Picomolar, selective, and subtype-specific small-molecule inhibition of TRPC1/4/5 channels

The concentration of free cytosolic Ca(2+) and the voltage across the plasma membrane are major determinants of cell function. Ca(2+)-permeable non-selective cationic channels are known to regulate these parameters but understanding of these channels remains inadequate. Here we focus on Transient Receptor Potential Canonical 4 and 5 proteins (TRPC4 and TRPC5) which assemble as homomers or heteromerize with TRPC1 to form Ca(2+)-permeable non-selective cationic channels in many mammalian cell types. Multiple roles have been suggested including in epilepsy, innate fear, pain and cardiac remodeling but limitations in tools to probe these channels have restricted progress. A key question is whether we can overcome these limitations and develop tools which are high-quality, reliable, easy to use and readily accessible for all investigators. Here, through chemical synthesis and studies of native and over-expressed channels by Ca(2+) and patch-clamp assays, we describe compound 31 (C31), a remarkable small-molecule inhibitor of TRPC1/4/5 channels. Its potency ranged from 9 to 1300 pM, depending on the TRPC1/4/5 subtype and activation mechanism. Other channel types investigated were unaffected, including TRPC3, TRPC6, TRPV1, TRPV4, TRPA1, TRPM2, TRPM8 and store-operated Ca(2+) entry mediated by Orai1. These findings suggest identification of an important experimental tool compound which has much higher potency for inhibiting TRPC1/4/5 channels than previously reported agents, impressive specificity, and graded subtype selectivity within the TRPC1/4/5 channel family. The compound should greatly facilitate future studies of these ion channels. We suggest naming this TRPC1/4/5-inhibitory compound Pico145

Private genome analysis through homomorphic encryption

Background: The rapid development of genome sequencing technology allows researchers to access large genome datasets. However, outsourcing the data processing o the cloud poses high risks for personal privacy. The aim of this paper is to give a practical solution for this problem using homomorphic encryption. In our approach, all the computations can be performed in an untrusted cloud without requiring the decryption key or any interaction with the data owner, which preserves the privacy of genome data. Methods: We present evaluation algorithms for secure computation of the minor allele frequencies and chi(2) statistic in a genome-wide association studies setting. We also describe how to privately compute the Hamming distance and approximate Edit distance between encrypted DNA sequences. Finally, we compare performance details of using two practical homomorphic encryption schemes -the BGV scheme by Gentry, Halevi and Smart and the YASHE scheme by Bos, Lauter, Loftus and Naehrig. Results: The approach with the YASHE scheme analyzes data from 400 people within about 2 seconds and picks a variant associated with disease from 311 spots. For another task, using the BGV scheme, it took about 65 seconds to securely compute the approximate Edit distance for DNA sequences of size 5K and figure out the differences between them. Conclusions: The performance numbers for BGV are better than YASHE when homomorphically evaluating deep circuits (like the Hamming distance algorithm or approximate Edit distance algorithm). On the other hand, it is more efficient to use the YASHE scheme for a low-degree computation, such as minor allele frequencies or chi(2) test statistic in a case-control study

Evidence from the archives of societies: historical sources in glaciology

Glaciers have been recognized as key indicators of climate change. To assess the current decline in glaciers worldwide, their changes must be compared with natural glacier fluctuations since the end of the last ice age. To reconstruct glacier changes over recent centuries, historical methods have proven especially valuable. Pictorial and cartographical documents as well as written accounts can provide a detailed picture of glacier fluctuations, in particular frontal length changes

Determining an Out-of-Core FFT Decomposition Strategy for Parallel Disks by Dynamic Programming

We present an out-of-core FFT algorithm based on the in-core FFT method developed by Swarztrauber. Our algorithm uses a recursive divide-and-conquer strategy, and each stage in the recursion presents several possibilities for how to split the problem into subproblems. We give a recurrence for the algorithm's I/O complexity on the Parallel Disk Model and show how to use dynamic programming to determine optimal splits at each recursive stage. The algorithm to determine the optimal splits takes only \Theta(lg 2 N) time for an N-point FFT, and it is practical. The out-of-core FFT algorithm itself takes considerably longer