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BackgroundA major pathological hallmark of AD is the deposition of insoluble extracellular β-amyloid (Aβ) plaques. There are compelling data suggesting that Aβ aggregation is catalysed by reaction with the metals zinc and copper.Methodology/Principal FindingsWe now report that the major human-expressed metallothionein (MT) subtype, MT-2A, is capable of preventing the in vitro copper-mediated aggregation of Aβ1–40 and Aβ1–42. This action of MT-2A appears to involve a metal-swap between Zn7MT-2A and Cu(II)-Aβ, since neither Cu10MT-2A or carboxymethylated MT-2A blocked Cu(II)-Aβ aggregation. Furthermore, Zn7MT-2A blocked Cu(II)-Aβ induced changes in ionic homeostasis and subsequent neurotoxicity of cultured cortical neurons.Conclusions/SignificanceThese results indicate that MTs of the type represented by MT-2A are capable of protecting against Aβ aggregation and toxicity. Given the recent interest in metal-chelation therapies for AD that remove metal from Aβ leaving a metal-free Aβ that can readily bind metals again, we believe that MT-2A might represent a different therapeutic approach as the metal exchange between MT and Aβ leaves the Aβ in a Zn-bound, relatively inert form.

Low translational yield for stroke may reflect the focus of discovery science on rodents rather than humans. Just how little is known about human neuronal ischaemic responses is confirmed by systematic review and meta-analysis revealing that data for the most commonly used SH-SY5Y human cells comprises only 84 papers. Oxygen-glucose deprivation, H2O2, hypoxia, glucose-deprivation and glutamate excitotoxicity yielded − 58, − 61, − 29, − 45 and − 49% injury, respectively, with a dose-response relationship found only for H2O2 injury (R2 = 29.29%, p < 0.002). Heterogeneity (I2 = 99.36%, df = 132, p < 0.0001) was largely attributable to the methods used to detect injury (R2 = 44.77%, p < 0.000) with cell death assays detecting greater injury than survival assays (− 71 vs − 47%, R2 = 28.64%, p < 0.000). Seventy-four percent of publications provided no description of differentiation status, but in the 26% that did, undifferentiated cells were susceptible to greater injury (R2 = 4.13%, p < 0.047). One hundred and sixty-nine interventions improved average survival by 34.67% (p < 0.0001). Eighty-eight comparisons using oxygen-glucose deprivation found both benefit and harm, but studies using glutamate and H2O2 injury reported only improvement. In studies using glucose deprivation, intervention generally worsened outcome. There was insufficient data to rank individual interventions, but of the studies reporting greatest improvement (> 90% effect size), 7/13 were of herbal medicine constituents (24.85% of the intervention dataset). We conclude that surprisingly little is known of the human neuronal response to ischaemic injury, and that the large impact of methodology on outcome indicates that further model validation is required. Lack of evidence for randomisation, blinding or power analysis suggests that the intervention data is at substantial risk of bias.Electronic supplementary materialThe online version of this article (10.1007/s12975-018-0620-4) contains supplementary material, which is available to authorized users.

ObjectiveTo determine whether a change in editorial policy, including the implementation of a checklist, has been associated with improved reporting of measures which might reduce the risk of bias.MethodsThe study protocol has been published at doi: 10.1007/s11192-016-1964-8.DesignObservational cohort study.PopulationArticles describing research in the life sciences published in Nature journals, submitted after 1 May 2013.InterventionMandatory completion of a checklist during manuscript revision.Comparators(1) Articles describing research in the life sciences published in Nature journals, submitted before May 2013; and (2) similar articles in other journals matched for date and topic.Primary outcomeThe primary outcome is change in the proportion of Nature articles describing in vivo research published before and after May 2013 reporting the ‘Landis 4’ items (randomisation, blinding, sample size calculation and exclusions). We included 448 Nature Publishing Group (NPG) articles (223 published before May 2013, and 225 after) identified by an individual hired by NPG for this specific task, working to a standard procedure; and an independent investigator used PubMed ‘Related Citations’ to identify 448 non-NPG articles with a similar topic and date of publication from other journals; and then redacted all articles for time-sensitive information and journal name. Redacted articles were assessed by two trained reviewers against a 74-item checklist, with discrepancies resolved by a third.Results394 NPG and 353 matching non-NPG articles described in vivo research. The number of NPG articles meeting all relevant Landis 4 criteria increased from 0/203 prior to May 2013 to 31/181 (16.4%) after (two-sample test for equality of proportions without continuity correction, Χ²=36.2, df=1, p=1.8×10−9). There was no change in the proportion of non-NPG articles meeting all relevant Landis 4 criteria (1/164 before, 1/189 after). There were more substantial improvements in the individual prevalences of reporting of randomisation, blinding, exclusions and sample size calculations for in vivo experiments, and less substantial improvements for in vitro experiments.ConclusionThere was an improvement in the reporting of risks of bias in in vivo research in NPG journals following a change in editorial policy, to a level that to our knowledge has not been previously observed. However, there remain opportunities for further improvement.

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