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Understanding and targeting functional RNA structures towards treatment of coronavirus infection can help us to prepare for novel variants of SARS-CoV-2 (the virus causing COVID-19), and any other coronaviruses that could emerge via human-to-human transmission or potential zoonotic (inter-species) events. Leveraging the fact that all coronaviruses use a mechanism known as -1 programmed ribosomal frameshifting (-1 PRF) to replicate, we apply algorithms to predict the most energetically favourable secondary structures (each nucleotide involved in at most one pairing) that may be involved in regulating the -1 PRF event in coronaviruses, especially SARS-CoV-2. We compute previously unknown most stable structure predictions for the frameshift site of coronaviruses via hierarchical folding, a biologically motivated framework where initial non-crossing structure folds first, followed by subsequent, possibly crossing (pseudoknotted), structures. Using mutual information from 181 coronavirus sequences, in conjunction with the algorithm KnotAli, we compute secondary structure predictions for the frameshift site of different coronaviruses. We then utilize the Shapify algorithm to obtain most stable SARS-CoV-2 secondary structure predictions guided by frameshift sequence-specific and genome-wide experimental data. We build on our previous secondary structure investigation of the singular SARS-CoV-2 68 nt frameshift element sequence, by using Shapify to obtain predictions for 132 extended sequences and including covariation information. Previous investigations have not applied hierarchical folding to extended length SARS-CoV-2 frameshift sequences. By doing so, we simulate the effects of ribosome interaction with the frameshift site, providing insight to biological function. We contribute in-depth discussion to contextualize secondary structure dual-graph motifs for SARS-CoV-2, highlighting the energetic stability of the previously identified 3_8 motif alongside the known dominant 3_3 and 3_6 (native-type) -1 PRF structures. Using a combination of thermodynamic methods and sequence covariation, our novel predictions suggest function of the attenuator hairpin via previously unknown pseudoknotted base pairing. While certain initial RNA folding is consistent, other pseudoknotted base pairs form which indicate potential conformational switching between the two structures.

Abstract Motivation Deep learning has become a prevalent method in identifying genomic regulatory sequences such as promoters. In a number of recent papers, the performance of deep learning models has continually been reported as an improvement over alternatives for sequence-based promoter recognition. However, the performance improvements in these models do not account for the different datasets that models are evaluated on. The lack of a consensus dataset and procedure for benchmarking purposes has made the comparison of each model’s true performance difficult to assess. Results We present a framework called Supervised Promoter Recognition Framework (‘SUPR REF’) capable of streamlining the complete process of training, validating, testing, and comparing promoter recognition models in a systematic manner. SUPR REF includes the creation of biologically relevant benchmark datasets to be used in the evaluation process of deep learning promoter recognition models. We showcase this framework by comparing the models’ performances on alternative datasets, and properly evaluate previously published models on new benchmark datasets. Our results show that the reliability of deep learning ab initio promoter recognition models on eukaryotic genomic sequences is still not at a sufficient level, as overall performance is still low. These results originate from a subset of promoters, the well-known RNA Polymerase II core promoters. Furthermore, given the observational nature of these data, cross-validation results from small promoter datasets need to be interpreted with caution.

Quantum computing is aninterdisciplinary field that lies at the intersection of mathematics, quantum physics, and computer science, and finds applications in areas including optimization, machine learning, and simulation of chemical, physical, and biological systems. It has the potential to help solve problems that so far have no satisfying method solving them, and to provide significant speedup to solutions when compared with their best classical approaches. In turn, quantum computing may allow us to solve problems for inputs that so far are deemed practically intractable. With the computational power of quantum computers and the proliferation of quantum development kits, quantum computing is anticipated to become mainstream, and the demand for a skilled workforce in quantum computing is expected to increase significantly. Therefore, quantum computing education is ramping up. This article describes our experiences in designing and delivering quantum computing workshops for youth (Grades 9–12). We introduce students to the world of quantum computing in innovative ways, such as newly designed unplugged activities for teaching basic quantum computing concepts. We also take a programmatic approach and introduce students to the IBM Quantum Experience using Qiskit and Jupyter notebooks. Our contributions are as follows. First, we present creative ways to teach quantum computing to youth with little or no experience in science, technology, engineering, and mathematics areas; second, we discuss diversity and highlight various pathways into quantum computing from quantum software to quantum hardware; and third, we discuss the design and delivery of online and in-person motivational, introductory, and advanced workshops for youth.

Multiple coronaviruses including MERS-CoV causing Middle East Respiratory Syndrome, SARS-CoV causing SARS, and SARS-CoV-2 causing COVID-19, use a mechanism known as -1 programmed ribosomal frameshifting (-1 PRF) to replicate. SARS-CoV-2 possesses a unique RNA pseudoknotted structure that stimulates -1 PRF. Targeting -1 PRF in SARS-CoV-2 to impair viral replication can improve patients' prognoses. Crucial to developing these therapies is understanding the structure of the SARS-CoV-2 -1 PRF pseudoknot. Our goal is to expand knowledge of -1 PRF structural conformations. Following a structural alignment approach, we identify similarities in -1 PRF pseudoknots of SARS-CoV-2, SARS-CoV, and MERS-CoV. We provide in-depth analysis of the SARS-CoV-2 and MERS-CoV -1 PRF pseudoknots, including reference and noteworthy mutated sequences. To better understand the impact of mutations, we provide insight on -1 PRF pseudoknot sequence mutations and their effect on resulting structures. We introduce Shapify, a novel algorithm that given an RNA sequence incorporates structural reactivity (SHAPE) data and partial structure information to output an RNA secondary structure prediction within a biologically sound hierarchical folding approach. Shapify enhances our understanding of SARS-CoV-2 -1 PRF pseudoknot conformations by providing energetically favourable predictions that are relevant to structure-function and may correlate with -1 PRF efficiency. Applied to the SARS-CoV-2 -1 PRF pseudoknot, Shapify unveils previously unknown paths from initial stems to pseudoknotted structures. By contextualizing our work with available experimental data, our structure predictions motivate future RNA structure-function research and can aid 3-D modeling of pseudoknots.