pwc-archive/papers-with-abstracts huggingface dataset:
PhenoKG: Knowledge Graph-Driven Gene Discovery and Patient Insights from Phenotypes Alone
Authors: Kamilia Zaripova, Ege Özsoy, Nassir Navab, Azade Farshad
Date: 2025-06-16 00:00:00

Identifying causative genes from patient phenotypes remains a significant challenge in precision medicine, with important implications for the diagnosis and treatment of genetic disorders. We propose a novel graph-based approach for predicting causative genes from patient phenotypes, with or without an available list of candidate genes, by integrating a rare disease knowledge graph (KG). Our model, combining graph neural networks and transformers, achieves substantial improvements over the current state-of-the-art. On the real-world MyGene2 dataset, it attains a mean reciprocal rank (MRR) of 24.64\% and nDCG@100 of 33.64\%, surpassing the best baseline (SHEPHERD) at 19.02\% MRR and 30.54\% nDCG@100. We perform extensive ablation studies to validate the contribution of each model component. Notably, the approach generalizes to cases where only phenotypic data are available, addressing key challenges in clinical decision support when genomic information is incomplete.
SemanticST: Spatially Informed Semantic Graph Learning for Clustering, Integration, and Scalable Analysis of Spatial Transcriptomics
Authors: Roxana Zahedi, Ahmadreza Argha, Nona Farbehi, Ivan Bakhshayeshi, Youqiong Ye, Nigel H. Lovell, Hamid Alinejad-Rokny
Date: 2025-06-13 00:00:00
Tasks: Benchmarking, Contrastive Learning, graph construction, Graph Learning, Graph Neural Network

Spatial transcriptomics (ST) technologies enable gene expression profiling with spatial resolution, offering unprecedented insights into tissue organization and disease heterogeneity. However, current analysis methods often struggle with noisy data, limited scalability, and inadequate modelling of complex cellular relationships. We present SemanticST, a biologically informed, graph-based deep learning framework that models diverse cellular contexts through multi-semantic graph construction. SemanticST builds multiple context-specific graphs capturing spatial proximity, gene expression similarity, and tissue domain structure, and learns disentangled embeddings for each. These are fused using an attention-inspired strategy to yield a unified, biologically meaningful representation. A community-aware min-cut loss improves robustness over contrastive learning, particularly in sparse ST data. SemanticST supports mini-batch training, making it the first graph neural network scalable to large-scale datasets such as Xenium (500,000 cells). Benchmarking across four platforms (Visium, Slide-seq, Stereo-seq, Xenium) and multiple human and mouse tissues shows consistent 20 percentage gains in ARI, NMI, and trajectory fidelity over DeepST, GraphST, and IRIS. In re-analysis of breast cancer Xenium data, SemanticST revealed rare and clinically significant niches, including triple receptor-positive clusters, spatially distinct DCIS-to-IDC transition zones, and FOXC2 tumour-associated myoepithelial cells, suggesting non-canonical EMT programs with stem-like features. SemanticST thus provides a scalable, interpretable, and biologically grounded framework for spatial transcriptomics analysis, enabling robust discovery across tissue types and diseases, and paving the way for spatially resolved tissue atlases and next-generation precision medicine.
Improving spliced alignment by modeling splice sites with deep learning
Authors: Siying Yang, Neng Huang, Heng Li
Date: 2025-06-15 00:00:00

Motivation: Spliced alignment refers to the alignment of messenger RNA (mRNA) or protein sequences to eukaryotic genomes. It plays a critical role in gene annotation and the study of gene functions. Accurate spliced alignment demands sophisticated modeling of splice sites, but current aligners use simple models, which may affect their accuracy given dissimilar sequences. Results: We implemented minisplice to learn splice signals with a one-dimensional convolutional neural network (1D-CNN) and trained a model with 7,026 parameters for vertebrate and insect genomes. It captures conserved splice signals across phyla and reveals GC-rich introns specific to mammals and birds. We used this model to estimate the empirical splicing probability for every GT and AG in genomes, and modified minimap2 and miniprot to leverage pre-computed splicing probability during alignment. Evaluation on human long-read RNA-seq data and cross-species protein datasets showed our method greatly improves the junction accuracy especially for noisy long RNA-seq reads and proteins of distant homology. Availability and implementation: https://github.com/lh3/minisplice
Viral Dark Matter: Illuminating Protein Function, Ecology, and Biotechnological Promises
Authors: James C. Kosmopoulos, Karthik Anantharaman
Date: 2025-06-13 00:00:00

Viruses are the most abundant biological entities on Earth and play central roles in shaping microbiomes and influencing ecosystem functions. Yet, most viral genes remain uncharacterized, comprising what is commonly referred to as "viral dark matter." Metagenomic studies across diverse environments consistently show that 40-90% of viral genes lack known homologs or annotated functions. This persistent knowledge gap limits our ability to interpret viral sequence data, understand virus-host interactions, and assess the ecological or applied significance of viral genes. Among the most intriguing components of viral dark matter are auxiliary viral genes (AVGs), including auxiliary metabolic genes (AMGs), regulatory genes (AReGs), and host physiology-modifying genes (APGs), which may alter host function during infection and contribute to microbial metabolism, stress tolerance, or resistance. In this review, we explore recent advances in the discovery and functional characterization of viral dark matter. We highlight representative examples of novel viral proteins across diverse ecosystems including human microbiomes, soil, oceans, and extreme environments, and discuss what is known, and still unknown, about their roles. We then examine the bioinformatic and experimental challenges that hinder functional characterization, and present emerging strategies to overcome these barriers. Finally, we highlight both the fundamental and applied benefits that multidisciplinary efforts to characterize viral proteins can bring. By integrating computational predictions with experimental validation, and fostering collaboration across disciplines, we emphasize that illuminating viral dark matter is both feasible and essential for advancing microbial ecology and unlocking new tools for biotechnology.
GlobDB: A comprehensive species-dereplicated microbial genome resource
Authors: Daan R. Speth, Nick Pullen, Samuel T. N. Aroney, Benjamin L. Coltman, Jay T. Osvatic, Ben J. Woodcroft, Thomas Rattei, Michael Wagner
Date: 2025-06-13 00:00:00

Over the past years, substantial numbers of microbial species' genomes have been deposited outside of conventional INSDC databases. The GlobDB aggregates 14 independent genomic catalogues to provide a comprehensive database of species-dereplicated microbial genomes, with consistent taxonomy, annotations, and additional analysis resources. The GlobDB is available at https://globdb.org/.
Multimodal Modeling of CRISPR-Cas12 Activity Using Foundation Models and Chromatin Accessibility Data
Authors: Azim Dehghani Amirabad, Yanfei Zhang, Artem Moskalev, Sowmya Rajesh, Tommaso Mansi, Shuwei Li, Mangal Prakash, Rui Liao
Date: 2025-06-12 00:00:00
Tasks: Activity Prediction

Predicting guide RNA (gRNA) activity is critical for effective CRISPR-Cas12 genome editing but remains challenging due to limited data, variation across protospacer adjacent motifs (PAMs-short sequence requirements for Cas binding), and reliance on large-scale training. We investigate whether pre-trained biological foundation model originally trained on transcriptomic data can improve gRNA activity estimation even without domain-specific pre-training. Using embeddings from existing RNA foundation model as input to lightweight regressor, we show substantial gains over traditional baselines. We also integrate chromatin accessibility data to capture regulatory context, improving performance further. Our results highlight the effectiveness of pre-trained foundation models and chromatin accessibility data for gRNA activity prediction.
Brain-wide interpolation and conditioning of gene expression in the human brain using Implicit Neural Representations
Authors: Xizheng Yu, Justin Torok, Sneha Pandya, Sourav Pal, Vikas Singh, Ashish Raj
Date: 2025-06-11 00:00:00

In this paper, we study the efficacy and utility of recent advances in non-local, non-linear image interpolation and extrapolation algorithms, specifically, ideas based on Implicit Neural Representations (INR), as a tool for analysis of spatial transcriptomics data. We seek to utilize the microarray gene expression data sparsely sampled in the healthy human brain, and produce fully resolved spatial maps of any given gene across the whole brain at a voxel-level resolution. To do so, we first obtained the 100 top AD risk genes, whose baseline spatial transcriptional profiles were obtained from the Allen Human Brain Atlas (AHBA). We adapted Implicit Neural Representation models so that the pipeline can produce robust voxel-resolution quantitative maps of all genes. We present a variety of experiments using interpolations obtained from Abagen as a baseline/reference.
Unlasting: Unpaired Single-Cell Multi-Perturbation Estimation by Dual Conditional Diffusion Implicit Bridges
Authors: Changxi Chi, Jun Xia, Yufei Huang, Jingbo Zhou, Siyuan Li, Yunfan Liu, Chang Yu, Stan Z. Li
Date: 2025-06-26 00:00:00
Tasks: Data Augmentation

Estimating single-cell responses across various perturbations facilitates the identification of key genes and enhances drug screening, significantly boosting experimental efficiency. However, single-cell sequencing is a destructive process, making it impossible to capture the same cell's phenotype before and after perturbation. Consequently, data collected under perturbed and unperturbed conditions are inherently unpaired. Existing methods either attempt to forcibly pair unpaired data using random sampling, or neglect the inherent relationship between unperturbed and perturbed cells during the modeling. In this work, we propose a framework based on Dual Diffusion Implicit Bridges (DDIB) to learn the mapping between different data distributions, effectively addressing the challenge of unpaired data. We further interpret this framework as a form of data augmentation. We integrate gene regulatory network (GRN) information to propagate perturbation signals in a biologically meaningful way, and further incorporate a masking mechanism to predict silent genes, improving the quality of generated profiles. Moreover, gene expression under the same perturbation often varies significantly across cells, frequently exhibiting a bimodal distribution that reflects intrinsic heterogeneity. To capture this, we introduce a more suitable evaluation metric. We propose Unlasting, dual conditional diffusion models that overcome the problem of unpaired single-cell perturbation data and strengthen the model's insight into perturbations under the guidance of the GRN, with a dedicated mask model designed to improve generation quality by predicting silent genes. In addition, we introduce a biologically grounded evaluation metric that better reflects the inherent heterogeneity in single-cell responses.
Enhancing Biosecurity in Tamper-Resistant Large Language Models With Quantum Gradient Descent
Authors: Fahmida Hai, Saif Nirzhor, Rubayat Khan, Don Roosan
Date: 2025-06-23 00:00:00
Tasks: Question Answering, Sensitivity

This paper introduces a tamper-resistant framework for large language models (LLMs) in medical applications, utilizing quantum gradient descent (QGD) to detect malicious parameter modifications in real time. Integrated into a LLaMA-based model, QGD monitors weight amplitude distributions, identifying adversarial fine-tuning anomalies. Tests on the MIMIC and eICU datasets show minimal performance impact (accuracy: 89.1 to 88.3 on MIMIC) while robustly detecting tampering. PubMedQA evaluations confirm preserved biomedical question-answering capabilities. Compared to baselines like selective unlearning and cryptographic fingerprinting, QGD offers superior sensitivity to subtle weight changes. This quantum-inspired approach ensures secure, reliable medical AI, extensible to other high-stakes domains.
Central Dogma Cycle and Network: A Model for Cell Memory
Authors: Martin R. Schiller
Date: 2025-06-19 00:00:00
Tasks: Protein Folding

This paper proposes an extension of the traditional Central Dogma of molecular biology to a more dynamic model termed the Central Dogma Cycle (CDC) and a broader network called the Central Dogma Cyclic Network (CDCN). While the Central Dogma is necessary for genetic information flow, it is not sufficient to fully explain cellular memory and information management. The CDC incorporates additional well-established steps, including protein folding and protein networking, highlighting the cyclical nature of information flow in cells. This cyclic architecture is proposed as a key mechanism for cellular memory, drawing analogies to memory functions in computers, such as input, read, write, execute, and erase. The interconnected cycles within the CDCN, including metabolic cycles and signaling pathways, are suggested to function akin to latches in computer memory, contributing to the storage and processing of cellular information beyond nucleic acid sequences. Understanding cellular memory through this cyclic network model offers a new perspective on heredity, cell processes, and the potential disruptions in disease pathology.
Attractor Stability of Boolean networks under noise
Authors: Byungjoon Min, Jeehye Choi, Reinhard Laubenbacher
Date: 2025-06-18 00:00:00

We study the impact of noise on attractor dynamics in Boolean networks, focusing on their stability and transition behaviors. By constructing attractor matrices based on single-node perturbations, we propose a framework to quantify attractor stability and identify dominant attractors. We find that attractors are more stable than predicted by basin sizes, showing the importance of dynamical structure in noisy environments. In addition, under global perturbations, basin sizes dictate long-term behavior; under local noise, however, attractor dominance is determined by noise-induced transition patterns rather than basin sizes. Our results show that transition dynamics induced by stochastic perturbations provide an efficient and quantitative description for the attractor stability and dynamics in Boolean networks under noise.
Complex forming behaviour of α, \b{eta} and γ-cyclodextrins with varying size probe particles in silico
Authors: N. R. M. Nelumdeniya, R. J. K. U. Ranatunga
Date: 2025-06-16 00:00:00

Cyclodextrins (CDs) are cyclic oligosaccharides composed of glucopyranose units bonded together to form a truncated cone that can make inclusion complexes with guest molecules. The {\alpha}, \b{eta}, and {\gamma}-CDs, which respectively comprise six, seven or eight glucopyranose units, are used extensively in pharmaceutical formulations as functional excipients. The cavity sizes of all three natural CDs have been approximated using static structures but a growing consensus is that the CDs are flexible; moreover, the size range of molecules that CDs can accommodate has not been systematically studied. Here the results of molecular dynamics simulations performed using spherical continuum probe particles of different sizes to observe the complex-forming behaviour of CDs are presented. Results revealed that CDs can make dynamic complexes with guest molecules that are larger than their reported cavity sizes.
Network Pharmacology Reveals HSPA1A/BST2 as Potential Targets of Ci Bai Capsule's Active Compounds Intervening in Leukopenia
Authors: DingFan Zhang, Congshu Huang, Lei Zhou, Boyang Wang, Wei Zhou, Tiantian Xia, Pan Shen, Shao Li, Yue Gao
Date: 2025-06-13 00:00:00

Background: Radiation-induced leukopenia caused by low-dose exposure is frequently associated with Traditional Chinese Medicine (TCM) syndromes like "blood deficiency" and "fatigue syndrome". Ci Bai Capsule (CB) has been reported to enhance white blood cell levels; however, its mechanisms and bioactive compounds remain unclear.Aim: This study aimed to identify the bioactive compounds group of CB and elucidate its potential mechanisms in radiation-induced leukopenia.Methods: Syndrome-related data were gathered from SYMMAP and CTD database. CB's target profile is predicted by DrugCIPHER. Network pharmacology approaches were employed to identify active compounds and related pathways. Experimental validation was conducted through flow cytometry and RNA-sequencing in both ex vivo and in vivo models.Results: A total of 22 pathways related to cellular processes, immune responses, and signal transduction were identified. Five key bioactive compounds (kaempferol-3-glucorhamnoside, syringin, schisandrin, 3-hydroxytyrosol 3-O-glucoside and salidroside) were found to significantly modulate syndrome-related pathways. Optimal dosing of this compound combination enhanced leukocyte counts and splenic immune cell proliferation in irradiated mice. Transcriptomic analysis revealed that the compounds exert regulatory effects on PP1A, RB, CDK4/6, CDK2, and CDK1, thereby modulating downstream immune and hematopoietic markers such as MNDA, BST2, and HSPA1A.Conclusion: Our findings suggest that CB mitigates radiation-induced leukopenia by enhancing immune and hematopoietic recovery, offering a promising therapeutic approach for managing radiation-related hematological disorders.
Input-to-state stability-based chemical reaction networks composition for molecular computations
Authors: Renlei Jiang, Yuzhen Fan, Di Fan, Chuanhou Gao, Denis Dochain
Date: 2025-05-30 00:00:00

Molecular computation based on chemical reaction networks (CRNs) has emerged as a promising paradigm for designing programmable biochemical systems. However, the implementation of complex computations still requires excessively large and intricate network structures, largely due to the limited understanding of composability, that is, how multiple subsystems can be coupled while preserving computational functionality. Existing composability frameworks primarily focus on rate-independent CRNs, whose computational capabilities are severely restricted. This article aims to establish a systematic framework for composable CRNs governed by mass-action kinetics, a common type of rate-dependent CRNs. Drawing upon the concepts of composable rate-independent CRNs, we introduce the notions of mass-action chemical reaction computers (msCRCs), dynamic computation and dynamic composability to establish a rigorous mathematical framework for composing two or more msCRCs to achieve layer-by-layer computation of composite functions. Further, we derive several sufficient conditions based on the notions of input-to-state stability (ISS) to characterize msCRCs that can be composed to implement desired molecular computations, thereby providing theoretical support for this framework. Some examples are presented to illustrate the efficiency of our method. Finally, comparative results demonstrate that the proposed method exhibits notable advantages in both computational ability and accuracy over the state-of-the-art methods.
The assumptions that restrain us from understanding consciousness
Authors: Jaan Aru
Date: 2025-06-26 00:00:00

The science of consciousness has been successful over the last decades. Yet, it seems that some of the key questions remain unanswered. Perhaps, as a science of consciousness, we cannot move forward using the same theoretical commitments that brought us here. It might be necessary to revise some assumptions we have made along the way. In this piece, I offer no answers, but I will question some of these fundamental assumptions. We will try to take a fresh look at the classical question about the neural and explanatory correlates of consciousness. A key assumption is that neural correlates are to be found at the level of spiking responses. However, perhaps we should not simply take it for granted that this assumption holds true. Another common assumption is that we are close to understanding the computations underlying consciousness. I will try to show that computations related to consciousness might be far more complex than our current theories envision. There is little reason to think that consciousness is an abstract computation, as traditionally believed. Furthermore, I will try to demonstrate that consciousness research could benefit from investigating internal changes of consciousness, such as aha-moments. Finally, I will ask which theories the science of consciousness really needs.
Wirelessly transmitted subthalamic nucleus signals predict endogenous pain levels in Parkinson's disease patients
Authors: Abdi Reza, Takufumi Yanagisawa, Naoki Tani, Ryohei Fukuma, Takuto Emura, Satoru Oshino, Ben Seymour, Haruhiko Kishima
Date: 2025-06-26 00:00:00

Parkinson disease (PD) patients experience pain fluctuations that significantly reduce their quality of life. Despite the vast knowledge of the subthalamic nucleus (STN) role in PD, the STN biomarkers for pain fluctuations and the relationship between bilateral subthalamic nucleus (STN) activities and pain occurrence are still less understood. This observational study used data-driven methods by collecting annotated pain followed by a series of corresponding binary pain ratings and wirelessly transmitted STN signals, then leveraging the explainable machine learning algorithm to predict binary pain levels and sort the feature influence. The binary pain levels could be predicted among annotated pain reports corresponding to PD-related pain characteristics. The STN activity from both sides could impact pain prediction, with gamma and beta bands in the contralateral STN and delta and theta bands in the ipsilateral STN showing a prominent role. This study emphasizes the role of bilateral STN biomarkers on endogenous pain fluctuations.
Amortizing personalization in virtual brain twins
Authors: Nina Baldy, Marmaduke M Woodman, Viktor K Jirsa
Date: 2025-06-26 00:00:00

Virtual brain twins are personalized digital models of individual human subject or patient's brains, allowing for mechanistic interpretation of neuroimaging data features. Training and inference with these models however presents a pair of challenges: large shared infrastructure do not allow for use of personal data and inference in clinical applications should not require significant resources. We introduce "anonymized personalization" to address both by expanding model priors to include personalization which under amortized inference allows training to be performed anonymously, while inference is both personalized and lightweight. We illustrate the basic approach, demonstrate reliability in an example, and discuss the impact on both experimental and computational neuroscience. Code is available at https://github.com/ins-amu/apvbt.