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Bitter taste is sensed by bitter taste receptors (TAS2Rs) that belong to the G protein-coupled receptor (GPCR) superfamily. In addition to bitter taste perception, TAS2Rs have been reported recently to be expressed in many extraoral tissues and are now known to be involved in health and disease. Despite important roles of TAS2Rs in biological functions and diseases, no crystal structure is available to help understand the signal transduction mechanism or to help develop selective ligands as new therapeutic targets. We report here the three-dimensional structure of the fully activated TAS2R4 human bitter taste receptor predicted using the GEnSeMBLE complete sampling method. This TAS2R4 structure is coupled to the gustducin G protein and to each of several agonists. We find that the G protein couples to TAS2R4 by forming strong salt bridges to each of the three intracellular loops, orienting the activated Gα5 helix of the Gα subunit to interact extensively with the cytoplasmic region of the activated receptor. We find that the TAS2Rs exhibit unique motifs distinct from typical Class A GPCRs, leading to a distinct activation mechanism and a less stable inactive state. This fully activated bitter taste receptor complex structure provides insight into the signal transduction mechanism and into ligand binding to TAS2Rs.
Clozapine is the most effective antipsychotic medication, but it has the highest propensity for metabolic side effects. A clozapine clinic was established within an early intervention for psychosis service to facilitate the timely commencement of clozapine and to manage the associated adverse effects. This study describes the changes in the weight, body mass index (BMI), waist circumference and blood pressure after 6 months in young people commenced on clozapine.
This was a prospective cohort study of all young people, aged 15–24 years, commenced on clozapine within an early intervention service in Melbourne, Australia, between 01.04.2016 and 30.06.2018. Continuous data were analyzed with paired t-test and categorical with Wilcoxon signed-rank test.
Twenty-six young people received 6 months of treatment with clozapine, of whom the mean age was 19.8 years (s.d. ±3.1) and 66.7% were male. After 6 months, the mean weight gain was 5.1 kg (s.d. ±10.1 kg) and over half (53.8%) gained clinically significant weight. The proportion of young people classified as either overweight or obese rose from 69.2% to 88.5% (p = 0.006). The proportion of young people with a waist circumference above the recommended parameters increased from 57.9% to 78.9% (p = 0.008). Hypertension was present in 30%, and after 6 months, 45% had hypertension (p = 0.64). Metformin was prescribed to 34.6%, typically to those with the greatest and most rapid weight gain.
Among young people with treatment resistant psychosis, clozapine is associated with significant metabolic side effects in the early stages of commencement. More interventions aimed at attenuating this weight gain are needed.
A longstanding issue in the field of nutrition is the potential inaccuracy of methods traditionally used for dietary assessment (i.e. food diaries and food frequency questionnaires). It is possible to overcome the limitations and biases of these techniques by combining them with analytical measurements in human biofluids. Metabolomic technologies are gaining popularity as nutritional tools due to their capacity to measure metabolic responses to external stimuli, such as the ingestion of certain foods. This project performed both LC-MS and 1H-NMR metabolomic profiling on serum samples collected as part of the NICOLA study (Northern Irish Cohort for the Longitudinal Study of Aging) in order to discover novel dietary biomarkers. A dietary validation cohort (NIDAS) was incorporated within NICOLA, involving 45 males and 50 females, aged 50 years and over. Participants provided detailed dietary data (4-day food diary) and blood samples at two time-points, six months apart. Serum samples were processed on two analytical platforms. 1H-NMR spectra were acquired using a Bruker 600 MHz Ascent coupled to a TCI cryoprobe and processed using Bayesil (University of Alberta, Canada). A Waters TQ-S coupled with an Acquity I-class UPLC was used in combination with a targeted commercially available kit (AbsoluteIDQ p180 kit, Biocrates). Mass spectra obtained were processed with MetIDQ and verified using MassLynx (v4.1). Data were tested for normality, and metabolite concentrations were correlated with recorded dietary intake of each food type using SPSS. Additional tests (PCA, PLS-DA, ROC Curves) were performed on MetaboAnalyst 4.0 (University of Alberta, Canada). More than 50 statistically significant (P < 0.05) food-metabolite correlations were detected, 15 of which remained significant after eliminating potential confounding from sex, age and BMI. The strongest correlations were between fruit consumption and acetic acid, and between dairy consumption and certain glycerophospholipids (e.g. LysoPC aa C20:3). Stratifying the cohort by gender yielded further correlations, including PC ae C38:2 (dairy; males), PC aa C34:4 (dairy; females), PC aa C36:4 (dairy; females) and trans-4-Hydroxyproline (meat; males). A number of potential blood-based food biomarkers were detected, many of which are gender-specific, and some are corroborated by previously published studies. However, further validation work is required. For example, biological plausibility needs to be established, and the findings need to be reproduced in other cohorts to demonstrate their applicability in larger and more diverse populations. These results contribute greatly to the ongoing efforts to discover and validate reliable nutritional biomarkers as an objective and unbiased measurement of food intake.
Edward Gibbon's History of the Decline and Fall of the Roman Empire, published in three instalments from 1776 to 1788, is widely regarded as the greatest work of history in the English language. Starting with the accession of the Roman Emperor Commodus in the late second century CE, Gibbon's work traverses thirteen centuries, encompassing the rise of Christianity and of Islam, the collapse of the Roman Empire in the West, and the fall of the Byzantine Empire in 1453. This Companion provides a comprehensive overview of the intellectual roots, contemporary European contexts, literary style and thematic scale of Gibbon's achievement. Alongside the History, it gives an introduction to Gibbon's other works, including the Memoirs he left unfinished at his death and previously unpublished material. Leading international scholars in the fields of classics, geography, history and literature provide a comprehensive account of Gibbon's monumental account of decline, fall and global historical transformation.
Many commentators on Benjamin Britten's life and music have remarked on his preoccupation with the public/private dichotomy that the artist constantly confronts. It was an issue that also informed much of the poetry produced between the 1790s and the 1820s that Britten set at intervals throughout his astonishingly creative life, from schoolboy settings of Shelley to his courtly Birthday Hansel of 1975, a setting for tenor and harp of poems by the fiercely republican Robert Burns commissioned by Queen Elizabeth, the Queen Mother, to celebrate her seventy-fifth birthday. As this last work abundantly testifies, there are paradoxes at work here, to the resolution of which this essay is primarily dedicated. It is well to bear in mind that poetry and music are often irreducibly private, and that even when they are publicly performed or shared something of that privacy is preserved. This was abundantly clear to William Wordsworth, whose occupancy of the Laureateship is consequently all the more interesting. Indeed, one might legitimately argue that Wordsworth was one of the most public of private poets, just as Britten was a determinedly private public musician.
This is a rich subject, and in order to begin to contain it this essay will concentrate on three English poets from the Romantic era – Wordsworth, Blake and Shelley – to whom Britten's musical sensibility gave further voice, giving the lion's share of its argument to his encounters with the first two. Britten responded emotionally and hence musically to Wordsworth and Blake in a way that goes to the core of his ethical and religious thinking. Although Britten made more settings of Shelley, they are of less telling significance psychologically than is his responsiveness to Wordsworth and Blake, and consequently the essay will briefly concentrate on his use of lines from Queen Mab, interpolated into the libretto of Owen Wingrave, showing in the process how Britten's pacifism was less political than Shelley's critique of militarism, and also more profoundly moral. The interpretation of Britten's settings of Wordsworth, Blake and Shelley offered here will also place his engagement with all three poets in their cultural contexts, demonstrating that Britten's place in the cultural landscape of his time was both more contested and more challenging than many modern critics allow.
East Africa is a global hot spot for the diversity of ixodid ticks. As ectoparasites and as vectors of pathogens, ticks negatively affect the well-being of humans, livestock and wildlife. To prevent tick infestations, livestock owners and managers typically treat livestock with acaricides that kill ticks when they attempt to feed on livestock hosts. Because of the costs of preventing and mitigating tick parasitism, predicting where and when ticks will be abundant is an important challenge in this region. We used a 7-year monthly record of tick abundance on large experimental plots to assess the effects of rainfall, wildlife and cattle on larvae, nymphs and adults of two common tick species, Rhipicephalus pulchellus and Rhipicephalus praetextatus. Nymphal and adult ticks were more abundant when there had been high cumulative rainfall in the prior months. They were less abundant when cattle were present than when only large wild mammals were. Larval abundance was not affected by the presence of cattle, and larvae did not appear to be sensitive to rainfall in prior months, though they were less abundant in our surveys when rainfall was high in the sampling month. The challenges of managing ticks in this region are being exacerbated rapidly by changes in rainfall patterns wrought by climate change, and by overall increases in livestock, making efforts to predict the impacts of these drivers all the more pressing.
The Darwin–Hatherton Glacial system (DHGS) connects the East Antarctic Ice Sheet (EAIS) with the Ross Ice Shelf and is a key area for understanding past variations in ice thickness of surrounding ice masses. Here we present the first detailed measurements of ice thickness and grounding zone characteristics of the DHGS as well as new measurements of ice velocity. The results illustrate the changes that occur in glacier geometry and ice flux as ice flows from the polar plateau and into the Ross Ice Shelf. The ice discharge and the mean basal ice shelf melt for the first 8.5 km downstream of the grounding line amount to 0.24 ± 0.05 km3 a−1 and 0.3 ± 0.1 m a−1, respectively. As the ice begins to float, ice thickness decreases rapidly and basal terraces develop. Constructed maps of glacier geometry suggest that ice drainage from the EAIS into the Darwin Glacier occurs primarily through a deep subglacial canyon. By contrast, ice thins to <200 m at the head of the much slower flowing Hatherton Glacier. The glaciological field study establishes an improved basis for the interpretation of glacial drift sheets at the link between the EAIS and the Ross Ice Sheet.
Few randomised controlled trials (RCTs) have shown decreases in suicide.
To identify interventions for preventing suicide.
We searched EMBASE and Medline from inception until 31 December 2015. We included RCTs comparing prevention strategies with control. We pooled odds ratios (ORs) for suicide using the Peto method.
Among 8647 citations, 72 RCTs and 6 pooled analyses met inclusion criteria. Three RCTs (n = 2028) found that the World Health Organization (WHO) brief intervention and contact (BIC) was associated with significantly lower odds of suicide (OR = 0.20, 95% CI 0.09–0.42). Six RCTs (n = 1040) of cognitive–behavioural therapy (CBT) for suicide prevention and six RCTs of lithium (n = 619) yielded non-significant findings (OR = 0.34, 95% CI 0.12–1.03 and OR = 0.23, 95% CI 0.05–1.02, respectively).
The WHO BIC is a promising suicide prevention strategy. No other intervention showed a statistically significant effect in reducing suicide.
Paradoxically, Historicism established itself as the dominant interpretative mode in British historical thought more gradually than in allied human sciences. The leading British historian of the first half of the century, Macaulay, was not a historicist, although he wrote appreciatively about Ranke. Macaulay was not associated with a university; this amateur status permeated many historical circles in this period. Historicism, very much a professional doctrine, made its initial impact on British historical consciousness through the work of the ‘Liberal Anglican Historians’, all of whom were divines in the Church of England, for whom the religious orientation of German Historicism was especially attractive. Combatively secular social thinkers were critical of Historicism, particularly those heavily influenced by evolutionary theory, such as Bagehot and most defiantly Buc kle, and similarly the leading Positivist, Frederic Harrison The ideal of History as a science continued to be promoted by historians such as Bury into the opening decades of the twentieth century; it was strenuously opposed by the leading academic Historicists, Stubbs at Oxford and Acton at Cambridge, both of whom were resolutely religious. The hegemony of Historicism in History was transitory, fragmenting in the wake of the First World War and increasingly inimical Anglo-German relations.
Palmer amaranth, a dioecious summer annual forb, originating in Sonoran desert washes, compromises crop yields in much of the southern United States and its range is expanding northward. Appropriate tactics for managing this weed proactively in the Upper Midwest will depend on characterizing its damage niche, the geographic range in which it can reduce crop yields. We implemented a common garden study in 2011 and 2012, planting eight accessions of Palmer amaranth from the southern and midwestern United States, into soybean crops in southern, central, and northern Illinois, at a population density of 8 plants m−2 with a biocontainment protocol. Once Palmer amaranth plants initiated flowering, they were removed and burned. Weed survival, flowering, and weed biomass were measured, in addition to soybean yield and weather data. Analyses indicated that Palmer amaranth's damage niche in Illinois soybean was independent of weed genotype or maternal environment. Despite competing only briefly, Palmer amaranth reduced soybean yields in all site–years, indicating its damage niche in Illinois, and much of the Midwest, is limited primarily by seed immigration rate. These results highlight the urgent need for weed managers to learn Palmer amaranth identification, prevent seed introduction, and maintain a policy of zero seed return.
The amplitude of the cortically generated somatosensory evoked potential (SSEP) is used to predict outcome in comatose patients. The relationship between epileptiform discharges and SSEP amplitude has not been elucidated in those patients.
Bilateral median nerve SSEP and electroencephalograph (EEG) studies were performed in a comatose patient (patient 1) 1 day after cardiac surgery and repeated 4 days later. He had tranexamic acid administered before and during surgery. Another comatose patient (patient 2) had the same studies performed 1 day after sustaining 10 minutes of pulseless electrical cardiac activity.
Both comatose patients had epileptiform discharges (on EEG) that were coincident with giant cortically generated SSEPs. In patient 1, the EEG and SSEP studies repeated 5 days postoperatively showed no epileptiform discharges, and the cortically generated SSEP amplitude was decreased (normalized) compared with that obtained one day postoperatively. He emerged from coma and had a good recovery. Patient 2 died shortly after EEG and SSEP testing.
Epileptiform discharges were associated with giant cortically generated median nerve SSEP amplitude (tranexamic acid was implicated in patient 1 and anoxic brain injury in patient 2). Accordingly, those who use the amplitude of cortically generated SSEPs for predicting outcome in comatose patients should consider the presence of epileptiform discharges (detected by EEG) as a potential confounding factor.