Biocatalyzed C-C bond formation for the production of alkaloids

Traditional methods of chemical synthesis of alkaloids exhibit various problems such as lack of enantioselectivity, the use of toxic chemical and intermediates, and multiple numbers of synthetic steps. Consequently, various enzymatic methods for the formation of C-C bonds in the alkaloid skeleton have been developed. Herein, we report advances achieved in the enzymatic or chemo-enzymatic synthesis of pharmaceutically important alkaloids that employ three C-C bond forming enzymes: two Pictet-Spenglerases and the oxidative C-C bond forming flavoenzyme Berberine Bridge Enzyme. Protein engineering studies, improving the substrate scope of these enzymes, and thereby leading to the synthesis of non-natural alkaloids possessing higher or newer pharmacological activities, are also discussed. Furthermore, the integration of these biocatalysts with other enzymes, in multi-enzymatic cascades for the enantioselective synthesis of alkaloids, is also reviewed. Current results suggest that these enzymes hold great promise for the generation of C-C bonds in the selective synthesis of alkaloid compounds possessing diverse pharmacological properties

Mental Imagery-Based Training to Modify Mood and Cognitive Bias in Adolescents: Effects of Valence and Perspective

Mental imagery has a powerful impact on emotion and cognitive processing in adults, and is implicated in emotional disorders. Research suggests the perspective adopted in mental imagery modulates its emotional impact. However, little is known about the impact of mental imagery in adolescence, despite adolescence being the key time for the onset of emotional dysfunction. We administered computerised positive versus mixed valence picture-word mental imagery training to male adolescent participants (N = 60, aged 11–16 years) across separate field and observer perspective sessions. Positive mood increased more following positive than mixed imagery; pleasantness ratings of ambiguous pictures increased following positive versus mixed imagery generated from field but not observer perspective; negative interpretation bias on a novel scrambled sentences task was smaller following positive than mixed imagery particularly when imagery was generated from field perspective. These findings suggest positive mental imagery generation alters mood and cognition in male adolescents, with the latter moderated by imagery perspective. Identifying key components of such training, such as imagery perspective, extends understanding of the relationship between mental imagery, mood, and cognition in adolescence

Scaling of the distribution of fluctuations of financial market indices

We study the distribution of fluctuations over a time scale $\Delta t$ (i.e., the returns) of the S&P 500 index by analyzing three distinct databases. Database (i) contains approximately 1 million records sampled at 1 min intervals for the 13-year period 1984-1996, database (ii) contains 8686 daily records for the 35-year period 1962-1996, and database (iii) contains 852 monthly records for the 71-year period 1926-1996. We compute the probability distributions of returns over a time scale $\Delta t$, where $\Delta t$ varies approximately over a factor of 10^4 - from 1 min up to more than 1 month. We find that the distributions for $\Delta t \leq$ 4 days (1560 mins) are consistent with a power-law asymptotic behavior, characterized by an exponent $\alpha \approx 3$, well outside the stable L\'evy regime $0 < \alpha < 2$. To test the robustness of the S&P result, we perform a parallel analysis on two other financial market indices. Database (iv) contains 3560 daily records of the NIKKEI index for the 14-year period 1984-97, and database (v) contains 4649 daily records of the Hang-Seng index for the 18-year period 1980-97. We find estimates of $\alpha$ consistent with those describing the distribution of S&P 500 daily-returns. One possible reason for the scaling of these distributions is the long persistence of the autocorrelation function of the volatility. For time scales longer than $(\Delta t)_{\times} \approx 4$ days, our results are consistent with slow convergence to Gaussian behavior.Comment: 12 pages in multicol LaTeX format with 27 postscript figures (Submitted to PRE May 20, 1999). See http://polymer.bu.edu/~amaral/Professional.html for more of our work on this are

Asymptotic analysis of the dominant mechanisms in the coffee extraction process

peer-reviewedExtraction of coffee solubles from roast and ground coffee is a highly complex process, depending on a large number of brewing parameters. We consider a recent, experimentally validated, model of coffee extraction, describing extraction from a coffee bed using a double porosity model, which includes dissolution and transport of coffee. It was shown that this model can accurately describe coffee extraction in two situations: extraction from a dilute suspension of coffee grains and extraction from a packed coffee bed. Despite being based on some simplifying assumptions, this model can only be solved numerically. In this paper we consider asymptotic solutions of the model describing extraction from a packed coffee bed. Such solutions can explicitly relate coffee concentration to the process parameters. For an individual coffee grain, extraction is controlled by a rapid dissolution of coffee from the surface of the grain, in conjunction with a slower diffusion of coffee through the intragranular pore network to the grain surface. Extraction of coffee from the bed also depends on the speed of advection of coffee from the bed. We utilize the small parameter resulting from the ratio of the advection timescale to the grain diffusion timescale to construct asymptotic solutions using the method of matched asymptotic expansions. The asymptotic solutions are compared to numerical solutions and data from coffee extraction experiments. The asymptotic solutions depend on a small number of dimensionless parameters and so are useful to quickly fit extraction curves and investigate the influence of various process parameters on the extraction.PUBLISHEDpeer-reviewe

When we should worry more: Using cognitive bias modification to drive adaptive health behaviour

A lack of behavioural engagement in health promotion or disease prevention is a problem across many health domains. In these cases where people face a genuine danger, a reduced focus on threat and low levels of anxiety or worry are maladaptive in terms of promoting protection or prevention behaviour. Therefore, it is possible that increasing the processing of threat will increase worry and thereby enhance engagement in adaptive behaviour. Laboratory studies have shown that cognitive bias modification (CBM) can increase or decrease anxiety and worry when increased versus decreased processing of threat is encouraged. In the current study, CBM for interpretation (CBM-I) is used to target engagement in sun protection behaviour. The goal was to investigate whether inducing a negative rather than a positive interpretation bias for physical threat information can enhance worry elicited when viewing a health campaign video (warning against melanoma skin cancer), and consequently lead to more adaptive behaviour (sun protection). Participants were successfully trained to either adopt a positive or negative interpretation bias using physical threat scenarios. However, contrary to expectations results showed that participants in the positive training condition reported higher levels of worry elicited by the melanoma video than participants in the negative training condition. Video elicited worry was, however, positively correlated with a measure of engagement in sun protection behaviour, suggesting that higher levels of worry do promote adaptive behaviour. These findings imply that more research is needed to determine under which conditions increased versus decreased processing of threat can drive adaptive worry. Various potential explanations for the current findings and suggestions for future research are discussed

Islet Formation during the Neonatal Development in Mice

The islet of Langerhans is a unique micro-organ within the exocrine pancreas, which is composed of insulin-secreting beta-cells, glucagon-secreting alpha-cells, somatostatin-secreting delta-cells, pancreatic polypeptide-secreting PP cells and ghrelin-secreting epsilon-cells. Islets also contain non-endocrine cell types such as endothelial cells. However, the mechanism(s) of islet formation is poorly understood due to technical difficulties in capturing this dynamic event in situ. We have developed a method to monitor beta-cell proliferation and islet formation in the intact pancreas using transgenic mice in which the beta-cells are specifically tagged with a fluorescent protein. Endocrine cells proliferate contiguously, forming branched cord-like structures in both embryos and neonates. Our study has revealed long stretches of interconnected islets located along large blood vessels in the neonatal pancreas. Alpha-cells span the elongated islet-like structures, which we hypothesize represent sites of fission and facilitate the eventual formation of discrete islets. We propose that islet formation occurs by a process of fission following contiguous endocrine cell proliferation, rather than by local aggregation or fusion of isolated beta-cells and islets. Mathematical modeling of the fission process in the neonatal islet formation is also presented

Retinoic Acid Promotes the Generation of Pancreatic Endocrine Progenitor Cells and Their Further Differentiation into β-Cells

The identification of secreted factors that can selectively stimulate the generation of insulin producing β-cells from stem and/or progenitor cells represent a significant step in the development of stem cell-based β-cell replacement therapy. By elucidating the molecular mechanisms that regulate the generation of β-cells during normal pancreatic development such putative factors may be identified. In the mouse, β-cells increase markedly in numbers from embryonic day (e) 14.5 and onwards, but the extra-cellular signal(s) that promotes the selective generation of β-cells at these stages remains to be identified. Here we show that the retinoic acid (RA) synthesizing enzyme Raldh1 is expressed in developing mouse and human pancreas at stages when β-cells are generated. We also provide evidence that RA induces the generation of Ngn3+ endocrine progenitor cells and stimulates their further differentiation into β-cells by activating a program of cell differentiation that recapitulates the normal temporal program of β-cell differentiation