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Background: Protein repeats can confound sequence analyses because the repetitiveness of their amino acid sequences lead to difficulties in identifying whether similar repeats are due to convergent or divergent evolution. We noted that the patterns derived from traditional "dot plot" protein sequence self-similarity analysis tended to be conserved in sets of related repeat proteins and this conservation could be quantitated using a Jaccard metric. Results: Comparison of these dot plots obviated the issues due to sequence similarity for analysis of repeat proteins. A high Jaccard similarity score was suggestive of a conserved relationship between closely related repeat proteins. The dot plot patterns decayed quickly in the absence of selective pressure with an expected loss of 50% of Jaccard similarity due to a loss of 8.2% sequence identity. To perform method testing, we assembled a standard set of 79 repeat proteins representing all the subgroups in RepeatsDB. Comparison of known repeat and non-repeat proteins from the PDB suggested that the information content in dot plots could be used to identify repeat proteins from pure sequence with no requirement for structural information. Analysis of the UniRef90 database suggested that 16.9% of all known proteins could be classified as repeat proteins. These 13.3 million putative repeat protein chains were clustered and a significant amount (82.9%) of clusters containing between 5 and 200 members were of a single functional type. Conclusions: Dot plot analysis of repeat proteins attempts to obviate issues that arise due to the sequence degeneracy of repeat proteins. These results show that this kind of analysis can efficiently be applied to analyze repeat proteins on a large scale. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the leading cause of dementia and is characterized by a presence of amyloid plaques, composed mostly of the amyloid-β (Aβ) peptides, in the brains of AD patients. The peptides are generated from the amyloid precursor protein (APP), which undergoes a sequence of cleavages, referred as trimming, performed by γ-secretase. Here, we investigated conformational changes in a series of β-amyloid substrates (from less and more amyloidogenic pathways) in the active site of presenilin-1, the catalytic subunit of γ-secretase. The substrates are trimmed every three residues, finally leading to Aβ40 and Aβ42, which are the major components of amyloid plaques. To study conformational changes, we employed all-atom molecular dynamics simulations, while for unfolding, we used steered molecular dynamics simulations in an implicit membrane-water environment to accelerate changes. We have found substantial differences in the flexibility of extended C-terminal parts between more and less amyloidogenic pathway substrates. We also propose that the positively charged residues of presenilin-1 may facilitate the stretching and unfolding of substrates. The calculated forces and work/energy of pulling were exceptionally high for Aβ40, indicating why trimming of this substrate is so infrequent. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is the most common progressive neurodegenerative disorder and is characterized by the presence of amyloid β (Aβ) plaques in the brain. The γ-secretase complex, which produces Aβ, is an intramembrane-cleaving protease consisting of four membrane proteins. In this paper we investigated the amyloidogenic fragments of amyloid precursor protein (substrates Aβ43 and Aβ45, leading to less amyloidogenic Aβ40 and more amyloidogenic Aβ42, respectively) docked to the binding site of presenilin, the catalytic subunit of γ-secretase. In total, we performed 9 μs of all-atom molecular dynamics simulations of the whole γ-secretase complex with both substrates in low (10%) and high (50%) concentrations of cholesterol in the membrane. We found that, at the high cholesterol level, the Aβ45 helix was statistically more flexible in the binding site of presenilin than Aβ43. An increase in the cholesterol concentration was also correlated with a higher flexibility of the Aβ45 helix, which suggests incompatibility between Aβ45 and the binding site of presenilin potentiated by a high cholesterol level. However, at the C-terminal part of Aβ45, the active site of presenilin was more compact in the case of a high cholesterol level, which could promote processing of this substrate. We also performed detailed mapping of the cholesterol binding sites at low and high cholesterol concentrations, which were independent of the typical cholesterol binding motifs. [ABSTRACT FROM AUTHOR]

Simplified, No-X-Ray Catheter Ablation of SVT Introduction Although the 'near-zero-X-Ray' or 'No-X-Ray' catheter ablation (CA) approach has been reported for treatment of various arrhythmias, few prospective studies have strictly used 'No-X-Ray,' simplified 2-catheter approaches for CA in patients with supraventricular tachycardia (SVT). We assessed the feasibility of a minimally invasive, nonfluoroscopic (MINI) CA approach in such patients. Methods Data were obtained from a prospective multicenter CA registry of patients with regular SVTs. After femoral access, 2 catheters were used to create simple, 3D electroanatomic maps and to perform electrophysiologic studies. Medical staff did not use lead aprons after the first 10 MINI CA cases. Results A total of 188 patients (age, 45 ± 21 years; 17% <19 years; 55% women) referred for the No-X-Ray approach were included. They were compared to 714 consecutive patients referred for a simplified approach using X-rays (age, 52 ± 18 years; 7% <19 years; 55% women). There were 9 protocol exceptions that necessitated the use of X-rays. Ultimately, 179/188 patients underwent the procedure without fluoroscopy, with an acute success rate of 98%. The procedure times (63 ± 26 vs. 63 ± 29 minutes, P > 0.05), major complications (0% vs. 0%, P > 0.05) and acute (98% vs. 98%, P > 0.05) and long-term (93% vs. 94%, P > 0.05) success rates were similar in the 'No-X-Ray' and control groups. Conclusions Implementation of a strict 'No-X-Ray, simplified 2-catheter' CA approach is safe and effective in majority of the patients with SVT. This modified approach for SVTs should be prospectively validated in a multicenter study. [ABSTRACT FROM AUTHOR]

In this paper, we present WaterSpy, a project developing an innovative, compact, cost-effective photonic device for pervasive water quality sensing, operating in the mid-IR spectral range. The approach combines the use of advanced Quantum Cascade Lasers (QCLs) employing the Vernier effect, used as light source, with novel, fibre-coupled, fast and sensitive Higher Operation Temperature (HOT) photodetectors, used as sensors. These will be complemented by optimised laser driving and detector electronics, laser modulation and signal conditioning technologies. The paper presents the WaterSpy concept, the requirements elicited, the preliminary architecture design of the device, the use cases in which it will be validated, while highlighting the innovative technologies that contribute to the advancement of the current state of the art. [ABSTRACT FROM AUTHOR]