ArXiv最新文献

{"title":"Minibeam-pLATTICE: A novel proton LATTICE modality using minibeams.","authors":"Nimita Shinde, Weijie Zhang, Yuting Lin, Hao Gao","doi":"","DOIUrl":"","url":null,"abstract":"<p><strong>Purpose: </strong>LATTICE, a form of spatially fractionated radiation therapy (SFRT) that delivers high-dose peaks and low-dose valleys within the target volume, has been clinically utilized for treating bulky tumors. However, its application to small-to-medium-sized target volumes remains challenging due to beam size limitations. To address this challenge, this work proposes a novel proton LATTICE (pLATTICE) modality using minibeams, namely minibeam-pLATTICE, that can extend the LATTICE approach for small-to-medium target volumes.</p><p><strong>Methods: </strong>Three minibeam-pLATTICE methods are introduced. (1) M0: a fixed minibeam aperture orientation (e.g., 0°) for all beam angles; (2) M1: alternated minibeam aperture orientations (e.g., between 0° and 90°), for consecutive beam angles; (3) M2: multiple minibeam aperture orientations (e.g., 0° and 90°) for each beam angle. The purpose of M1 or M2 is to correct anisotropic dose distribution at lattice peaks due to the planar spatial modulation of minibeams. For each minibeam-pLATTICE method, an optimization problem is formulated to optimize dose uniformity in target peaks and valleys, as well as dose-volume-histogram-based objectives. This optimization problem is solved using iterative convex relaxation and alternating direction method of multipliers (ADMM).</p><p><strong>Results: </strong>Three minibeam-pLATTICE methods are validated to demonstrate the feasibility of minibeam-pLATTICE for the head-and-neck (HN) patients. The advantages of this modality over conventional beam (CONV) pLATTICE are evaluated by comparing peak-to-valley dose ratio (PVDR) and dose delivered to organs at risk (OAR). All three minibeam-pLATTICE modalities achieved improved plan quality compared to CONV, with M2 yielding the best results. For example, in terms of PVDR, M2=5.89, compared to CONV=4.13, M0=4.87 and M1=4.7; in terms of max brainstem dose, M2=5.8 Gy, compared to CONV=16.57 Gy, M0=6.54 Gy and M1=7.04 Gy.</p><p><strong>Conclusions: </strong>A novel minibeam-pLATTICE modality is proposed that can generate lattice dose patterns for small-to-medium target volumes, which are not achievable with conventional pLATTICE due to beam size limitations. Peak dose anisotropy due to 1D planar minibeam apertures is corrected through inverse treatment planning with alternating or multiple minibeam apertures per beam angle.</p>","PeriodicalId":93888,"journal":{"name":"ArXiv","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888559/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of normalization, non-differentially expressed genes and data source with machine learning performance in intra-dataset or cross-dataset modelling of transcriptomic and clinical data.","authors":"Fei Deng, Lanjing Zhang","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Cross-dataset testing is critical for examining machine learning (ML) model's performance. However, most studies on modelling transcriptomic and clinical data only conducted intra-dataset testing. It is also unclear whether normalization and non-differentially expressed genes (NDEG) can improve cross-dataset modeling performance of ML. We thus aim to understand whether normalization, NDEG and data source are associated with performance of ML in cross-dataset testing. The transcriptomic and clinical data shared by the lung adenocarcinoma cases in TCGA and ONCOSG were used. The best cross-dataset ML performance was reached using transcriptomic data alone and statistically better than those using transcriptomic and clinical data. The best balance accuracy (BA), area under curve (AUC) and accuracy were significantly better in ML algorithms training on TCGA and tested on ONCOSG than those trained on ONCOSG and tested on TCGA (p<0.05 for all). Normalization and NDEG greatly improved intra-dataset ML performances in both datasets, but not in cross-dataset testing. Strikingly, modelling transcriptomic data of ONCOSG alone outperformed modelling transcriptomic and clinical data whereas including clinical data in TCGA did not significantly impact ML performance, suggesting limited clinical data value or an overwhelming influence of transcriptomic data in TCGA. Performance gains in intra-dataset testing were more pronounced for ML models trained on ONCOSG than TCGA. Among the six ML models compared, Support vector machine was the most frequent best-performer in both intra-dataset and cross-dataset testing. Therefore, our data show data source, normalization and NDEG are associated with intra-dataset and cross-dataset ML performance in modelling transcriptomic and clinical data.</p>","PeriodicalId":93888,"journal":{"name":"ArXiv","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validating the predictions of mathematical models describing tumor growth and treatment response.","authors":"Guillermo Lorenzo, David A Hormuth, Chengyue Wu, Graham Pash, Anirban Chaudhuri, Ernesto A B F Lima, Lois C Okereke, Reshmi Patel, Karen Willcox, Thomas E Yankeelov","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Despite advances in methods to interrogate tumor biology, the observational and population-based approach of classical cancer research and clinical oncology does not enable anticipation of tumor outcomes to hasten the discovery of cancer mechanisms and personalize disease management. To address these limitations, individualized cancer forecasts have been shown to predict tumor growth and therapeutic response, inform treatment optimization, and guide experimental efforts. These predictions are obtained <i>via</i> computer simulations of mathematical models that are constrained with data from a patient's cancer and experiments. This book chapter addresses the validation of these mathematical models to forecast tumor growth and treatment response. We start with an overview of mathematical modeling frameworks, model selection techniques, and fundamental metrics. We then describe the usual strategies employed to validate cancer forecasts in preclinical and clinical scenarios. Finally, we discuss existing barriers in validating these predictions along with potential strategies to address them.</p>","PeriodicalId":93888,"journal":{"name":"ArXiv","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588452","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SE(3)-Equivariant Ternary Complex Prediction Towards Target Protein Degradation.","authors":"Fanglei Xue, Meihan Zhang, Shuqi Li, Xinyu Gao, James A Wohlschlegel, Wenbing Huang, Yi Yang, Weixian Deng","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Targeted protein degradation (TPD) induced by small molecules has emerged as a rapidly evolving modality in drug discovery, targeting proteins traditionally considered \"undruggable.\" This strategy induces the degradation of target proteins rather than inhibiting their activity, achieving desirable therapeutic outcomes. Proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs) are the primary small molecules that induce TPD. Both types of molecules form a ternary complex linking an E3 ubiquitin ligase with a target protein, a crucial step for drug discovery. While significant advances have been made in in-silico binary structure prediction for proteins and small molecules, ternary structure prediction remains challenging due to obscure interaction mechanisms and insufficient training data. Traditional methods relying on manually assigned rules perform poorly and are computationally demanding due to extensive random sampling. In this work, we introduce DeepTernary, a novel deep learning-based approach that directly predicts ternary structures in an end-to-end manner using an encoder-decoder architecture. DeepTernary leverages an SE(3)-equivariant graph neural network (GNN) with both intra-graph and ternary inter-graph attention mechanisms to capture intricate ternary interactions from our collected high-quality training dataset, TernaryDB. The proposed query-based Pocket Points Decoder extracts the 3D structure of the final binding ternary complex from learned ternary embeddings, demonstrating state-of-the-art accuracy and speed in existing PROTAC benchmarks without prior knowledge from known PROTACs. It also achieves notable accuracy on the more challenging MGD benchmark under the blind docking protocol. Remarkably, our experiments reveal that the buried surface area calculated from DeepTernary-predicted structures correlates with experimentally obtained degradation potency-related metrics. Consequently, DeepTernary shows potential in effectively assisting and accelerating the development of TPDs for previously undruggable targets.</p>","PeriodicalId":93888,"journal":{"name":"ArXiv","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complexity reduction by symmetry: uncovering the minimal regulatory network for logical computation in bacteria.","authors":"Luis A Álvarez-García, Wolfram Liebermeister, Ian Leifer, Hernán A Makse","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Symmetry principles play an important role in geometry, and physics, allowing for the reduction of complicated systems to simpler, more comprehensible models that preserve the system's features of interest. Biological systems are often highly complex and may consist of a large number of interacting parts. Using symmetry fibrations, the relevant symmetries for biological \"message-passing\" networks, we introduce a scheme, called Complexity Reduction by Symmetry or ComSym, to reduce the gene regulatory networks of <i>Escherichia coli</i> and <i>Bacillus subtilis</i> bacteria to core networks in a way that preserves the dynamics and uncovers the computational capabilities of the network. Gene nodes in the original network that share isomorphic input trees are collapsed by the fibration into equivalence classes called fibers, whereby nodes that receive signals with the same \"history\" belong to one fiber and synchronize. Then we reduce the networks to its minimal computational core via k-core decomposition. This computational core consists of a few strongly connected components or \"signal vortices\", in which signals can cycle through. While between them, these \"signal vortices\" transmit signals in a feedforward manner. These connected components perform signal processing and decision making in the bacterial cell by employing a series of genetic toggle-switch circuits that store memory, plus oscillator circuits. These circuits act as the central computation device of the network, whose output signals then spread to the rest of the network. Our reduction method opens the door to narrow the vast complexity of biological systems to their minimal parts in a systematic way by using fundamental theoretical principles of symmetry.</p>","PeriodicalId":93888,"journal":{"name":"ArXiv","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71415970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"gRNAde: Geometric Deep Learning for 3D RNA inverse design.","authors":"Chaitanya K Joshi, Arian R Jamasb, Ramon Viñas, Charles Harris, Simon V Mathis, Alex Morehead, Rishabh Anand, Pietro Liò","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Computational RNA design tasks are often posed as inverse problems, where sequences are designed based on adopting a single desired secondary structure without considering 3D conformational diversity. We introduce gRNAde, a geometric RNA design pipeline operating on 3D RNA backbones to design sequences that explicitly account for structure and dynamics. gRNAde uses a multi-state Graph Neural Network and autoregressive decoding to generates candidate RNA sequences conditioned on one or more 3D backbone structures where the identities of the bases are unknown. On a single-state fixed backbone re-design benchmark of 14 RNA structures from the PDB identified by Das et al. (2010), gRNAde obtains higher native sequence recovery rates (56% on average) compared to Rosetta (45% on average), taking under a second to produce designs compared to the reported hours for Rosetta. We further demonstrate the utility of gRNAde on a new benchmark of multi-state design for structurally flexible RNAs, as well as zero-shot ranking of mutational fitness landscapes in a retrospective analysis of a recent ribozyme. Experimental wet lab validation on 10 different structured RNA backbones finds that gRNAde has a success rate of 50% at designing pseudoknotted RNA structures, a significant advance over 35% for Rosetta. Open source code and tutorials are available at: https://github.com/chaitjo/geometric-rna-design.</p>","PeriodicalId":93888,"journal":{"name":"ArXiv","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11142323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141201624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modeling Neural Activity with Conditionally Linear Dynamical Systems.","authors":"Victor Geadah, Amin Nejatbakhsh, David Lipshutz, Jonathan W Pillow, Alex H Williams","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Neural population activity exhibits complex, non-linear dynamics, varying in time, over trials, and across experimental conditions. Here, we develop <i>Conditionally Linear Dynamical System</i> (CLDS) models as a general-purpose method to characterize these dynamics. These models use Gaussian Process (GP) priors to capture the nonlinear dependence of circuit dynamics on task and behavioral variables. Conditioned on these covariates, the data is modeled with linear dynamics. This allows for transparent interpretation and tractable Bayesian inference. We find that CLDS models can perform well even in severely data-limited regimes (e.g. one trial per condition) due to their Bayesian formulation and ability to share statistical power across nearby task conditions. In example applications, we apply CLDS to model thalamic neurons that nonlinearly encode heading direction and to model motor cortical neurons during a cued reaching task.</p>","PeriodicalId":93888,"journal":{"name":"ArXiv","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888554/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamics of Supervised and Reinforcement Learning in the Non-Linear Perceptron.","authors":"Christian Schmid, James M Murray","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>The ability of a brain or a neural network to efficiently learn depends crucially on both the task structure and the learning rule. Previous works have analyzed the dynamical equations describing learning in the relatively simplified context of the perceptron under assumptions of a student-teacher framework or a linearized output. While these assumptions have facilitated theoretical understanding, they have precluded a detailed understanding of the roles of the nonlinearity and input-data distribution in determining the learning dynamics, limiting the applicability of the theories to real biological or artificial neural networks. Here, we use a stochastic-process approach to derive flow equations describing learning, applying this framework to the case of a nonlinear perceptron performing binary classification. We characterize the effects of the learning rule (supervised or reinforcement learning, SL/RL) and input-data distribution on the perceptron's learning curve and the forgetting curve as subsequent tasks are learned. In particular, we find that the input-data noise differently affects the learning speed under SL vs. RL, as well as determines how quickly learning of a task is overwritten by subsequent learning. Additionally, we verify our approach with real data using the MNIST dataset. This approach points a way toward analyzing learning dynamics for more-complex circuit architectures.</p>","PeriodicalId":93888,"journal":{"name":"ArXiv","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11398553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142303246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MIML: Multiplex Image Machine Learning for High Precision Cell Classification via Mechanical Traits within Microfluidic Systems.","authors":"Khayrul Islam, Ratul Paul, Shen Wang, Yuwen Zhao, Partho Adhikary, Qiying Li, Xiaochen Qin, Yaling Liu","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>Label-free cell classification is advantageous for supplying pristine cells for further use or examination, yet existing techniques frequently fall short in terms of specificity and speed. In this study, we address these limitations through the development of a novel machine learning framework, Multiplex Image Machine Learning (MIML). This architecture uniquely combines label-free cell images with biomechanical property data, harnessing the vast, often underutilized biophysical information intrinsic to each cell. By integrating both types of data, our model offers a holistic understanding of cellular properties, utilizing cell biomechanical information typically discarded in traditional machine learning models. This approach has led to a remarkable 98.3% accuracy in cell classification, a substantial improvement over models that rely solely on image data. MIML has been proven effective in classifying white blood cells and tumor cells, with potential for broader application due to its inherent flexibility and transfer learning capability. It is particularly effective for cells with similar morphology but distinct biomechanical properties. This innovative approach has significant implications across various fields, from advancing disease diagnostics to understanding cellular behavior.</p>","PeriodicalId":93888,"journal":{"name":"ArXiv","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10516114/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41124135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A single-snapshot inverse solver for two-species graph model of tau pathology spreading in human Alzheimer disease.","authors":"Zheyu Wen, Ali Ghafouri, George Biros","doi":"","DOIUrl":"","url":null,"abstract":"<p><p>We propose a method that uses a two-species ordinary differential equation (ODE) model to characterize misfolded tau (or simply tau) protein spreading in Alzheimer's disease (AD) and calibrates it from clinical data. The unknown model parameters are the initial condition (IC) for tau and three scalar parameters representing the migration, proliferation, and clearance of tau proteins. Driven by imaging data, these parameters are estimated by formulating a constrained optimization problem with a sparsity regularization for the IC. This optimization problem is solved with a projection-based quasi-Newton algorithm. We investigate the sensitivity of our method to different algorithm parameters. We evaluate the performance of our method on both synthetic and clinical data. The latter comprises cases from the AD Neuroimaging Initiative (ADNI) datasets: 455 cognitively normal (CN), 212 mild cognitive impairment (MCI), and 45 AD subjects. We compare the performance of our approach to the commonly used Fisher-Kolmogorov (FK) model with a fixed IC at the entorhinal cortex (EC). Our method demonstrates an average improvement of 25.7% relative error compared to the FK model on the AD dataset. HFK also achieves an R-squared score of 0.664 for fitting AD data compared with 0.55 from FK model results under the same optimization scheme. Furthermore, for cases that have longitudinal data, we estimate a subject-specific AD onset time.</p>","PeriodicalId":93888,"journal":{"name":"ArXiv","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11888549/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143588835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}