pwc-archive/papers-with-abstracts huggingface dataset:
CoPRA: Bridging Cross-domain Pretrained Sequence Models with Complex Structures for Protein-RNA Binding Affinity Prediction
Authors: Rong Han, Xiaohong Liu, Tong Pan, Jing Xu, Xiaoyu Wang, Wuyang Lan, Zhenyu Li, Zixuan Wang, Jiangning Song, Guangyu Wang, Ting Chen
Date: 2024-08-21 00:00:00
Tasks: Drug Design, Prediction

Accurately measuring protein-RNA binding affinity is crucial in many biological processes and drug design. Previous computational methods for protein-RNA binding affinity prediction rely on either sequence or structure features, unable to capture the binding mechanisms comprehensively. The recent emerging pre-trained language models trained on massive unsupervised sequences of protein and RNA have shown strong representation ability for various in-domain downstream tasks, including binding site prediction. However, applying different-domain language models collaboratively for complex-level tasks remains unexplored. In this paper, we propose CoPRA to bridge pre-trained language models from different biological domains via Complex structure for Protein-RNA binding Affinity prediction. We demonstrate for the first time that cross-biological modal language models can collaborate to improve binding affinity prediction. We propose a Co-Former to combine the cross-modal sequence and structure information and a bi-scope pre-training strategy for improving Co-Former's interaction understanding. Meanwhile, we build the largest protein-RNA binding affinity dataset PRA310 for performance evaluation. We also test our model on a public dataset for mutation effect prediction. CoPRA reaches state-of-the-art performance on all the datasets. We provide extensive analyses and verify that CoPRA can (1) accurately predict the protein-RNA binding affinity; (2) understand the binding affinity change caused by mutations; and (3) benefit from scaling data and model size.
Advances in practical k-mer sets: essentials for the curious
Authors: Camille Marchet
Date: 2024-09-08 00:00:00

This paper provides a comprehensive survey of data structures for representing k-mer sets, which are fundamental in high-throughput sequencing analysis. It categorizes the methods into two main strategies: those using fingerprinting and hashing for compact storage, and those leveraging lexicographic properties for efficient representation. The paper reviews key operations supported by these structures, such as membership queries and dynamic updates, and highlights recent advancements in memory efficiency and query speed. A companion paper explores colored k-mer sets, which extend these concepts to integrate multiple datasets or genomes.
Highly conserved sequence-specific double-stranded DNA binding networks contributing to divergent genomic evolution of human and chimpanzee brain development
Authors: Gennadi Glinsky
Date: 2024-09-12 00:00:00

Emergence during mammalian evolution of concordant and divergent traits of genomic regulatory networks encompassing ubiquitous, qualitatively nearly identical yet quantitatively distinct arrays of sequences of transcription factor binding sites (TFBS) for 716 proteins is reported. A vast majority of TFs (770 of 716; 98%) comprising protein constituents of these networks appear to share common Gene Ontology (GO) features of sequence-specific double-stranded DNA binding (GO: 1990837). Genome-wide and individual chromosome-level analyses of 17,935 ATAC-seq-defined brain development regulatory regions (BDRRs) revealed nearly universal representations of TFBS for TF-constituents of these networks, TFBS densities of which appear consistently higher within thousands BDRRs of Modern Humans compare to Chimpanzee. Transposable elements (TE), including LTR/HERV, SINE/Alu, SVA, and LINE families, appear to harbor and spread genome-wide consensus regulatory nodes of identified herein highly conserved sequence-specific double-stranded DNA binding networks, selections of TFBS panels of which manifest individual chromosome-specific profiles and species-specific divergence patterns. Collectively, observations reported in this contribution highlight a previously unrecognized essential function of human genomic DNA sequences encoded by TE in providing genome-wide regulatory seed templates of highly conserved sequence-specific double-stranded DNA binding networks likely contributing to continuing divergent genomic evolution of human and chimpanzee brain development.
Advances in colored k-mer sets: essentials for the curious
Authors: Camille Marchet
Date: 2024-09-08 00:00:00

This paper provides a comprehensive review of recent advancements in k-mer-based data structures representing collections of several samples (sometimes called colored de Bruijn graphs) and their applications in large-scale sequence indexing and pangenomics. The review explores the evolution of k-mer set representations, highlighting the trade-offs between exact and inexact methods, as well as the integration of compression strategies and modular implementations. I discuss the impact of these structures on practical applications and describe recent utilization of these methods for analysis. By surveying the state-of-the-art techniques and identifying emerging trends, this work aims to guide researchers in selecting and developing methods for large scale and reference-free genomic data. For a broader overview of k-mer set representations and foundational data structures, see the accompanying article on practical k-mer sets.
Selecting Differential Splicing Methods: Practical Considerations
Authors: Ben J Draper, Mark J Dunning, David C James
Date: 2024-09-09 00:00:00
Tasks: Benchmarking

Alternative splicing is crucial in gene regulation, with significant implications in clinical settings and biotechnology. This review article compiles bioinformatics RNA-seq tools for investigating differential splicing; offering a detailed examination of their statistical methods, case applications, and benefits. A total of 22 tools are categorised by their statistical family (parametric, non-parametric, and probabilistic) and level of analysis (transcript, exon, and event). The central challenges in quantifying alternative splicing include correct splice site identification and accurate isoform deconvolution of transcripts. Benchmarking studies show no consensus on tool performance, revealing considerable variability across different scenarios. Tools with high citation frequency and continued developer maintenance, such as DEXSeq and rMATS, are recommended for prospective researchers. To aid in tool selection, a guide schematic is proposed based on variations in data input and the required level of analysis. Additionally, advancements in long-read RNA sequencing are expected to drive the evolution of differential splicing tools, reducing the need for isoform deconvolution and prompting further innovation.
Discovering Candidate Genes Regulated by GWAS Signals in Cis and Trans
Authors: Samhita Pal, Xinge Jessie Jeng
Date: 2024-08-30 00:00:00

Understanding the genetic underpinnings of complex traits and diseases has been greatly advanced by genome-wide association studies (GWAS). However, a significant portion of trait heritability remains unexplained, known as ``missing heritability". Most GWAS loci reside in non-coding regions, posing challenges in understanding their functional impact. Integrating GWAS with functional genomic data, such as expression quantitative trait loci (eQTLs), can bridge this gap. This study introduces a novel approach to discover candidate genes regulated by GWAS signals in both cis and trans. Unlike existing eQTL studies that focus solely on cis-eQTLs or consider cis- and trans-QTLs separately, we utilize adaptive statistical metrics that can reflect both the strong, sparse effects of cis-eQTLs and the weak, dense effects of trans-eQTLs. Consequently, candidate genes regulated by the joint effects can be prioritized. We demonstrate the efficiency of our method through theoretical and numerical analyses and apply it to adipose eQTL data from the METabolic Syndrome in Men (METSIM) study, uncovering genes playing important roles in the regulatory networks influencing cardiometabolic traits. Our findings offer new insights into the genetic regulation of complex traits and present a practical framework for identifying key regulatory genes based on joint eQTL effects.
Understanding how chromatin folding and enzyme competition affect rugged epigenetic landscapes
Authors: Daria Stepanova, Meritxell Brunet Guasch, Helen M. Byrne, Tomás Alarcón
Date: 2024-09-09 00:00:00

Epigenetics plays a key role in cellular differentiation and maintaining cell identity, enabling cells to regulate their genetic activity without altering the DNA sequence. Epigenetic regulation occurs within the context of hierarchically folded chromatin, yet the interplay between the dynamics of epigenetic modifications and chromatin architecture remains poorly understood. In addition, it remains unclear what mechanisms drive the formation of rugged epigenetic patterns, characterised by alternating genomic regions enriched in activating and repressive marks. In this study, we focus on post-translational modifications of histone H3 tails, particularly H3K27me3, H3K4me3, and H3K27ac. We introduce a mesoscopic stochastic model that incorporates chromatin architecture and competition of histone-modifying enzymes into the dynamics of epigenetic modifications in small genomic loci comprising several nucleosomes. Our approach enables us to investigate the mechanisms by which epigenetic patterns form on larger scales of chromatin organisation, such as loops and domains. Through bifurcation analysis and stochastic simulations, we demonstrate that the model can reproduce uniform chromatin states (open, closed, and bivalent) and generate previously unexplored rugged profiles. Our results suggest that enzyme competition and chromatin conformations with high-frequency interactions between distant genomic loci can drive the emergence of rugged epigenetic landscapes. Additionally, we hypothesise that bivalent chromatin can act as an intermediate state, facilitating transitions between uniform and rugged landscapes. This work offers a powerful mathematical framework for understanding the dynamic interactions between chromatin architecture and epigenetic regulation, providing new insights into the formation of complex epigenetic patterns.
Irreversibility in Bacterial Regulatory Networks
Authors: Yi Zhao, Thomas P. Wytock, Kimberly A. Reynolds, Adilson E. Motter
Date: 2024-09-06 00:00:00

Irreversibility, in which a transient perturbation leaves a system in a new state, is an emergent property in systems of interacting entities. This property has well-established implications in statistical physics but remains underexplored in biological networks, especially for bacteria and other prokaryotes whose regulation of gene expression occurs predominantly at the transcriptional level. Focusing on the reconstructed regulatory network of \emph{Escherichia coli}, we examine network responses to transient single-gene perturbations. We predict irreversibility in numerous cases and find that the incidence of irreversibility increases with the proximity of the perturbed gene to positive circuits in the network. Comparison with experimental data suggests a connection between the predicted irreversibility to transient perturbations and the evolutionary response to permanent perturbations.
A Molecular Communication Perspective of Alzheimer's Disease: Impact of Amyloid Beta Oligomers on Glutamate Diffusion in the Synaptic Cleft
Authors: Nayereh FallahBagheri, Ozgur B. Akan
Date: 2024-09-05 00:00:00

Molecular communication (MC) within the synaptic cleft is vital for neurotransmitter diffusion, a process critical to cognitive functions. In Alzheimer's Disease (AD), beta-amyloid oligomers (A$\beta$os) disrupt this communication, leading to synaptic dysfunction. This paper investigates the molecular interactions between glutamate, a key neurotransmitter, and A$\beta$os within the synaptic cleft, aiming to elucidate the underlying mechanisms of this disruption. Through stochastic modeling, we simulate the dynamics of A$\beta$os and their impact on glutamate diffusion. The findings, validated by comparing simulated results with existing experimental data, demonstrate that A$\beta$os serve as physical obstacles, hindering glutamate movement and increasing collision frequency. This impairment of synaptic transmission and long-term potentiation (LTP) by binding to receptors on the postsynaptic membrane is further validated against known molecular interaction behaviors observed in similar neurodegenerative contexts. The study also explores potential therapeutic strategies to mitigate these disruptions. By enhancing our understanding of these molecular interactions, this research contributes to the development of more effective treatments for AD, with the ultimate goal of alleviating synaptic impairments associated with the disease.
Universal scale-free representations in human visual cortex
Authors: Raj Magesh Gauthaman, Brice Ménard, Michael F. Bonner
Date: 2024-09-10 00:00:00
Tasks: Anatomy

How does the human brain encode complex visual information? While previous research has characterized individual dimensions of visual representation in cortex, we still lack a comprehensive understanding of how visual information is organized across the full range of neural population activity. Here, analyzing fMRI responses to natural scenes across multiple individuals, we discover that neural representations in human visual cortex follow a remarkably consistent scale-free organization -- their variance systematically decays as a power law, detected across four orders of magnitude of latent dimensions. This scale-free structure appears consistently across multiple visual regions and across individuals, suggesting it reflects a fundamental organizing principle of visual processing. Critically, when we align neural responses across individuals using hyperalignment, we find that these representational dimensions are largely shared between people, revealing a universal high-dimensional spectrum of visual information that emerges despite individual differences in brain anatomy and visual experience. Traditional analysis approaches in cognitive neuroscience have focused primarily on a small number of high-variance dimensions, potentially missing crucial aspects of visual representation. Our results demonstrate that visual information is distributed across the full dimensionality of cortical activity in a systematic way, suggesting we need to move beyond low-dimensional characterizations to fully understand how the brain represents the visual world. This work reveals a new fundamental principle of neural coding in human visual cortex and highlights the importance of examining neural representations across their full dimensionality.
The Neuroscientific Basis of Flow: Learning Progress Guides Task Engagement and Cognitive Control
Authors: Hairong Lu, Dimitri van der Linden, Arnold B. Bakker
Date: 2024-09-10 00:00:00

People often strive for deep engagement in activities which is usually associated with feelings of flow: a state of full task absorption accompanied by a sense of control and fulfillment. The intrinsic factors driving such engagement and facilitating subjective feelings of flow remain unclear. Building on computational theories of intrinsic motivation, this study examines how learning progress predicts engagement and directs cognitive control. Results showed that task engagement, indicated by feelings of flow and distractibility, is a function of learning progress. Electroencephalography data further revealed that learning progress is associated with enhanced proactive preparation (e.g., reduced pre-stimulus contingent negativity variance and parietal alpha desynchronization) and improved feedback processing (e.g., increased P3b amplitude and parietal alpha desynchronization). The impact of learning progress on cognitive control is observed at the task-block and goal-episode levels, but not at the trial level. This suggests that learning progress shapes cognitive control over extended periods as progress accumulates. These findings highlight the critical role of learning progress in sustaining engagement and cognitive control in goal-directed behavior.
Predictive Coding with Spiking Neural Networks: a Survey
Authors: Antony W. N'dri, William Gebhardt, Céline Teulière, Fleur Zeldenrust, Rajesh P. N. Rao, Jochen Triesch, Alexander Ororbia
Date: 2024-09-09 00:00:00
Tasks: Edge-computing, Prediction, Survey

In this article, we review a class of neuro-mimetic computational models that we place under the label of spiking predictive coding. Specifically, we review the general framework of predictive processing in the context of neurons that emit discrete action potentials, i.e., spikes. Theoretically, we structure our survey around how prediction errors are represented, which results in an organization of historical neuromorphic generalizations that is centered around three broad classes of approaches: prediction errors in explicit groups of error neurons, in membrane potentials, and implicit prediction error encoding. Furthermore, we examine some applications of spiking predictive coding that utilize more energy-efficient, edge-computing hardware platforms. Finally, we highlight important future directions and challenges in this emerging line of inquiry in brain-inspired computing. Building on the prior results of work in computational cognitive neuroscience, machine intelligence, and neuromorphic engineering, we hope that this review of neuromorphic formulations and implementations of predictive coding will encourage and guide future research and development in this emerging research area.
Triple equivalence for the emergence of biological intelligence
Authors: Takuya Isomura
Date: 2024-09-07 00:00:00
Tasks: Bayesian Inference, Model Selection

Characterising the intelligence of biological organisms is challenging. This work considers intelligent algorithms developed evolutionarily within neural systems. Mathematical analyses unveil a natural equivalence between canonical neural networks, variational Bayesian inference under a class of partially observable Markov decision processes, and differentiable Turing machines, by showing that they minimise the shared Helmholtz energy. Consequently, canonical neural networks can biologically plausibly equip Turing machines and conduct variational Bayesian inferences of external Turing machines in the environment. Applying Helmholtz energy minimisation at the species level facilitates deriving active Bayesian model selection inherent in natural selection, resulting in the emergence of adaptive algorithms. In particular, canonical neural networks with two mental actions can separately memorise transition mappings of multiple external Turing machines to form a universal machine. These propositions were corroborated by numerical simulations of algorithm implementation and neural network evolution. These notions offer a universal characterisation of biological intelligence emerging from evolution in terms of Bayesian model selection and belief updating.
Anatomical Connections of Primate Mediodorsal and Motor Thalamic Nuclei with the Cortex
Authors: Bianca Sieveritz, Roozbeh Kiani
Date: 2024-09-03 00:00:00

Non-sensory thalamic nuclei interact with the cortex through thalamocortical and cortico-basal ganglia-thalamocortical loops. Reciprocal connections between the mediodorsal thalamus (MD) and the prefrontal cortex are particularly important in cognition, while the reciprocal connections of the ventromedial (VM), ventral anterior (VA), and ventrolateral (VL) thalamus with the prefrontal and motor cortex are necessary for sensorimotor information processing. However, limited and often oversimplified understanding of the connectivity of the MD, VA, and VL nuclei in primates have hampered development of accurate models that explain their contribution to cognitive and sensorimotor functions. The current prevalent view suggests that the MD connects with the prefrontal cortex, while the VA and VL primarily connect with the premotor and motor cortices. However, past studies have also reported diverse connections that enable these nuclei to integrate information across a multitude of brain systems. In this review, we provide a comprehensive overview of the anatomical connectivity of the primate MD, VA, and VL with the cortex. By synthesizing recent findings, we aim to offer a valuable resource for students, newcomers to the field, and experts developing new theories or models of thalamic function. Our review highlights the complexity of these connections and underscores the need for further research to fully understand the diverse roles of these thalamic nuclei in primates.
Anti-seizure medication load is not correlated with early termination of seizure spread
Authors: Nathan Evans, Sarah J. Gascoigne, Guillermo M. Besne, Chris Thornton, Gabrielle M. Schroeder, Fahmida A Chowdhury, Beate Diehl, John S Duncan, Andrew W McEvoy, Anna Miserocchi, Rhys Thomas, Jane de Tisi, Peter N. Taylor, Yujiang Wang
Date: 2024-09-03 00:00:00
Tasks: EEG

Objective: Anti-seizure medications (ASMs) are the mainstay of treatment for epilepsy, yet their effect on seizure spread is not fully understood. Higher ASM doses have been associated with shorter and less severe seizures. We aimed to test if this effect was due to limiting seizure spread through early termination of otherwise unchanged seizures. Methods: We retrospectively examined intracranial EEG (iEEG) recordings in 15 subjects who underwent ASM tapering during pre-surgical monitoring. We estimated ASM plasma concentrations based on pharmaco-kinetic modeling. In each subject, we identified seizures that followed the same onset and initial spread patterns, but some seizures terminated early (truncated seizures), and other seizures continued to spread (continuing seizures). We first compared seizure duration to ASM concentration for all seizures and the subset of seizures included in truncated-continuing pairs. Then we compared durations of the matched truncated and continuing seizures. Finally, we compared ASM concentrations at the times of truncated seizures and continuing seizures. Results: Seizure durations were found to be significantly longer at lower ASM concentrations. Continuing seizures were significantly longer in duration than matched truncated seizures. We found no substantial difference between ASM concentrations when truncated vs. continuing seizures occurred. Significance: The lack of difference between ASM concentrations at the time of truncated vs. continuing seizures implies a separate mechanism for shortening the duration of seizures beyond stopping the spread pathways early. Additionally, the mechanism causing seizures to be truncated remains unclear. Further research is needed to understand how ASM may modulate seizure duration and severity.