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Many RNAs fold into multiple structures at equilibrium, and there is a need to sample these structures according to their probabilities in the ensemble. The conventional sampling algorithm suffers from two limitations: (i) the sampling phase is slow due to many repeated calculations; and (ii) the end-to-end runtime scales cubically with the sequence length. These issues make it difficult to be applied to long RNAs, such as the full genomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To address these problems, we devise a new sampling algorithm, LazySampling, which eliminates redundant work via on-demand caching. Based on LazySampling, we further derive LinearSampling, an end-to-end linear time sampling algorithm. Benchmarking on nine diverse RNA families, the sampled structures from LinearSampling correlate better with the well-established secondary structures than Vienna RNAsubopt and RNAplfold. More importantly, LinearSampling is orders of magnitude faster than standard tools, being 428× faster (72 s versus 8.6 h) than RNAsubopt on the full genome of SARS-CoV-2 (29 903 nt). The resulting sample landscape correlates well with the experimentally guided secondary structure models, and is closer to the alternative conformations revealed by experimentally driven analysis. Finally, LinearSampling finds 23 regions of 15 nt with high accessibilities in the SARS-CoV-2 genome, which are potential targets for COVID-19 diagnostics and therapeutics.

 

Predicting the secondary structure of an ribonucleic acid (RNA) sequence is useful in many applications. Existing algorithms [based on dynamic programming] suffer from a major limitation: their runtimes scale cubically with the RNA length, and this slowness limits their use in genome-wide applications.

We present a novel alternative O(n3)-time dynamic programming algorithm for RNA folding that is amenable to heuristics that make it run in O(n) time and O(n) space, while producing a high-quality approximation to the optimal solution. Inspired by incremental parsing for context-free grammars in computational linguistics, our alternative dynamic programming algorithm scans the sequence in a left-to-right (5′-to-3′) direction rather than in a bottom-up fashion, which allows us to employ the effective beam pruning heuristic. Our work, though inexact, is the first RNA folding algorithm to achieve linear runtime (and linear space) without imposing constraints on the output structure. Surprisingly, our approximate search results in even higher overall accuracy on a diverse database of sequences with known structures. More interestingly, it leads to significantly more accurate predictions on the longest sequence families in that database (16S and 23S Ribosomal RNAs), as well as improved accuracies for long-range base pairs (500+ nucleotides apart), both of which are well known to be challenging for the current models.

Our source code is available at https://github.com/LinearFold/LinearFold, and our webserver is at http://linearfold.org (sequence limit: 100 000nt).

Supplementary data are available at Bioinformatics online.

 

The constant emergence of COVID-19 variants reduces the effectiveness of existing vaccines and test kits. Therefore, it is critical to identify conserved structures in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes as potential targets for variant-proof diagnostics and therapeutics. However, the algorithms to predict these conserved structures, which simultaneously fold and align multiple RNA homologs, scale at best cubically with sequence length and are thus infeasible for coronaviruses, which possess the longest genomes (∼30,000 nt) among RNA viruses. As a result, existing efforts on modeling SARS-CoV-2 structures resort to single-sequence folding as well as local folding methods with short window sizes, which inevitably neglect long-range interactions that are crucial in RNA functions. Here we present LinearTurboFold, an efficient algorithm for folding RNA homologs that scales linearly with sequence length, enabling unprecedented global structural analysis on SARS-CoV-2. Surprisingly, on a group of SARS-CoV-2 and SARS-related genomes, LinearTurboFold’s purely in silico prediction not only is close to experimentally guided models for local structures, but also goes far beyond them by capturing the end-to-end pairs between 5 ′ and 3 ′ untranslated regions (UTRs) (∼29,800 nt apart) that match perfectly with a purely experimental work. Furthermore, LinearTurboFold identifies undiscovered conserved structures and conserved accessible regions as potential targets for designing efficient and mutation-insensitive small-molecule drugs, antisense oligonucleotides, small interfering RNAs (siRNAs), CRISPR-Cas13 guide RNAs, and RT-PCR primers. LinearTurboFold is a general technique that can also be applied to other RNA viruses and full-length genome studies and will be a useful tool in fighting the current and future pandemics. 

Simultaneous speech-to-text translation is widely useful in many scenarios. The conventional cascaded approach uses a pipeline of streaming ASR followed by simultaneous MT, but suffers from error propagation and extra latency. To alleviate these issues, recent efforts attempt to directly translate the source speech into target text simultaneously, but this is much harder due to the combination of two separate tasks. We instead propose a new paradigm with the advantages of both cascaded and endto-end approaches. The key idea is to use two separate, but synchronized, decoders on streaming ASR and direct speech-to-text translation (ST), respectively, and the intermediate results of ASR guide the decoding policy of (but is not fed as input to) ST. During training time, we use multitask learning to jointly learn these two tasks with a shared encoder. En-toDe and En-to-Es experiments on the MuSTC dataset demonstrate that our proposed technique achieves substantially better translation quality at similar levels of latency. 

Simultaneous translation is vastly different from full-sentence translation, in the sense that it starts translation before the source sentence ends, with only a few words delay. However, due to the lack of large-scale, high-quality simultaneous translation datasets, most such systems are still trained on conventional full-sentence bitexts. This is far from ideal for the simultaneous scenario due to the abundance of unnecessary long-distance reorderings in those bitexts. We propose a novel method that rewrites the target side of existing full-sentence corpora into simultaneous-style translation. Experiments on Zh→En and Ja→En simultaneous translation show substantial improvements (up to +2.7 BLEU) with the addition of these generated pseudo-references. 

Abstract Motivation RNA secondary structure prediction is widely used to understand RNA function. Recently, there has been a shift away from the classical minimum free energy methods to partition function-based methods that account for folding ensembles and can therefore estimate structure and base pair probabilities. However, the classical partition function algorithm scales cubically with sequence length, and is therefore prohibitively slow for long sequences. This slowness is even more severe than cubic-time free energy minimization due to a substantially larger constant factor in runtime. Results Inspired by the success of our recent LinearFold algorithm that predicts the approximate minimum free energy structure in linear time, we design a similar linear-time heuristic algorithm, LinearPartition, to approximate the partition function and base-pairing probabilities, which is shown to be orders of magnitude faster than Vienna RNAfold and CONTRAfold (e.g. 2.5 days versus 1.3 min on a sequence with length 32 753 nt). More interestingly, the resulting base-pairing probabilities are even better correlated with the ground-truth structures. LinearPartition also leads to a small accuracy improvement when used for downstream structure prediction on families with the longest length sequences (16S and 23S rRNAs), as well as a substantial improvement on long-distance base pairs (500+ nt apart). Availability and implementation Code: http://github.com/LinearFold/LinearPartition; Server: http://linearfold.org/partition. Supplementary information Supplementary data are available at Bioinformatics online. 

Simultaneous translation has many important application scenarios and attracts much attention from both academia and industry recently. Most existing frameworks, however, have difficulties in balancing between the translation quality and latency, i.e., the decoding policy is usually either too aggressive or too conservative. We propose an opportunistic decoding technique with timely correction ability, which always (over-)generates a certain mount of extra words at each step to keep the audience on track with the latest information. At the same time, it also corrects, in a timely fashion, the mistakes in the former overgenerated words when observing more source context to ensure high translation quality. Experiments show our technique achieves substantial reduction in latency and up to +3.1 increase in BLEU, with revision rate under 8% in Chinese-to-English and English-to-Chinese translation. 

Beam search optimization (Wiseman and Rush, 2016) resolves many issues in neural machine translation. However, this method lacks principled stopping criteria and does not learn how to stop during training, and the model naturally prefers longer hypotheses during the testing time in practice since they use the raw score instead of the probability-based score. We propose a novel ranking method which enables an optimal beam search stop- ping criteria. We further introduce a structured prediction loss function which penalizes suboptimal finished candidates produced by beam search during training. Experiments of neural machine translation on both synthetic data and real languages (German→English and Chinese→English) demonstrate our pro- posed methods lead to better length and BLEU score.