Cellular Models of Aggregation-Dependent Template-Directed Proteolysis to Characterize Tau Aggregation Inhibitors for Treatment of Alzheimer's Disease

Copyright © 2015, The American Society for Biochemistry and Molecular Biology. Acknowledgements-We thank Drs Timo Rager and Rolf Hilfiker (Solvias, Switzerland) for polymorph analyses.Peer reviewedPublisher PD

Spitzer IRS Observations of the Galactic Center: Shocked Gas in the Radio Arc Bubble

We present Spitzer IRS spectra (R ~600, 10 - 38 micron) of 38 positions in the Galactic Center (GC), all at the same Galactic longitude and spanning plus/minus 0.3 degrees in latitude. Our positions include the Arches Cluster, the Arched Filaments, regions near the Quintuplet Cluster, the ``Bubble'' lying along the same line-of-sight as the molecular cloud G0.11-0.11, and the diffuse interstellar gas along the line-of-sight at higher Galactic latitudes. From measurements of the [O IV], [Ne II], [Ne III], [Si II], [S III], [S IV], [Fe II], [Fe III], and H_2 S(0), S(1), and S(2) lines we determine the gas excitation and ionic abundance ratios. The Ne/H and S/H abundance ratios are ~ 1.6 times that of the Orion Nebula. The main source of excitation is photoionization, with the Arches Cluster ionizing the Arched Filaments and the Quintuplet Cluster ionizing the gas nearby and at lower Galactic latitudes including the far side of the Bubble. In addition, strong shocks ionize gas to O^{+3} and destroy dust grains, releasing iron into the gas phase (Fe/H ~ 1.3 times 10^{-6} in the Arched Filaments and Fe/H ~ 8.8 times 10^{-6} in the Bubble). The shock effects are particularly noticeable in the center of the Bubble, but O$^{+3}$ is present in all positions. We suggest that the shocks are due to the winds from the Quintuplet Cluster Wolf-Rayet stars. On the other hand, the H_2 line ratios can be explained with multi-component models of warm molecular gas in photodissociation regions without the need for H_2 production in shocks.Comment: 51 pages, 17 figures To be published in the Astrophysical Journa

Dynamic instability of a rotating Bose-Einstein condensate

We consider a Bose-Einstein condensate subject to a rotating harmonic potential, in connection with recent experiments leading to the formation of vortices. We use the classical hydrodynamic approximation to the non-linear Schr\"odinger equation to determine almost analytically the evolution of the condensate. We predict that this evolution can exhibit dynamical instabilities, for the stirring procedure previously demonstrated at ENS and for a new stirring procedure that we put forward. These instabilities take place within the range of stirring frequency and amplitude for which vortices are produced experimentally. They provide therefore an initiating mechanism for vortex nucleation.Comment: 4 pages, 3 figures, last version including comparison with experiment

Early Computed Tomography Coronary Angiography and Preventative Treatment in Patients with Suspected Acute Coronary Syndrome A secondary analysis of the RAPID-CTCA trial

BackgroundComputed tomography coronary angiography (CTCA) offers detailed assessment of the presence of coronary atherosclerosis and helps guide patient management. We investigated influences of early CTCA on the subsequent use of preventative treatment in patients with suspected acute coronary syndrome.MethodsIn this secondary analysis of a multicentre randomised controlled trial of early CTCA in intermediate-risk patients with suspected acute coronary syndrome, prescription of aspirin, P2Y12 receptor antagonist, statin, renin–angiotensin system blocker, and beta-blocker therapies from randomisation to discharge were compared within then between those randomised to early CTCA or to standard of care only. Effects of CTCA findings on adjustment of these therapies were further examined.ResultsIn 1743 patients (874 randomised to early CTCA and 869 to standard of care only), prescription of P2Y12 receptor antagonist, dual antiplatelet, and statin therapiesincreased more in the early CTCA group (between-group difference: 4.6% (95% confidence interval, 0.3 to 8.9), 4.5% (95% confidence interval, 0.2 to 8.7), and 4.3% (95% confidence interval, 0.2 to 8.5), respectively), whereas prescription of other preventative therapies increased by similar extent in both study groups. Amongst patients randomised to early CTCA, there were additional increments of preventative treatment in those with obstructive coronary artery disease and higher rates of 6 reductions in antiplatelet and beta-blocker therapies in those with normal coronary arteries.ConclusionsPrescription patterns of preventative treatment varied during index hospitalisation in patients with suspected acute coronary syndrome. Early CTCA facilitated targeted individualisation of these therapies based on the extent of coronary artery disease.<br/

Early computed tomography coronary angiography in adults presenting with suspected acute coronary syndrome:the RAPID-CTCA RCT

Abstract Background Acute coronary syndrome is a common medical emergency. The optimal strategy to investigate patients who are at intermediate risk of acute coronary syndrome has not been fully determined. Objective To investigate the role of early computed tomography coronary angiography in the investigation and treatment of adults presenting with suspected acute coronary syndrome. Design A prospective, multicentre, open, parallel-group randomised controlled trial with blinded end-point adjudication. Setting Thirty-seven hospitals in the UK. Participants Adults (aged ≥ 18 years) presenting to the emergency department, acute medicine services or cardiology department with suspected or provisionally diagnosed acute coronary syndrome and at least one of the following: (1) a prior history of coronary artery disease, (2) a cardiac troponin level > 99th centile and (3) an abnormal 12-lead electrocardiogram. Interventions Early computed tomography coronary angiography in addition to standard care was compared with standard care alone. Participants were followed up for 1 year. Main outcome measure One-year all-cause death or subsequent type 1 (spontaneous) or type 4b (stent thrombosis) myocardial infarction, measured as the time to such event adjudicated by two cardiologists blinded to the computerised tomography coronary angiography (CTCA) arm. Cost-effectiveness was estimated as the lifetime incremental cost per quality-adjusted life-year gained. Results Between 23 March 2015 and 27 June 2019, 1748 participants [mean age 62 years (standard deviation 13 years), 64% male, mean Global Registry Of Acute Coronary Events score 115 (standard deviation 35)] were randomised to receive early computed tomography coronary angiography (n = 877) or standard care alone (n = 871). The primary end point occurred in 51 (5.8%) participants randomised to receive computed tomography coronary angiography and 53 (6.1%) participants randomised to receive standard care (adjusted hazard ratio 0.91, 95% confidence interval 0.62 to 1.35; p = 0.65). Computed tomography coronary angiography was associated with a reduced use of invasive coronary angiography (adjusted hazard ratio 0.81, 95% confidence interval 0.72 to 0.92; p = 0.001) but no change in coronary revascularisation (adjusted hazard ratio 1.03, 95% confidence interval 0.87 to 1.21; p = 0.76), acute coronary syndrome therapies (adjusted odds ratio 1.06, 95% confidence interval 0.85 to 1.32; p = 0.63) or preventative therapies on discharge (adjusted odds ratio 1.07, 95% confidence interval 0.87 to 1.32; p = 0.52). Early computed tomography coronary angiography was associated with longer hospitalisations (median increase 0.21 days, 95% confidence interval 0.05 to 0.40 days) and higher mean total health-care costs over 1 year (£561 more per patient) than standard care. Limitations The principal limitation of the trial was the slower than anticipated recruitment, leading to a revised sample size, and the requirement to compromise and accept a larger relative effect size estimate for the trial intervention. Future work The potential role of computed tomography coronary angiography in selected patients with a low probability of obstructive coronary artery disease (intermediate or mildly elevated level of troponin) or who have limited access to invasive cardiac catheterisation facilities needs further prospective evaluation. Conclusions In patients with suspected or provisionally diagnosed acute coronary syndrome, computed tomography coronary angiography did not alter overall coronary therapeutic interventions or 1-year clinical outcomes, but it did increase the length of hospital stay and health-care costs. These findings do not support the routine use of early computed tomography coronary angiography in intermediate-risk patients with acute chest pain

Re-sampling strategy to improve the estimation of number of null hypotheses in FDR control under strong correlation structures

<p>Abstract</p> <p>Background</p> <p>When conducting multiple hypothesis tests, it is important to control the number of false positives, or the False Discovery Rate (FDR). However, there is a tradeoff between controlling FDR and maximizing power. Several methods have been proposed, such as the q-value method, to estimate the proportion of true null hypothesis among the tested hypotheses, and use this estimation in the control of FDR. These methods usually depend on the assumption that the test statistics are independent (or only weakly correlated). However, many types of data, for example microarray data, often contain large scale correlation structures. Our objective was to develop methods to control the FDR while maintaining a greater level of power in highly correlated datasets by improving the estimation of the proportion of null hypotheses.</p> <p>Results</p> <p>We showed that when strong correlation exists among the data, which is common in microarray datasets, the estimation of the proportion of null hypotheses could be highly variable resulting in a high level of variation in the FDR. Therefore, we developed a re-sampling strategy to reduce the variation by breaking the correlations between gene expression values, then using a conservative strategy of selecting the upper quartile of the re-sampling estimations to obtain a strong control of FDR.</p> <p>Conclusion</p> <p>With simulation studies and perturbations on actual microarray datasets, our method, compared to competing methods such as q-value, generated slightly biased estimates on the proportion of null hypotheses but with lower mean square errors. When selecting genes with controlling the same FDR level, our methods have on average a significantly lower false discovery rate in exchange for a minor reduction in the power.</p

A Protein Aggregation Inhibitor, Leuco-Methylthioninium Bis(Hydromethanesulfonate), Decreases α-Synuclein Inclusions in a Transgenic Mouse Model of Synucleinopathy

The authors acknowledge Heide Lueck for excellent technical assistance and for maintenance of animals. AMS Biotechnology generated monoclonal antibodies from recombinant α-Syn prepared by JR.Peer reviewedPublisher PD

GENCODE: producing a reference annotation for ENCODE

BACKGROUND: The GENCODE consortium was formed to identify and map all protein-coding genes within the ENCODE regions. This was achieved by a combination of initial manual annotation by the HAVANA team, experimental validation by the GENCODE consortium and a refinement of the annotation based on these experimental results. RESULTS: The GENCODE gene features are divided into eight different categories of which only the first two (known and novel coding sequence) are confidently predicted to be protein-coding genes. 5' rapid amplification of cDNA ends (RACE) and RT-PCR were used to experimentally verify the initial annotation. Of the 420 coding loci tested, 229 RACE products have been sequenced. They supported 5' extensions of 30 loci and new splice variants in 50 loci. In addition, 46 loci without evidence for a coding sequence were validated, consisting of 31 novel and 15 putative transcripts. We assessed the comprehensiveness of the GENCODE annotation by attempting to validate all the predicted exon boundaries outside the GENCODE annotation. Out of 1,215 tested in a subset of the ENCODE regions, 14 novel exon pairs were validated, only two of them in intergenic regions. CONCLUSION: In total, 487 loci, of which 434 are coding, have been annotated as part of the GENCODE reference set available from the UCSC browser. Comparison of GENCODE annotation with RefSeq and ENSEMBL show only 40% of GENCODE exons are contained within the two sets, which is a reflection of the high number of alternative splice forms with unique exons annotated. Over 50% of coding loci have been experimentally verified by 5' RACE for EGASP and the GENCODE collaboration is continuing to refine its annotation of 1% human genome with the aid of experimental validation

Cis and Trans Effects of Human Genomic Variants on Gene Expression

This work was funded by the Louis-Jeantet Foundation (http://www.jeantet.ch/), the European Research Council (Grant ID: 260927 http://erc.europa.eu/), the Swiss National Foundation (Grant ID: 130342 http://www.snf.ch), NCCR Frontiers In Genetics (http://www.frontiers-in-genetics.org), the UK Medical Research Council (http://www.mrc.ac.uk) and the Wellcome Trust (Grant ID: 092731).