Pyroglutamate-modified amyloid-␤ (pE-A␤) is a highly neurotoxic amyloid-␤ (A␤) isoform and is enriched in the brains of individuals with Alzheimer disease compared with healthy aged controls. Pyroglutamate formation increases the rate of A␤ oligomerization and alters the interactions of A␤ with Cu 2؉ and lipids; however, a link between these properties and the toxicity of pE-A␤ peptides has not been established. We report here that A␤3pE-42 has an enhanced capacity to cause lipid peroxidation in primary cortical mouse neurons compared with the fulllength isoform (A␤(1-42)). In contrast, A␤(1-42) caused a significant elevation in cytosolic reactive oxygen species, whereas A␤3pE-42 did not. We also report that A␤3pE-42 preferentially associates with neuronal membranes and triggers Ca 2؉ influx that can be partially blocked by the N-methyl-D-aspartate receptor antagonist MK-801. A␤3pE-42 further caused a loss of plasma membrane integrity and remained bound to neurons at significantly higher levels than A␤(1-42) over extended incubations. Pyroglutamate formation was additionally found to increase the relative efficiency of A␤-dityrosine oligomer formation mediated by copper-redox cycling.A␤ 3 peptides are found in every human brain; however, the concentration and composition of A␤ peptide isoforms are distinctly different in healthy individuals and people with AD (1-3). Amino-truncated A␤ peptides are abundant in the AD brain (4, 5) and increase in prevalence with disease progression (6). The process of A␤ amino-truncation can occur via the actions of aminopeptidases on full-length A␤ peptides (7, 8), via altered cleavage of amyloid precursor protein in the generation of A␤ (9 -11), and potentially by A␤-copper-redox cycling reactions (12). As a consequence, aminotruncation can expose glutamate residues (positions 3 and 11 of A␤) to cyclization by the action of glutaminyl cyclase (QC), forming the highly amyloidogenic pyroglutamate-A␤ (pE-A␤) peptides A␤3pE-40, A␤3pE-42, A␤11pE-40, and A␤11pE-42 (7, 13).Pyroglutamate formation significantly increases the hydrophobicity of A␤, causing the peptide to aggregate more rapidly and form oligomers at lower concentration thresholds (5, 14, 15). pE-A␤ peptides also demonstrate increased ␤-sheet (aggregate structure) stability (16, 17), differences in fibril ultrastructure (18,19), and altered interactions with copper ions (20, 21) and synthetic lipid membranes (22, 23). Notably, trace quantities of A␤3pE-42 have been observed to dramatically enhance the aggregation and neurotoxicity of A␤(1-42) (24), prompting descriptions of pE-A␤ as "prionlike." Still, it remains unclear as to the cytotoxic potency of pE-A␤ peptides compared with their full-length A␤ counterparts. Some studies have demonstrated pE-A␤ peptides to have enhanced toxicity (24 -26), although others have reported no difference in toxicity between the isoforms (27-30). Methodological differences may account somewhat for variability in the relative toxicities reported (Table 1), yet molecular mechanisms to explain...

Cyclopropyl malonoyl peroxide (1), which can be prepared in a single step from the commercially available diacid, is an effective reagent for the dihydroxylation of alkenes. Reaction of 1 with an alkene in the presence of 1 equiv of water at 40 °C followed by alkaline hydrolysis leads to the corresponding diol (40-93%). With 1,2-disubstituted alkenes, the reaction proceeds with syn selectivity (3:1 to >50:1). A mechanism consistent with the experimental findings that is supported by oxygen-labeling studies is proposed.

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This article first makes a case for the need to establish evaluation reporting standards, support for which is rooted in the growing demand for professionalization, in the growing metaevaluation literature, and in growing efforts to develop reporting standards for inquiry efforts. Then, a case is made for a particular set of such standards introduced in this article—the CHecklist for Evaluation-Specific Standards (CHESS). In doing so, this article outlines the process used and presents the resulting checklist and associated standards, which are defined as the minimum, evaluation-specific elements that must be reported to make judgments about the quality of the evaluation. This article also describes a few of the categories to offer illustrative information to help readers better understand and consider the usefulness of the proposed checklist. A discussion of CHESS, including challenges and next steps, is also included.