Three Repeat Isoforms of Tau Inhibit Assembly of Four Repeat Tau Filaments

Tauopathies are defined by assembly of the microtubule associated protein tau into filamentous tangles and classified by the predominant tau isoform within these aggregates. The major isoforms are determined by alternative mRNA splicing of exon 10 generating tau with three (3R) or four (4R) ∼32 amino acid imperfect repeats in the microtubule binding domain. In normal adult brains there is an approximately equimolar ratio of 3R and 4R tau which is altered by several disease-causing mutations in the tau gene. We hypothesized that when 4R and 3R tau isoforms are not at equimolar ratios aggregation is favored. Here we provide evidence for the first time that the combination of 3R and 4R tau isoforms results in less in vitro heparin induced polymerization than with 4R preparations alone. This effect was independent of reducing conditions and the presence of alternatively spliced exons 2 and 3 N-terminal inserts. The addition of even small amounts of 3R to 4R tau assembly reactions significantly decreased 4R assembly. Together these findings suggest that co-expression of 3R and 4R tau isoforms reduce tau filament assembly and that 3R tau isoforms inhibit 4R tau assembly. Expression of equimolar amounts of 3R and 4R tau in adult humans may be necessary to maintain proper neuronal microtubule dynamics and to prevent abnormal tau filament assembly. Importantly, these findings indicate that disruption of the normal equimolar 3R to 4R ratio may be sufficient to drive tau aggregation and that restoration of the tau isoform balance may have important therapeutic implications in tauopathies

Frequent high-level expression of the immunotherapeutic target Ep-CAM in colon, stomach, prostate and lung cancers

Epithelial cell adhesion molecule (Ep-CAM; CD326) is used as a target by many immunotherapeutic approaches, but little data are available about Ep-CAM expression in major human malignancies with respect to level, frequency, tumour stage, grade, histologic tumour type and impact on survival. We analysed by immunohistochemical staining tissue microarrays with 4046 primary human carcinoma samples from colon, stomach, prostate and lung cancers for both frequency and intensity of Ep-CAM expression under highly standardised conditions. A total of 3360 samples were analysable. High-level Ep-CAM expression was observed in 97.7% (n=1186) of colon, 90.7% of gastric (n=473), and 87.2% of prostate cancers (n=414), and in 63.9% of lung cancers (n=1287). No detectable Ep-CAM staining was found with only 0.4% of colon, 2.5% of gastric, 1.9% of prostate cancers, and 13.5% of lung cancers. The only significant correlation of Ep-CAM expression with tumour grading was observed in colon cancer where high-level Ep-CAM expression on grade 3 tumours was down to 92.1% (P<0.0001). Adenosquamous and squamous carcinomas of the lung had a lower percentage of high-level Ep-CAM expression compared to adenocarcinomas with 35.4 and 53.6%, respectively, and with 45.5 and 17.3% of tumours being Ep-CAM negative. With the exception of moderately differentiated colon carcinoma, where patients not expressing Ep-CAM on their tumours showed an inferior survival (P=0.0014), correlation of Ep-CAM expression with survival did not reach statistical significance for any of the other cancer indications and subgroups. In conclusion, the data strongly support the notion that Ep-CAM is a prime target for immunotherapies in major human malignancies. This is because the most common human cancers show (i) a low frequency of Ep-CAM-negative tumours, (ii) a high frequency of Ep-CAM expression on cells of a given tumour, and (iii) for most cancers, an insignificant influence of tumour staging, grading and histology on Ep-CAM expression

Effective use of cerium anomalies as a redox proxy in carbonate-dominated marine settings

Rare earth elements and yttrium (REY) have a distinct distribution pattern in seawater, and this pattern may be faithfully preserved in carbonate sediments and rocks. Anomalous concentrations of redox-sensitive cerium (Ce) compared with neighbouring REY originate in oxic water column conditions, and as such, Ce anomalies can provide a potentially useful redox proxy in carbonate-dominated marine settings. The methods used to extract REY from carbonates vary widely, and may suffer from widespread leaching of REY from accessory non-carbonate minerals and organic matter, limiting the application of Ce anomalies for palaeo-redox reconstruction. We have systematically compared different methods on 195 carbonate samples with varying purity (% carbonate) from both modern and ancient environments. We used sequential leaching experiments in nitric acid to identify the most ‘seawater-like’ portion of the carbonate sample where contributions from non-carbonate minerals and organic matter are minimised. We also compared the results of sample dissolution in different types and strengths of acid. Our results confirm that REY concentrations can be inadvertently contaminated by partial leaching of clays and Fe (oxyhydr)oxides during a single-step digestion, and we suggest a pre-leach of 20% of the sample, followed by a partial leach of 40% of the sample to selectively dissolve carbonate. We suggest that REY studies are optimised in carbonates with > 85% CaCO₃, and show that dolomites behave differently during the leaching process and must be treated separately. We present REY patterns for modern carbonate-rich sediments from a range of environments, and show that seawater REY are faithfully preserved in some non-skeletal carbonate, but modified leaching procedures are necessary for impure, unlithified or organic rich carbonate sediments. We combine REY with Fe-speciation data to identify how Fe oxides and clays contribute to the REY signal and explore how the two proxies can be used together to provide a complex and high-resolution redox reconstruction in carbonate-dominated marine environments

Mass Media, Instrumental Information, and Electoral Accountability

Journalism is widely believed to be crucial for holding elected officials accountable. At the same time economic theory has a hard time providing an instrumental explanation for the existence of “accountability journalism”. According to the common Downsian reasoning, rational voters should not be willing to pay for information out of purely instrumental motives because the individual probabilities of casting the decisive vote are typically very low. We show that this rationale does not apply when a group of voters shares a common goal such as accountability and information is delivered via mass media. In contrast to the pessimistic Downsian view, rational voters can have a considerable willingness to pay for the provision of instrumental information in these scenarios. Our model thus reconciles the rational voter approach with the common perception of journalism as a watchdog that holds elected officials accountable