may underlie differential interactions with B- and T-cell populations, and thus different effects on various memory B-cell subsets. A MenC-TT/Hib-MenC-TT combination for priming/boosting may offer an advantage in inducing more persistent antibody.peer-reviewe