DFT-Assisted Design and Evaluation of Bifunctional Amine/Pyridine-Oxazoline Metal Catalysts for Additions of Ketones to Unactivated Alkenes and Alkynes

Bifunctional catalyst systems for the direct addition of ­ketones to unactivated alkenes/alkynes were designed and modeled by density functional theory (DFT). The designed catalysts possess bidentate ligands suitable for binding of pi-acidic group 10 metals capable of activating alkenes/alkynes, and a tethered organocatalyst amine to ­activate the ketone via formation of a nucleophilic enamine intermediate. The structures of the designed catalysts before and after C–C bond formation were optimized using DFT, and reaction steps involving group 10 metals were predicted to be significantly exergonic. A novel oxazoline precatalyst with a tethered amine separated by a meta-substituted benzene spacer was synthesized via a 10-step sequence that ­includes a key regioselective epoxide ring-opening step. It was combined with group 10 metal salts, including cationic Pd(II) and Pt(II), and screened for the direct addition of ketones to several alkenes and an ­internal alkyne. 1H NMR studies suggest that catalyst-catalyst inter­actions with this system via amine–metal coordination may preclude the desired addition reactions. The catalyst design approach disclosed here, and the promising calculations obtained with square planar group 10 metals, light a path for the discovery of novel bifunctional catalysts for C–C bond formation

Predicting uncertainty and risk in the natural sciences: bridging the gap between academics and industry

The increase in large-scale disasters in recent years, such as the 2007 floods in the UK, has caused disruptions of livelihood, enormous economic losses and increase in fatalities. Losses from natural hazards are only partially derived from the physical event itself but are also caused by society’s vulnerability to it. In the first three months of 2010, an unprecedented US$16 billion in losses occurred from natural hazards caused by events such as the Haiti and Chilean earthquakes, and the European storm Xynthia. This made it the worst ever first quarter for natural hazard losses and left the insurance industry exposed financially to the more loss-prone third and forth quarters. NERC science has a central role to play in the forecasting and mitigation of natural hazards. Research in this area forms the basis for technological solutions to early warning systems, designing mitigation strategies and providing critical information for decision makers to help save lives and avoid economic losses. Understanding uncertainty is essential if reliable forecasting and risk assessments are to be made. However, the quantification and assessment of uncertainty in natural hazards has in general been limited particularly in terms of model limitations and multiplicity. There are several reasons for this; most notably the fragmented nature of natural hazard research which is split both across science areas and between research, risk management and policy. Because of this, each sector has developed its own concepts and language which has acted as a barrier for effective communication and prevented the production of generic methods that have the potential to be used across sectors. It is clear therefore that by bringing the natural hazard community together significant breakthroughs in the visualisation and understanding of risk and uncertainty could be achieved. To accomplish this, this research programme has 4 prime objectives: 1.To improve communication and networking between researchers and risk managers within the financial services sector 2.To provide a platform for the dissemination of information on uncertainty and risk analysis between a range of researchers and practitioners 3.To generate a portfolio of best practice in uncertainty and risk analysis 4.To act as a focal point between the financial sector and natural hazard research in NERC This paper will discuss how the Natural Environmental Research Council, in partnership with other organisations such as TSB, EA and EPSRC etc, is working with academics and industry to bring about a step change in the way that uncertainty and risk assessments are achieved throughout the natural hazard community

Altruism: Biological Rationale vs. Christian Love Command

The idea of altruism and self-sacrifice appears counter to a simple view of evolution. While a “survival of the fittest” mindset occurs in some Darwinian views, there are counter-examples of animals and humans with cooperative, pro-social, and even self-sacrificial behavior. Social animals such as bees and ants work for the community and provide for the queen due to a haploid-diploid system of genetic relatedness. Some humans sacrifice their lives and money to promote the well-being of others even without genetic relatedness and, rarely, without reciprocity. We will explore why human animals often help people who are less fortunate by giving away financial and time resources. Such behaviors appear to violate natural law. A further complication in human behavior is the “do unto others” teaching in several religions including the Christian love command

Can Manipulators Mislead Prediction Market Observers?

We study experimental markets where privately informed traders exchange simple assets, and where uninformed third parties are asked to forecast the values of these assets, guided only by market prices. Although prices only partially aggregate information, they significantly improve the forecasts of third parties. In a second treatment, a portion of traders are given preferences over the forecasts made by observers. Although we find evidence that these traders attempt to manipulate prices in order to influence the beliefs of observers, we find no evidence that observers make less accurate forecasts as a result.

Interleukin-6 blockade raises LDL via reduced catabolism rather than via increased synthesis: a cytokine-specific mechanism for cholesterol changes in rheumatoid arthritis

Objectives Patients with rheumatoid arthritis (RA) have reduced serum low-density lipoprotein cholesterol (LDL-c), which increases following therapeutic IL-6 blockade. We aimed to define the metabolic pathways underlying these lipid changes. Methods In the KALIBRA study, lipoprotein kinetic studies were performed on 11 patients with severe active RA at baseline and following three intravenous infusions of the IL-6R blocker tocilizumab. The primary outcome measure was the fractional catabolic rate (FCR) of LDL. Results Serum total cholesterol (4.8 vs 5.7 mmol/L, p=0.003), LDL-c (2.9 vs 3.4 mmol/L, p=0.014) and high-density lipoprotein cholesterol (1.23 vs 1.52 mmol/L, p=0.006) increased following tocilizumab therapy. The LDL FCR fell from a state of hypercatabolism to a value approximating that of the normal population (0.53 vs 0.27 pools/day, p=0.006). Changes in FCR correlated tightly with changes in serum LDL-c and C-reactive protein but not Clinical Disease Activity Index. Conclusions Patients with RA have low serum LDL-c due to hypercatabolism of LDL particles. IL-6 blockade normalises this catabolism in a manner associating with the acute phase response (and thus hepatic IL-6 signalling) but not with RA disease activity as measured clinically. We demonstrate that IL-6 is one of the key drivers of inflammation-driven dyslipidaemia

Web-based eTutor for learning electrical circuit analysis

This paper discusses a web-based eTutor for learning electrical circuit analysis. The eTutor system components, mainly the user-interface and the assessment model, are described. The system architecture developed provides a framework to support interactive sessions between the human and the machine for the case when the human is a student and the machine a tutor and also for the case when the roles of the human and the machine are swapped. To motivate the usefulness of the data gathered, some examples of interactive sessions are given and models to capture both declarative and procedural knowledge during learning are discussed. A probabilistic assessment model is reviewed and future directions in the field of eTutors for electrical circuits are discussed.peer-reviewe