Reexamination of Lead(II) Coordination Preferences in Sulfur-Rich Sites: Implications for a Critical Mechanism of Lead Poisoning

Recent studies suggest that the developmental toxicity associated with childhood lead poisoning may be attributable to interactions of Pb(II) with proteins containing thiol-rich structural zinc-binding sites. Here, we report detailed structural studies of Pb(II) in such sites, providing critical insights into the mechanism by which lead alters the activity of these proteins. X-ray absorption spectroscopy of Pb(II) bound to structural zinc-binding peptides reveals that Pb(II) binds in a three-coordinate Pb(II)-S3 mode, while Zn(II) is known to bind in a four-coordinate mode in these proteins. This Pb(II)-S_3 coordination in peptides is consistent with a trigonal pyramidal Pb(II)-S_3 model compound previously reported by Bridgewater and Parkin, but it differs from many other reports in the small molecule literature which have suggested Pb(II)-S_4 as a preferred coordination mode for lead. Reexamination of the published structures of these “Pb(II)-S_4” compounds reveals that, in almost all cases, the coordination number of Pb is actually 5, 6, or 8. The results reported herein combined with this new review of published structures suggest that lead prefers to avoid four-coordination in sulfur-rich sites, binding instead as trigonal pyramidal Pb(II)-S_3 or as Pb(II)-S_(5-8). In the case of structural zinc-binding protein sites, the observation that lead binds in a three-coordinate mode, and in a geometry that is fundamentally different from the natural coordination of zinc in these sites, explains why lead disrupts the structure of these peptides and thus provides the first detailed molecular understanding of the developmental toxicity of lead

British Society of Gastroenterology guidelines for the diagnosis and management of cholangiocarcinoma

These guidelines for the diagnosis and management of cholangiocarcinoma (CCA) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included a multidisciplinary team of experts from various specialties involved in the management of CCA, as well as patient/public representatives from AMMF (the Cholangiocarcinoma Charity) and PSC Support. Quality of evidence is presented using the Appraisal of Guidelines for Research and Evaluation (AGREE II) format. The recommendations arising are to be used as guidance rather than as a strict protocol-based reference, as the management of patients with CCA is often complex and always requires individual patient-centred considerations

The Electronic Influence of Ring Substituents and Ansa Bridges in Zirconocene Complexes as Probed by Infrared Spectroscopic, Electrochemical, and Computational Studies

The electronic influence of unbridged and ansa-bridged ring substituents on a zirconocene center has been studied by means of IR spectroscopic, electrochemical, and computational methods. With respect to IR spectroscopy, the average of the symmetric and asymmetric stretches (ν_(CO(av))) of a large series of dicarbonyl complexes (Cp^R)_2Zr(CO)_2 has been used as a probe of the electronic influence of a cyclopentadienyl ring substituent. For unbridged substituents (Me, Et, Pri, But, SiMe_3), ν_(CO(av)) on a per substituent basis correlates well with Hammett σ_(meta) parameters, thereby indicating that the influence of these substituents is via a simple inductive effect. In contrast, the reduction potentials (E°) of the corresponding dichloride complexes (Cp^R)_2ZrCl_2 do not correlate well with Hammett σ_(meta) parameters, thereby suggesting that factors other than the substituent inductive effect also influence E°. Ansa bridges with single-atom linkers, for example [Me_2C] and [Me_2Si], exert a net electron-withdrawing effect, but the effect is diminished upon increasing the length of the bridge. Indeed, with a linker comprising a three-carbon chain, the [CH_2CH_2CH_2] ansa bridge becomes electron-donating. In contrast to the electron-withdrawing effect observed for a single [Me_2Si] ansa bridge, a pair of vicinal [Me_2Si] ansa bridges exerts an electron-donating effect relative to that from the single bridge. DFT calculations demonstrate that the electron-withdrawing effect of the [Me_2C] and [Me_2Si] ansa-bridges is due to stabilization of the cyclopentadienyl ligand acceptor orbital, which subsequently enhances back-donation from the metal. The calculations also indicate that the electron-donating effect of two vicinal [Me_2Si] ansa bridges, relative to that of a single bridge, is a result of it enforcing a ligand conformation that reduces back-donation from the metal

Managing the whole landscape: historical, hybrid, and novel ecosystems

The reality confronting ecosystem managers today is one of heterogeneous, rapidly transforming landscapes, particularly in the areas more affected by urban and agricultural development. A landscape management framework that incorporates all systems, across the spectrum of degrees of alteration, provides a fuller set of options for how and when to intervene, uses limited resources more effectively, and increases the chances of achieving management goals. That many ecosystems have departed so substantially from their historical trajectory that they defy conventional restoration is not in dispute. Acknowledging novel ecosystems need not constitute a threat to existing policy and management approaches. Rather, the development of an integrated approach to management interventions can provide options that are in tune with the current reality of rapid ecosystem change