Autophagy and migrasome formation constitute critical cellular mechanisms for maintaining cellular homeostasis, however, their potential compensatory interplay remains poorly understood. In this study, we identify VPS39, a core component of the HOPS complex, as a molecular switch coordinating these processes. Genetic ablation of VPS39 not only impairs autophagic flux but also triggers cell migration through RhoA/Rac1 GTPases upregulation, consequently facilitating migrasome formation. Using super-resolution microscopy, we further demonstrate that migrasomes serve as an alternative disposal route for damaged mitochondria during VPS39-induced autophagy impairment, revealing a novel stress adaptation mechanism. Our work establishes a previously unrecognized autophagy-migrasome axis and provides direct visual evidence of organelle quality control via migrasomal extrusion. These findings position VPS39-regulated pathway switching as a potential therapeutic strategy for neurodegenerative diseases characterized by autophagy dysfunction.
Purpose: We investigated the utilization of privacy-preserving, locally-deployed, open-source Large Language Models (LLMs) to extract diagnostic information from free-text cardiovascular magnetic resonance (CMR) reports. Materials and Methods: We evaluated nine open-source LLMs on their ability to identify diagnoses and classify patients into various cardiac diagnostic categories based on descriptive findings in 109 clinical CMR reports. Performance was quantified using standard classification metrics including accuracy, precision, recall, and F1 score. We also employed confusion matrices to examine patterns of misclassification across models. Results: Most open-source LLMs demonstrated exceptional performance in classifying reports into different diagnostic categories. Google's Gemma2 model achieved the highest average F1 score of 0.98, followed by Qwen2.5:32B and DeepseekR1-32B with F1 scores of 0.96 and 0.95, respectively. All other evaluated models attained average scores above 0.93, with Mistral and DeepseekR1-7B being the only exceptions. The top four LLMs outperformed our board-certified cardiologist (F1 score of 0.94) across all evaluation metrics in analyzing CMR reports.
With the growth of global maritime transportation, energy optimization has become crucial for reducing costs and ensuring operational efficiency. Shaft power is the mechanical power transmitted from the engine to the shaft and directly impacts fuel consumption, making its accurate prediction a paramount step in optimizing vessel performance. Power consumption is highly correlated with ship parameters such as speed and shaft rotation per minute, as well as weather and sea conditions. Frequent access to this operational data can improve prediction accuracy. However, obtaining high-quality sensor data is often infeasible and costly, making alternative sources such as noon reports a viable option. In this paper, we propose a transfer learning-based approach for predicting vessels shaft power, where a model is initially trained on high-frequency data from a vessel and then fine-tuned with low-frequency daily noon reports from other vessels. We tested our approach on sister vessels (identical dimensions and configurations), a similar vessel (slightly larger with a different engine), and a different vessel (distinct dimensions and configurations). The experiments showed that the mean abso
Timely identification of issue reports reflecting software vulnerabilities is crucial, particularly for Internet-of-Things (IoT) where analysis is slower than non-IoT systems. While Machine Learning (ML) and Large Language Models (LLMs) detect vulnerability-indicating issues in non-IoT systems, their IoT use remains unexplored. We are the first to tackle this problem by proposing two approaches: (1) combining ML and LLMs with Natural Language Processing (NLP) techniques to detect vulnerability-indicating issues of 21 Eclipse IoT projects and (2) fine-tuning a pre-trained BERT Masked Language Model (MLM) on 11,000 GitHub issues for classifying \vul. Our best performance belongs to a Support Vector Machine (SVM) trained on BERT NLP features, achieving an Area Under the receiver operator characteristic Curve (AUC) of 0.65. The fine-tuned BERT achieves 0.26 accuracy, emphasizing the importance of exposing all data during training. Our contributions set the stage for accurately detecting IoT vulnerabilities from issue reports, similar to non-IoT systems.
The increasing significance of large models and their multi-modal variants in societal information processing has ignited debates on social safety and ethics. However, there exists a paucity of comprehensive analysis for: (i) the interactions between human and artificial intelligence systems, and (ii) understanding and addressing the associated limitations. To bridge this gap, we propose Model Autophagy Analysis (MONAL) for large models' self-consumption explanation. MONAL employs two distinct autophagous loops (referred to as ``self-consumption loops'') to elucidate the suppression of human-generated information in the exchange between human and AI systems. Through comprehensive experiments on diverse datasets, we evaluate the capacities of generated models as both creators and disseminators of information. Our key findings reveal (i) A progressive prevalence of model-generated synthetic information over time within training datasets compared to human-generated information; (ii) The discernible tendency of large models, when acting as information transmitters across multiple iterations, to selectively modify or prioritize specific contents; and (iii) The potential for a reduction
Generative Artificial Intelligence (AI) technologies and large models are producing realistic outputs across various domains, such as images, text, speech, and music. Creating these advanced generative models requires significant resources, particularly large and high-quality datasets. To minimise training expenses, many algorithm developers use data created by the models themselves as a cost-effective training solution. However, not all synthetic data effectively improve model performance, necessitating a strategic balance in the use of real versus synthetic data to optimise outcomes. Currently, the previously well-controlled integration of real and synthetic data is becoming uncontrollable. The widespread and unregulated dissemination of synthetic data online leads to the contamination of datasets traditionally compiled through web scraping, now mixed with unlabeled synthetic data. This trend, known as the AI autophagy phenomenon, suggests a future where generative AI systems may increasingly consume their own outputs without discernment, raising concerns about model performance, reliability, and ethical implications. What will happen if generative AI continuously consumes itself
Autophagy is a conserved biological stress response in mammalian cells that is responsible for clearing damaged proteins and organelles from the cytoplasm and recycling their contents via the lysosomal pathway. In cases of mild stress, autophagy acts as a survival mechanism, while in cases of severe stress cells may switch to programmed cell death. Understanding the decision process that moves a cell from autophagy to apoptosis is important since abnormal regulation of autophagy occurs in many diseases, including cancer. To integrate existing knowledge about this decision process into a rigorous, analytical framework, we built a mathematical model of cell fate decisions mediated by autophagy. Our dynamical model is consistent with existing quantitative measurements of autophagy and apoptosis in rat kidney proximal tubular cells responding to cisplatin-induced stress.
In 1984 Edward Witten proposed that an extremely dense form of matter composed of up, down, and strange quarks may be stable at zero pressure (Witten, 1984). Massive nuggets of such dense matter, if they exist, may pass through the Earth and be detectable by the seismic signals they generate (de Rujula and Glashow, 1984). With this motivation we investigated over 1 million seismic data reports to the U.S. Geological Survey for the years 1990-1993 not associated with epicentral sources. We report two results: (1) with an average of about 0.16 unassociated reports per minute after data cuts, we found a significant excess over statistical expectation for sets with ten or more reports in ten minutes; and (2) in spite of a very small a priori probability from random reports, we found one set of reports with arrival times and other features appropriate to signals from an epilinear source. This event has the properties predicted for the passage of a nugget of strange quark matter (SQM) through the earth, although there is no direct confirmation from other phenomenologies.
Screening mammography is high volume, time sensitive, and documentation heavy. Radiologists must translate subtle visual findings into consistent BI-RADS assessments, breast density categories, and structured narrative reports. While recent Vision Language Models (VLMs) enable image-to-text reporting, many rely on closed cloud systems or tightly coupled architectures that limit privacy, reproducibility, and adaptability. We present MammoWise, a local multi-model pipeline that transforms open source VLMs into mammogram report generators and multi-task classifiers. MammoWise supports any Ollama-hosted VLM and mammography dataset, and enables zero-shot, few-shot, and Chain-of-Thought prompting, with optional multimodal Retrieval Augmented Generation (RAG) using a vector database for case-specific context. We evaluate MedGemma, LLaVA-Med, and Qwen2.5-VL on VinDr-Mammo and DMID datasets, assessing report quality (BERTScore, ROUGE-L), BI-RADS classification, breast density, and key findings. Report generation is consistently strong and improves with few-shot prompting and RAG. Classification is feasible but sensitive to model and dataset choice. Parameter-efficient fine-tuning (QLoRA) of
The effects of molecularly targeted drug perturbations on cellular activities and fates are difficult to predict using intuition alone because of the complex behaviors of cellular regulatory networks. An approach to overcoming this problem is to develop mathematical models for predicting drug effects. Such an approach beckons for co-development of computational methods for extracting insights useful for guiding therapy selection and optimizing drug scheduling. Here, we present and evaluate a generalizable strategy for identifying drug dosing schedules that minimize the amount of drug needed to achieve sustained suppression or elevation of an important cellular activity/process, the recycling of cytoplasmic contents through (macro)autophagy. Therapeutic targeting of autophagy is currently being evaluated in diverse clinical trials but without the benefit of a control engineering perspective. Using a nonlinear ordinary differential equation (ODE) model that accounts for activating and inhibiting influences among protein and lipid kinases that regulate autophagy (MTORC1, ULK1, AMPK and VPS34) and methods guaranteed to find locally optimal control strategies, we find optimal drug dosin
In this paper, we propose a tumor growth model to incorporate and investigate the spatial effects of autophagy. The cells are classified into two phases: normal cells and autophagic cells, whose dynamics are also coupled with the nutrients. First, we construct a reaction-(cross-)diffusion system describing the evolution of cell densities, where the drift is determined by the negative gradient of the joint pressure, and the reaction terms manifest the unique mechanism of autophagy. Next, in the incompressible limit, such a cell density model naturally connects to a free boundary system, describing the geometric motion of the tumor region. Analyzing the free boundary model in a special case, we show that the ratio of the two phases of cells exponentially converges to a ``well-mixed" limit. Within this ``well-mixed" limit, we obtain an analytical solution of the free boundary system which indicates the exponential growth of the tumor size in the presence of autophagy in contrast to the linear growth without it. Numerical simulations are also provided to illustrate the analytical properties and to explore more scenarios.
We present a spectroscopic investigation of $^{169}\mathrm{Tm}^+$ that provides two key foundations for its use as a platform for advanced quantum applications. First, we establish the complete spectroscopic road map for optical cycling (including laser cooling) by performing high-resolution spectroscopy on $^{169}\mathrm{Tm}^+$ ions in an ion trap. We characterize the primary $313\,\mathrm{nm}$ and complementary $448/453\,\mathrm{nm}$ cycling transitions, identify the essential near-infrared repumping frequencies, and determine the magnetic-dipole hyperfine $A$ constants for all relevant levels. Second, we report a detailed characterization of a metastable state as a candidate for hosting a robust qubit, performing lifetime measurements and Zeeman-resolved microwave hyperfine spectroscopy with $\mathrm{kHz}$ precision.
Selective autophagy must not only select the correct type of organelle, but also must discriminate between individual organelles of the same kind so that some but not all of the organelles are removed. We propose that physical clustering of autophagy receptor proteins on the organelle surface can provide an appropriate all-or-none signal for organelle degradation. We explore this proposal using a computational model restricted to peroxisomes and the relatively well characterized pexophagy receptor proteins NBR1 and p62. We find that larger peroxisomes nucleate NBR1 clusters first and lose them last through competitive coarsening. This results in significant size-selectivity that favors large peroxisomes, and can explain the increased catalase signal that results from siRNA inhibition of p62. Excess ubiquitin, resulting from damaged organelles, suppresses size-selectivity but not cluster formation. Our proposed selectivity mechanism thus allows all damaged organelles to be degraded, while otherwise selecting only a portion of organelles for degradation.
In the face of an infectious disease, a key epidemiological measure is the basic reproduction number, which quantifies the average secondary infections caused by a single case in a susceptible population. In practice, the effective reproduction number, denoted as $R_t$, is widely used to assess the transmissibility of the disease at a given time $t$. Real-time estimating this metric is vital for understanding and managing disease outbreaks. Traditional statistical inference often relies on two assumptions. One is that samples are assumed to be drawn from a homogeneous population distribution, neglecting significant variations in individual transmission rates. The other is the ideal case reporting assumption, disregarding time delays between infection and reporting. In this paper, we thoroughly investigate these critical factors and assess their impact on estimating $R_t$. We first introduce negative binomial and Weibull distributions to characterize transmission rates and reporting delays, respectively, based on which observation and state equations are formulated. Then, we employ a Bayesian filtering for estimating $R_t$. Finally, validation using synthetic and empirical data demo
In this paper we study a cross-diffusion system whose coefficient matrix is non-symmetric and degenerate. The system arises in the study of tissue growth with autophagy. The existence of a weak solution is established. We also investigate the limiting behavior of solutions as the pressure gets stiff. The so-called incompressible limit is a free boundary problem of Hele-Shaw type. Our key new discovery is that the usual energy estimate still holds as long as the time variable stays away from $0$.
The qualitative behavior of a recently formulated ODE model for the dynamics of heterogenous aggregates is analyzed. Aggregates contain two types of particles, oligomers and cross-linkers. The motivation is a preparatory step of cellular autophagy, the aggregation of oligomers of the protein p62 in the presence of ubiquitin cross-linkers. A combination of explicit computations, formal asymptotics, and numerical simulations has led to conjectures on the bifurcation behavior, certain aspects of which are proven rigorously in this work. In particular, the stability of the zero state, where the model has a smoothness deficit is analyzed by a combination of regularizing transformations and blow-up techniques. On the other hand, in a different parameter regime, the existence of polynomially growing solutions is shown by Poincaré compactification, combined with a singular perturbation analysis .
The recent global pandemic of Coronavirus Disease 2019 (COVID-19) caused by the new coronavirus SARS-CoV-2 presents an urgent need for new therapeutic candidates. Many efforts have been devoted to screening existing drug libraries with the hope to repurpose approved drugs as potential treatments for COVID-19. However, the antiviral mechanisms of action for the drugs found active in these phenotypic screens are largely unknown. To deconvolute the viral targets for more effective anti-COVID-19 drug development, we mined our in-house database of approved drug screens against 994 assays and compared their activity profiles with the drug activity profile in a cytopathic effect (CPE) assay of SARS-CoV-2. We found that the autophagy and AP-1 signaling pathway activity profiles are significantly correlated with the anti-SARS-CoV-2 activity profile. In addition, a class of neurology/psychiatry drugs was found significantly enriched with anti-SARS-CoV-2 activity. Taken together, these results have provided new insights into SARS-CoV-2 infection and potential targets for COVID-19 therapeutics.
Influenza and respiratory syncytial virus (RSV) are the leading etiological agents of seasonal acute respiratory infections (ARI) around the world. Medical doctors typically base the diagnosis of ARI on patients' symptoms alone and do not always conduct virological tests necessary to identify individual viruses, which limits the ability to study the interaction between multiple pathogens and make public health recommendations. We consider a stochastic kinetic model (SKM) for two interacting ARI pathogens circulating in a large population and an empirically motivated background process for infections with other pathogens causing similar symptoms. An extended marginal sampling approach based on the Linear Noise Approximation to the SKM integrates multiple data sources and additional model components. We infer the parameters defining the pathogens' dynamics and interaction within a Bayesian hierarchical model and explore the posterior trajectories of infections for each illness based on aggregate infection reports from six epidemic seasons collected by the state health department, and a subset of virological tests from a sentinel program at a general hospital in San Luis Potosí, Méxic
Aggregation of ubiquitinated cargo by oligomers of the protein p62 is an important preparatory step in cellular autophagy. In this work a mathematical model for the dynamics of these heterogeneous aggregates in the form of a system of ordinary differential equations is derived and analyzed. Three different parameter regimes are identified, where either aggregates are unstable, or their size saturates at a finite value, or their size grows indefinitely as long as free particles are abundant. The boundaries of these regimes as well as the finite size in the second case can be computed explicitly. The growth in the third case (quadratic in time) can also be made explicit by formal asymptotic methods. The qualitative results are illustrated by numerical simulations. A comparison with recent experimental results permits a partial parametrization of the model.
The increasing use of artificial intelligence (AI) in news production raises important questions about how audiences perceive and respond to AI-generated journalism. This preregistered survey experiment (N = 599, German-speaking Switzerland) examines (i) perceptions of article quality (measured as credibility, readability, and expertise) across news excerpts that were human-written, AI-assisted, or fully AI-generated, and (ii) self-reported intentions to engage following disclosure of AI involvement. Participants rated two short news excerpts before learning how they had been produced. Articles across all conditions were evaluated similarly in perceived quality. After disclosure, participants in the AI-assisted and AI-generated conditions reported a higher willingness to continue reading their assigned articles compared to the control group, but future willingness to read AI-generated news did not differ across conditions. Overall, the findings suggest that readers assess AI-generated and human-written news comparably in quality, while disclosure of AI use can momentarily increase curiosity or interest without yet changing longer-term reading intentions.