Quantitative nucleotide level analysis of regulation of translation in response to depolarization of cultured neural cells

Studies on regulation of gene expression have contributed substantially to understanding mechanisms for the long-term activity-dependent alterations in neural connectivity that are thought to mediate learning and memory. Most of these studies, however, have focused on the regulation of mRNA transcription. Here, we utilized high-throughput sequencing coupled with ribosome footprinting to globally characterize the regulation of translation in primary mixed neuronal-glial cultures in response to sustained depolarization. We identified substantial and complex regulation of translation, with many transcripts demonstrating changes in ribosomal occupancy independent of transcriptional changes. We also examined sequence-based mechanisms that might regulate changes in translation in response to depolarization. We found that these are partially mediated by features in the mRNA sequence—notably upstream open reading frames and secondary structure in the 5′ untranslated region—both of which predict downregulation in response to depolarization. Translationally regulated transcripts are also more likely to be targets of FMRP and include genes implicated in autism in humans. Our findings support the idea that control of mRNA translation plays an important role in response to neural activity across the genome

Variational Quantum Circuit Decoupling

Decoupling systems into independently evolving components has a long history of simplifying seemingly complex systems. They enable a better understanding of the underlying dynamics and causal structures while providing more efficient means to simulate such processes on a computer. Here we outline a variational decoupling algorithm for decoupling unitary quantum dynamics -- allowing us to decompose a given $n$-qubit unitary gate into multiple independently evolving sub-components. We apply this approach to quantum circuit synthesis - the task of discovering quantum circuit implementations of target unitary dynamics. Our numerical studies illustrate significant benefits, showing that variational decoupling enables us to synthesize general $2$ and $4$-qubit gates to fidelity that conventional variational circuits cannot reach

MicroRNA profiling reveals marker of motor neuron disease in ALS models

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by the loss of motor neurons (MNs) in the brain and spinal cord, leading to fatally debilitating weakness. Because this disease predominantly affects MNs, we aimed to characterize the distinct expression profile of that cell type to elucidate underlying disease mechanisms and to identify novel targets that inform on MN health during ALS disease time course. microRNAs (miRNAs) are short, noncoding RNAs that can shape the expression profile of a cell and thus often exhibit cell-type-enriched expression. To determine MN-enriched miRNA expression, we used Cre recombinase-dependent miRNA tagging and affinity purification in mice. By defining thein vivomiRNA expression of MNs, all neurons, astrocytes, and microglia, we then focused on MN-enriched miRNAs via a comparative analysis and found that they may functionally distinguish MNs postnatally from other spinal neurons. Characterizing the levels of the MN-enriched miRNAs in CSF harvested from ALS models of MN disease demonstrated that one miRNA (miR-218) tracked with MN loss and was responsive to an ALS therapy in rodent models. Therefore, we have used cellular expression profiling tools to define the distinct miRNA expression of MNs, which is likely to enrich future studies of MN disease. This approach enabled the development of a novel, drug-responsive marker of MN disease in ALS rodents.SIGNIFICANCE STATEMENTAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons (MNs) in the brain and spinal cord are selectively lost. To develop tools to aid in our understanding of the distinct expression profiles of MNs and, ultimately, to monitor MN disease progression, we identified small regulatory microRNAs (miRNAs) that were highly enriched or exclusive in MNs. The signal for one of these MN-enriched miRNAs is detectable in spinal tap biofluid from an ALS rat model, where its levels change as disease progresses, suggesting that it may be a clinically useful marker of disease status. Furthermore, rats treated with ALS therapy have restored expression of this MN RNA marker, making it an MN-specific and drug-responsive marker for ALS rodents.</jats:p

Measures of distinguishability between stochastic processes

Quantifying how distinguishable two stochastic processes are lies at the heart of many fields, such as machine learning and quantitative finance. While several measures have been proposed for this task, none have universal applicability and ease of use. In this Letter, we suggest a set of requirements for a well-behaved measure of process distinguishability. Moreover, we propose a family of measures, called divergence rates, that satisfy all of these requirements. Focussing on a particular member of this family -- the co-emission divergence rate -- we show that it can be computed efficiently, behaves qualitatively similar to other commonly-used measures in their regimes of applicability, and remains well-behaved in scenarios where other measures break down

PTM4Tag+: Tag Recommendation of Stack Overflow Posts with Pre-trained Models

Stack Overflow is one of the most influential Software Question & Answer (SQA) websites, hosting millions of programming-related questions and answers. Tags play a critical role in efficiently organizing the contents in Stack Overflow and are vital to support a range of site operations, e.g., querying relevant content. Poorly selected tags often raise problems like tag ambiguity and tag explosion. Thus, a precise and accurate automated tag recommendation technique is demanded. Inspired by the recent success of pre-trained models (PTMs) in natural language processing (NLP), we present PTM4Tag+, a tag recommendation framework for Stack Overflow posts that utilizes PTMs in language modeling. PTM4Tag+ is implemented with a triplet architecture, which considers three key components of a post, i.e., Title, Description, and Code, with independent PTMs. We utilize a number of popular pre-trained models, including the BERT-based models (e.g., BERT, RoBERTa, CodeBERT, BERTOverflow, and ALBERT), and encoder-decoder models (e.g., PLBART, CoTexT, and CodeT5). Our results show that leveraging CodeT5 under the PTM4Tag+ framework achieves the best performance among the eight considered PTMs and outperforms the state-of-the-art Convolutional Neural Network-based approach by a substantial margin in terms of average P recision@k, Recall@k, and F1-score@k (k ranges from 1 to 5). Specifically, CodeT5 improves the performance of F1-score@1-5 by 8.8%, 12.4%, 15.3%, 16.4%, and 16.6%. Moreover, to address the concern with inference latency, we experiment PTM4Tag+ with smaller PTM models (i.e., DistilBERT, DistilRoBERTa, CodeBERT-small, and CodeT5-small). We find that although smaller PTMs cannot outperform larger PTMs, they still maintain over 93.96% of the performance on average, meanwhile shortening the mean inference time by more than 47.2%Comment: arXiv admin note: substantial text overlap with arXiv:2203.1096

Mendelian randomization and genetic colocalization infer the effects of the multi-tissue proteome on 211 complex disease-related phenotypes

BACKGROUND: Human proteins are widely used as drug targets. Integration of large-scale protein-level genome-wide association studies (GWAS) and disease-related GWAS has thus connected genetic variation to disease mechanisms via protein. Previous proteome-by-phenome-wide Mendelian randomization (MR) studies have been mainly focused on plasma proteomes. Previous MR studies using the brain proteome only reported protein effects on a set of pre-selected tissue-specific diseases. No studies, however, have used high-throughput proteomics from multiple tissues to perform MR on hundreds of phenotypes. METHODS: Here, we performed MR and colocalization analysis using multi-tissue (cerebrospinal fluid (CSF), plasma, and brain from pre- and post-meta-analysis of several disease-focus cohorts including Alzheimer disease (AD)) protein quantitative trait loci (pQTLs) as instrumental variables to infer protein effects on 211 phenotypes, covering seven broad categories: biological traits, blood traits, cancer types, neurological diseases, other diseases, personality traits, and other risk factors. We first implemented these analyses with cis pQTLs, as cis pQTLs are known for being less prone to horizontal pleiotropy. Next, we included both cis and trans conditionally independent pQTLs that passed the genome-wide significance threshold keeping only variants associated with fewer than five proteins to minimize pleiotropic effects. We compared the tissue-specific protein effects on phenotypes across different categories. Finally, we integrated the MR-prioritized proteins with the druggable genome to identify new potential targets. RESULTS: In the MR and colocalization analysis including study-wide significant cis pQTLs as instrumental variables, we identified 33 CSF, 13 plasma, and five brain proteins to be putative causal for 37, 18, and eight phenotypes, respectively. After expanding the instrumental variables by including genome-wide significant cis and trans pQTLs, we identified a total of 58 CSF, 32 plasma, and nine brain proteins associated with 58, 44, and 16 phenotypes, respectively. For those protein-phenotype associations that were found in more than one tissue, the directions of the associations for 13 (87%) pairs were consistent across tissues. As we were unable to use methods correcting for horizontal pleiotropy given most of the proteins were only associated with one valid instrumental variable after clumping, we found that the observations of protein-phenotype associations were consistent with a causal role or horizontal pleiotropy. Between 66.7 and 86.3% of the disease-causing proteins overlapped with the druggable genome. Finally, between one and three proteins, depending on the tissue, were connected with at least one drug compound for one phenotype from both DrugBank and ChEMBL databases. CONCLUSIONS: Integrating multi-tissue pQTLs with MR and the druggable genome may open doors to pinpoint novel interventions for complex traits with no effective treatments, such as ovarian and lung cancers