Characterization of the Active Site and Insight into the Binding Mode of the Anti-angiogenesis Agent Fumagillin to the Manganese(II)-Loaded Methionyl Aminopeptidase from \u3cem\u3eEscherichia coli\u3c/em\u3e

EPR spectra were recorded for methionine aminopeptidase from Escherichia coli (EcMetAP-I) samples (~2.5 mM) to which one and two equivalents of Mn(II) were added (the latter is referred to as [MnMn(EcMetAP-I)]). The spectra for each sample were indistinguishable except that the spectrum of [MnMn(EcMetAP-I)] was twice as intense. The EPR spectrum of [MnMn(EcMetAP-I)] exhibited the characteristic six-line g≈2 EPR signal of mononuclear Mn(II) with A av(55Mn)=9.3 mT (93 G) and exhibited Curie-law temperature dependence. This signal is typical of Mn(II) in a ligand sphere comprising oxygen and/or nitrogen atoms. Other features in the spectrum were observed only as the temperature was raised from that of liquid helium. The temperature dependences of these features are consistent with their assignment to excited state transitions in the S=1, 2 ... 5 non-Kramer’s doublets, due to two antiferromagnetically coupled Mn(II) ions with an S=0 ground state. This assignment is supported by the observation of a characteristic 4.5 mT hyperfine pattern, and by the presence of signals in the parallel mode consistent with a non-Kramers’ spin ladder. Upon the addition of the anti-angiogenesis agent fumagillin to [MnMn(EcMetAP-I)], very small changes were observed in the EPR spectrum. MALDI-TOF mass spectrometry indicated that fumagillin was, however, covalently coordinated to EcMetAP-I. Therefore, the inhibitory action of this anti-angiogenesis agent on EcMetAP-I appears to involve covalent binding to a polypeptide component at or near the active site rather than direct binding to the metal ions

Nonexistence of Informative Unbiased Estimators in Singular Problems

In many nonparametric problems, such as density estimation, nonparametric regression and so on, all the existing informative estimators are biased (asymptotic or finite sample). There has long been a suspicion that either informative unbiased estimators do not exist for such problems or they must be quite complicated. In this paper, we clarify the nonexistence of informative unbiased estimators in all singular problems both for fixed sample size and asymptotically (this includes most problems with optimal rate of convergence slower than n−1/2). We also discuss situations in regular problems where such nonexistences can occur

A blended-learning approach to supporting students in organic chemistry: Methodology and outcomes

In the recent past, we recognised the need to support students in developing an effective approach to learning mechanistic organic chemistry, as many were finding it challenging to identify appropriate strategies to tackle this key area of their studies. A set of supporting resources in the form of videos and animations to reinforce understanding of the basic principles behind mechanisms were designed to improve skill levels and confidence. An online approach to delivery and engagement was combined with selfassessment to produce a package that was delivered as a vacation activity which was not credit bearing. The outcomes of the initial experiment included excellent levels of uptake by students, with many expressing greater confidence in their ability to understand and apply their mechanistic knowledge. Since the first iteration of this project a thorough qualitative evaluation has been undertaken. The clear message is that students found these resources valuable in their learning. This paper will describe the methodology and the outcomes from both the student and tutor perspective

A short diastereoselective total synthesis of (±)-vibralactone

A total synthesis of the (±)-vibralactone has been achieved in 11 steps and 16% overall yield from malonic acid. Key steps include a highly diastereoselective allylation of an α-formyl ester containing an all carbon α-quaternary center, a Pd-catalyzed deallylative β-lactonization, and an aldehyde-selective Wacker oxidation of a terminal alkene

Towards understanding interactions between Sustainable Development Goals: the role of environment–human linkages

Only 10 years remain to achieve all Sustainable Development Goals (SDGs) globally, so there is a growing need to increase the effectiveness and efficiency of action by targeting multiple SDGs. The SDGs were conceived as an ‘indivisible whole’, but interactions between SDGs need to be better understood. Several previous assessments have begun to explore interactions including synergies and possible conflicts between the SDGs, and differ widely in their conclusions. Although some highlight the role of the more environmentally-focused SDGs in underpinning sustainable development, none specifically focuses on environment-human linkages. Assessing interactions between SDGs, and the influence of environment on them, can make an important contribution to informing decisions in 2020 and beyond. Here, we review previous assessments of interactions among SDGs, apply an influence matrix to assess pairwise interactions between all SDGs, and show how viewing these from the perspective of environment-human linkages can influence the outcome. Environment, and environment-human linkages, influence most interactions between SDGs. Our action-focused assessment enables decision makers to focus environmental management to have the greatest impacts, and to identify opportunities to build on synergies and reduce trade-offs between particular SDGs. It may enable sectoral decision makers to seek support from environment managers for achieving their goals. We explore cross-cutting issues and the relevance and potential application of our approach in supporting decision making for progress to achieve the SDGs

A Parallactic Distance of 389 +24/-21 parsecs to the Orion Nebula Cluster from Very Long Baseline Array Observations

We determine the parallax and proper motion of the flaring, non-thermal radio star GMR A, a member of the Orion Nebula Cluster, using Very Long Baseline Array observations. Based on the parallax, we measure a distance of 389 +24/-21 parsecs to the source. Our measurement places the Orion Nebula Cluster considerably closer than the canonical distance of 480 +/- 80 parsecs determined by Genzel et al. (1981). A change of this magnitude in distance lowers the luminosities of the stars in the cluster by a factor of ~ 1.5. We briefly discuss two effects of this change--an increase in the age spread of the pre-main sequence stars and better agreement between the zero-age main-sequence and the temperatures and luminosities of massive stars.Comment: 10 pages, 4 figures, emulateapj, accepted to Ap

A microflow electrolysis cell for laboratory synthesis on the multigram scale

A large microflow electrolysis cell for laboratory synthesis on a multigram scale is described. It is based on two circular electrodes with a diameter of 149 mm and a spiral electrolyte flow channel 2000 mm long, 5 mm wide, and 0.5 mm interelectrode gap. Using the methoxylation of N-formylpyrrolidine as a model reaction, it is demonstrated that the cell approaches 100% conversion in a single pass, and it is possible to achieve a reaction selectivity >95% and a product formation rate of >20 g h–1