Synthesis of substances related to rubrementinum salts

In 9152, the evidence available was still insufficient to decide between various structures proposed for the rubrementinium salts. The author has therefore attempted to gather further evidence. The evidence available in the literature is discussed in Part II, and the author’s work in Parts III and IV of this thesis. The substances which the present author has termed rubremetinium salts have more than one name in the literature. Karrer uses the name “dehydroemetin”. Pyman, who discovered the salts, at first used “rubremetine”. It was later found, however, that the salts are quaternary, so Pyman applied to the quaternary ion the name “rubremetinium”. This name will be used throughout the present thesis

Constitutively active FOXO1 diminishes activin induction of Fshb transcription in immortalized gonadotropes.

In the present study, we investigate whether the FOXO1 transcription factor modulates activin signaling in pituitary gonadotropes. Our studies show that overexpression of constitutively active FOXO1 decreases activin induction of murine Fshb gene expression in immortalized LβT2 cells. We demonstrate that FOXO1 suppression of activin induction maps to the -304/-95 region of the Fshb promoter containing multiple activin response elements and that the suppression requires the FOXO1 DNA-binding domain (DBD). FOXO1 binds weakly to the -125/-91 region of the Fshb promoter in a gel-shift assay. Since this region of the promoter contains a composite SMAD/FOXL2 binding element necessary for activin induction of Fshb transcription, it is possible that FOXO1 DNA binding interferes with SMAD and/or FOXL2 function. In addition, our studies demonstrate that FOXO1 directly interacts with SMAD3/4 but not SMAD2 in a FOXO1 DBD-dependent manner. Moreover, we show that SMAD3/4 induction of Fshb-luc and activin induction of a multimerized SMAD-binding element-luc are suppressed by FOXO1 in a DBD-dependent manner. These results suggest that FOXO1 binding to the proximal Fshb promoter as well as FOXO1 interaction with SMAD3/4 proteins may result in decreased activin induction of Fshb in gonadotropes

Role of physical activity in regulating appetite and body fat

Recent articles in the press have questioned the role of physical activity in regulating appetite and controlling bodyweight. These articles can be confusing and misleading for the public. Yet this is a complex area and there is disagreement about the importance of physical activity even among academics. Uncertainty and misunderstanding in this area may be related to the heterogeneity of the term ‘physical activity’ which encompasses sporting pursuits with extremely high levels of energy expenditure over prolonged periods of time, as well as everyday tasks involving much lower levels of energy expenditure on an intermittent basis. This latter form of physical activity includes what has been termed ‘non-exercise activity thermogenesis’ (NEAT). In the right circumstances, physical activity can make a major contribution to the maintenance of a healthy weight even in the absence of dietary control although a combination of the two is almost certain to be more effective. In the long-term, evidence suggests that for most people exercise is likely to lead to only modest weight loss. This may be due to an insufficient amount of physical activity being performed together with compensatory changes in eating and exercise behaviours. This is hard to prove because energy intake and energy expenditure are difficult to quantify in free-living situations. Individual differences in the way people respond to exercise due to both environmental (e.g. social class, education level, income, eating and exercise behaviours of family and peers, weather etc.) and genetic factors also contribute to uncertainty about the effectiveness of physical activity for weight control. Nevertheless, physical activity remains a vital component of a healthy lifestyle due to its positive influence on energy balance as well as its potential to reduce the risk of lifestyle-related diseases

Influence of prior walking on postprandial lipaemia in South Asian and White European women

Influence of prior walking on postprandial lipaemia in South Asian and White European wome

Polymorphisms at amino acid residues 141 and 154 influence conformational variation in ovine PrP

Polymorphisms in ovine PrP at amino acid residues 141 and 154 are associated with susceptibility to ovine prion disease: Leu141Arg154 with classical scrapie and Phe141Arg154 and Leu141His154 with atypical scrapie. Classical scrapie is naturally transmissible between sheep, whereas this may not be the case with atypical scrapie. Critical amino acid residues will determine the range or stability of structural changes within the ovine prion protein or its functional interaction with potential cofactors, during conversion of PrPC to PrPSc in these different forms of scrapie disease. Here we computationally identified that regions of ovine PrP, including those near amino acid residues 141 and 154, displayed more conservation than expected based on local structural environment. Molecular dynamics simulations showed these conserved regions of ovine PrP displayed genotypic differences in conformational repertoire and amino acid side-chain interactions. Significantly, Leu141Arg154 PrP adopted an extended beta sheet arrangement in the N-terminal palindromic region more frequently than the Phe141Arg154 and Leu141His154 variants. We supported these computational observations experimentally using circular dichroism spectroscopy and immunobiochemical studies on ovine recombinant PrP. Collectively, our observations show amino acid residues 141 and 154 influence secondary structure and conformational change in ovine PrP that may correlate with different forms of scrapie.This is the final published version. It is published by Hindawi in BioMed Research International here: http://www.hindawi.com/journals/bmri/2014/372491/

Interindividual responses of appetite to acute exercise: a replicated crossover study

This is an Open Access Article. It is published by Lippincott, Williams & Wilkins under the Creative Commons Attribution-NonCommercial 3.0 Unported Licence (CC BY-NC). Full details of this licence are available at: http://creativecommons.org/licenses/by-nc/4.0/Purpose: Acute exercise transiently suppresses appetite, which coincides with alterations in appetite-regulatory hormone concentrations. Individual variability in these responses is suspected, but replicated trials are needed to quantify them robustly. We examined the reproducibility of appetite and appetite-regulatory hormone responses to acute exercise and quantified the individual differences in responses. Methods: Fifteen healthy, recreationally-active men completed two control (60-min resting) and two exercise (60-min fasted treadmill running at 70% peak oxygen uptake) conditions in randomised sequences. Perceived appetite and circulating concentrations of acylated ghrelin and total peptide YY (PYY) were measured immediately before and after the interventions. Inter-individual differences were explored by correlating the two sets of response differences between exercise and control conditions. Within-participant covariate-adjusted linear mixed models were used to quantify participant-by-condition interactions. Results: Compared with control, exercise suppressed mean acylated ghrelin concentrations and appetite perceptions (all ES = 0.62 to 1.47, P < 0.001), and elevated total PYY concentrations (ES = 1.49, P < 0.001). For all variables, the SD of the change scores was substantially greater in the exercise versus control conditions. Moderate-to-large positive correlations were observed between the two sets of control-adjusted exercise responses for all variables (r = 0.54 to 0.82, P ≤ 0.036). After adjusting for baseline measurements, participant-by-condition interactions were present for all variables (P ≤ 0.053). Conclusion: Our replicated cross-over study allowed, for the first time, the interaction between participant and acute exercise response in appetite parameters to be quantified. Even after adjustment for individual baseline measurements, participants demonstrated individual differences in perceived appetite and hormone responses to acute exercise bouts beyond any random within-subject variability over time

Exercise, appetite and weight control: are there differences between men and women?

Recent years have witnessed significant research interest surrounding the interaction between exercise, appetite and energy balance which has important implications for health. The majority of exercise and appetite regulation studies have been conducted in males. Consequently, opportunities to examine sex-based differences have been limited, but represent an interesting avenue of inquiry considering postulations that men experience greater weight loss after exercise interventions than women. This article reviews the scientific literature relating to the acute and chronic effects of exercise on appetite control in men and women. The consensus of evidence demonstrates that appetite, appetite-regulatory hormone and energy intake responses to acute exercise do not differ between the sexes, and there is little evidence indicating compensatory changes occur after acute exercise in either sex. Limited evidence suggests women respond to the initiation of exercise training with more robust compensatory alterations in appetite-regulatory hormones than men, but whether this translates to long-term differences is unknown. Current exercise training investigations do not support sex-based differences in appetite or objectively assessed energy intake, and increasing exercise energy expenditure elicits at most a partial energy intake compensation in both sexes. Future well-controlled acute and chronic exercise studies directly comparing men and women are required to expand this evidence base

Acute effect of exercise intensity and duration on acylated ghrelin and hunger in men

Acute exercise transiently suppresses the orexigenic gut hormone acylated ghrelin, but the extent exercise intensity and duration determine this response is not fully understood. The effects of manipulating exercise intensity and duration on acylated ghrelin concentrations and hunger were examined in two experiments. In experiment one, nine healthy males completed three, 4-hour conditions (control, moderate-intensity running (MOD) and vigorous-intensity running (VIG)), with an energy expenditure of ~2.5 MJ induced in both MOD (55 min running at 52% peak oxygen uptake (VO2peak)) and VIG (36 min running at 75% VO2peak). In experiment two, nine healthy males completed three, 9-hour conditions (control, 45 min running (EX45) and 90 min running (EX90)). Exercise was performed at 70% VO2peak. In both experiments, participants consumed standardised meals, and acylated ghrelin concentrations and hunger were quantified at predetermined intervals. In experiment one, delta acylated ghrelin concentrations were lower than control in MOD (ES=0.44, P=0.01) and VIG (ES=0.98, P<0.001); VIG was lower than MOD (ES=0.54, P=0.003). Hunger ratings were similar across the conditions (P=0.35). In experiment two, delta acylated ghrelin concentrations were lower than control in EX45 (ES=0.77, P<0.001) and EX90 (ES=0.68, P<0.001); EX45 and EX90 were similar (ES=0.09, P=0.55). Hunger ratings were lower than control in EX45 (ES=0.20, P=0.01) and EX90 (ES=0.27, P=0.001); EX45 and EX90 were similar (ES=0.07, P=0.34). Hunger and delta acylated ghrelin concentrations remained suppressed at 1.5h in EX90 but not EX45. In conclusion, exercise intensity, and to a lesser extent duration, are determinants of the acylated ghrelin response to acute exercise

Direct Observation of Murine Prion Protein Replication in Vitro.

Prions are believed to propagate when an assembly of prion protein (PrP) enters a cell and replicates to produce two or more fibrils, leading to an exponential increase in PrP aggregate number with time. However, the molecular basis of this process has not yet been established in detail. Here, we use single-aggregate imaging to study fibril fragmentation and elongation of individual murine PrP aggregates from seeded aggregation in vitro. We found that PrP elongation occurs via a structural conversion from a PK-sensitive to PK-resistant conformer. Fibril fragmentation was found to be length-dependent and resulted in the formation of PK-sensitive fragments. Measurement of the rate constants for these processes also allowed us to predict a simple spreading model for aggregate propagation through the brain, assuming that doubling of the aggregate number is rate-limiting. In contrast, while α-synuclein aggregated by the same mechanism, it showed significantly slower elongation and fragmentation rate constants than PrP, leading to much slower replication rate. Overall, our study shows that fibril elongation with fragmentation are key molecular processes in PrP and α-synuclein aggregate replication, an important concept in prion biology, and also establishes a simple framework to start to determine the main factors that control the rate of prion and prion-like spreading in animals.J. C. S. is supported by a Cambridge Trust Scholarship and a Ministry of Education Technologies Incubation Scholarship, Republic of China (Taiwan). L. H. was supported by the Tsinghua University Initiative Scientific Research Program (Grants 20151080424) and the program of China Scholarships Council (CSC). A. M. T was supported in part by an MRC (NC3Rs) Project (Grant NC/K000462/1). G. M. and T. P. J. K. wish to acknowledge support from Sidney Sussex College Cambridge and the ERC grant PhysProt (337969). A. P. acknowledges funding from EPSRC (Grant EP/L027631/1). D. K. acknowledges funding from the Royal society and an ERC Advanced Grant (669237)