For over a century, immunology has masterfully discovered and dissected the components of our immune system, yet its collective behavior remains fundamentally unpredictable. In this perspective, we argue that building on the learnings of reductionist biology and systems immunology, the field is poised for a third revolution. This new era will be driven by the convergence of purpose-built, large-scale causal experiments and predictive, generalizable AI models. Here, we propose the Predictive Immunology Loop as the unifying engine to harness this convergence. This closed loop iteratively uses AI to design maximally informative experiments and, in turn, leverages the resulting data to improve dynamic, in silico models of the human immune system across biological scales, culminating in a Virtual Immune System. This engine provides a natural roadmap for addressing immunology's grand challenges, from decoding molecular recognition to engineering tissue ecosystems. It also offers a framework to transform immunology from a descriptive discipline into one capable of forecasting and, ultimately, engineering human health.
This article introduces a metamodel for the Business Model Canvas (BMC) using the Unified Modelling Language (UML), together with a dedicated Domain-Specific Modelling Language (DSML) tool. Although the BMC is widely adopted by both practitioners and scholars, significant challenges remain in formally modelling business models, particularly with regard to explicit specification of inter-component relationships, while preserving the simplicity that characterises the BMC. Addressing this tension between modelling rigour and practical relevance, this research adopts a Design Science Research approach to formally specify relationships among BMC components and to strengthen their theoretical grounding through an adaptation of the V 4 framework. The proposed metamodel consolidates BMC relationships into three core types: supports, determines, and affects, providing explicit semantics while remaining accessible to end users through graphical tooling. The findings highlight that formally specifying relationships significantly improves the interpretability and consistency of BMC representations. The proposed metamodel and tool offer a rigorous yet usable foundation for developing DSML-based
Bounded Model Checking (BMC) is a widely used software verification technique. Despite its successes, the technique has several limiting factors, from state-space explosion to lack of completeness. Over the years, interval analysis has repeatedly been proposed as a partial solution to these limitations. In this work, we evaluate whether the computational cost of interval analysis yields significant enough improvements in BMC's performance to justify its use. In more detail, we quantify the benefits of interval analysis on two benchmarks: the Intel Core Power Management firmware and 9537 programs in the ReachSafety category of the International Competition on Software Verification. Our results show that interval analysis is essential in solving 203 unique benchmarks.
Finding software vulnerabilities in concurrent programs is a challenging task due to the size of the state-space exploration, as the number of interleavings grows exponentially with the number of program threads and statements. We propose and evaluate EBF (Ensembles of Bounded Model Checking with Fuzzing) -- a technique that combines Bounded Model Checking (BMC) and Gray-Box Fuzzing (GBF) to find software vulnerabilities in concurrent programs. Since there are no publicly-available GBF tools for concurrent code, we first propose OpenGBF -- a new open-source concurrency-aware gray-box fuzzer that explores different thread schedules by instrumenting the code under test with random delays. Then, we build an ensemble of a BMC tool and OpenGBF in the following way. On the one hand, when the BMC tool in the ensemble returns a counterexample, we use it as a seed for OpenGBF, thus increasing the likelihood of executing paths guarded by complex mathematical expressions. On the other hand, we aggregate the outcomes of the BMC and GBF tools in the ensemble using a decision matrix, thus improving the accuracy of EBF. We evaluate EBF against state-of-the-art pure BMC tools and show that it can
Bounded model checking (BMC) and fuzzing techniques are among the most effective methods for detecting errors and security vulnerabilities in software. However, there are still shortcomings in detecting these errors due to the inability of existent methods to cover large areas in target code. We propose FuSeBMC v4, a test generator that synthesizes seeds with useful properties, that we refer to as smart seeds, to improve the performance of its hybrid fuzzer thereby achieving high C program coverage. FuSeBMC works by first analyzing and incrementally injecting goal labels into the given C program to guide BMC and Evolutionary Fuzzing engines. After that, the engines are employed for an initial period to produce the so-called smart seeds. Finally, the engines are run again, with these smart seeds as starting seeds, in an attempt to achieve maximum code coverage / find bugs. During both seed generation and normal running, coordination between the engines is aided by the Tracer subsystem. This subsystem carries out additional coverage analysis and updates a shared memory with information on goals covered so far. Furthermore, the Tracer evaluates test cases dynamically to convert cases
With the skyrocketing costs of GPUs and their virtual instances in the cloud, there is a significant desire to use CPUs for large language model (LLM) inference. KV cache update, often implemented as allocation, copying, and in-place strided update for each generated token, incurs significant overhead. As the sequence length increases, the allocation and copy overheads dominate the performance. Alternate approaches may allocate large KV tensors upfront to enable in-place updates, but these matrices (with zero-padded rows) cause redundant computations. In this work, we propose a new KV cache allocation mechanism called Balancing Memory and Compute (BMC). BMC allocates, once every r iterations, KV tensors with r redundant rows, allowing in-place update without copy overhead for those iterations, but at the expense of a small amount of redundant computation. Second, we make an interesting observation that the extra rows allocated in the KV tensors and the resulting redundant computation can be repurposed for Speculative Decoding (SD) that improves token generation efficiency. Last, BMC represents a spectrum of design points with different values of r. To identify the best-performing d
The study of immune cellular composition has been of great scientific interest in immunology because of the generation of multiple large-scale data. From the statistical point of view, such immune cellular data should be treated as compositional. In compositional data, each element is positive, and all the elements sum to a constant, which can be set to one in general. Standard statistical methods are not directly applicable for the analysis of compositional data because they do not appropriately handle correlations between the compositional elements. In this paper, we review statistical methods for compositional data analysis and illustrate them in the context of immunology. Specifically, we focus on regression analyses using log-ratio transformations and the generalized linear model with Dirichlet distribution, discuss their theoretical foundations, and illustrate their applications with immune cellular fraction data generated from colorectal cancer patients.
Bounded model checking (BMC) is an effective technique for hunting bugs by incrementally exploring the state space of a system. To reason about infinite traces through a finite structure and to ultimately obtain completeness, BMC incorporates loop conditions that revisit previously observed states. This paper focuses on developing loop conditions for BMC of HyperLTL- a temporal logic for hyperproperties that allows expressing important policies for security and consistency in concurrent systems, etc. Loop conditions for HyperLTL are more complicated than for LTL, as different traces may loop inconsistently in unrelated moments. Existing BMC approaches for HyperLTL only considered linear unrollings without any looping capability, which precludes both finding small infinite traces and obtaining a complete technique. We investigate loop conditions for HyperLTL BMC, where the HyperLTL formula can contain up to one quantifier alternation. We first present a general complete automata-based technique which is based on bounds of maximum unrollings. Then, we introduce alternative simulation-based algorithms that allow exploiting short loops effectively, generating SAT queries whose satisfia
Chimeric antigen receptor (CAR)-T and NK cell immunotherapies have transformed cancer treatment, and recent studies suggest that the quality of the CAR-T/NK cell immunological synapse (IS) may serve as a functional biomarker for predicting therapeutic efficacy. Accurate detection and segmentation of CAR-T/NK IS structures using artificial neural networks (ANNs) can greatly increase the speed and reliability of IS quantification. However, a persistent challenge is the limited size of annotated microscopy datasets, which restricts the ability of ANNs to generalize. To address this challenge, we integrate two complementary data-augmentation frameworks. First, we employ Instance Aware Automatic Augmentation (IAAA), an automated, instance-preserving augmentation method that generates synthetic CAR-T/NK IS images and corresponding segmentation masks by applying optimized augmentation policies to original IS data. IAAA supports multiple imaging modalities (e.g., fluorescence and brightfield) and can be applied directly to CAR-T/NK IS images derived from patient samples. In parallel, we introduce a Semantic-Aware AI Augmentation (SAAA) pipeline that combines a diffusion-based mask generato
Intervertebral discs are avascular and maintain immune privilege. However, during intervertebral disc degeneration (IDD), this barrier is disrupted, leading to extensive immune cell infiltration and localized inflammation. In degenerated discs, macrophages, T lymphocytes, neutrophils, and granulocytic myeloid-derived suppressor cells (G-MDSCs) are key players, exhibiting functional heterogeneity. Dysregulated activation of inflammatory pathways, including nuclear factor kappa-B (NF-kappaB), interleukin-17 (IL-17), and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation, drives local pro-inflammatory responses, leading to cell apoptosis and extracellular matrix (ECM) degradation. Innovative immunotherapies, including exosome-based treatments, CRISPR/Cas9-mediated gene editing, and chemokine-loaded hydrogel systems, have shown promise in reshaping the immunological niche of intervertebral discs. These strategies can modulate dysregulated immune responses and create a supportive environment for tissue regeneration. However, current studies have not fully elucidated the mechanisms of inflammatory memory and the immunometabolic axis, and the
Satisfiability Modulo Theories (SMT) solvers have been successfully applied to solve many problems in formal verification such as bounded model checking (BMC) for many classes of systems from integrated circuits to cyber-physical systems. Typically, BMC is performed by checking satisfiability of a possibly long, but quantifier-free formula. However, BMC problems can naturally be encoded as quantified formulas over the number of BMC steps. In this approach, we then use decision procedures supporting quantifiers to check satisfiability of these quantified formulas. This approach has previously been applied to perform BMC using a Quantified Boolean Formula (QBF) encoding for purely discrete systems, and then discharges the QBF checks using QBF solvers. In this paper, we present a new quantified encoding of BMC for rectangular hybrid automata (RHA), which requires using more general logics due to the real (dense) time and real-valued state variables modeling continuous states. We have implemented a preliminary experimental prototype of the method using the HyST model transformation tool to generate the quantified BMC (QBMC) queries for the Z3 SMT solver. We describe experimental result
Some common systems modelling and simulation approaches for immune problems are Monte Carlo simulations, system dynamics, discrete-event simulation and agent-based simulation. These methods, however, are still not widely adopted in immunology research. In addition, to our knowledge, there is few research on the processes for the development of simulation models for the immune system. Hence, for this work, we have two contributions to knowledge. The first one is to show the importance of systems simulation to help immunological research and to draw the attention of simulation developers to this research field. The second contribution is the introduction of a quick guide containing the main steps for modelling and simulation in immunology, together with challenges that occur during the model development. Further, this paper introduces an example of a simulation problem, where we test our guidelines.
The coming 5G networks have been enabling the creation of a wide variety of new services and applications which demand a new network security architecture. Immunology is the study of the immune system in vertebrates (including humans) which protects us from infection through various lines of defence. By studying the resemblance between the immune system and network security system, we acquire some inspirations from immunology and distill some guidelines for the design of network security architecture. We present a philosophical design principle, that is maintaining the balance between security and availability. Then, we derive two methodological principles: 1) achieving situation-awareness and fast response through community cooperation among heterogeneous nodes, and 2) Enhancing defense capability through consistently contesting with invaders in a real environment and actively mutating/evolving attack strategies. We also present a reference architecture designed based on the principles.
We attempt to set a mathematical foundation of immunology and amino acid chains. To measure the similarities of these chains, a kernel on strings is defined using only the sequence of the chains and a good amino acid substitution matrix (e.g. BLOSUM62). The kernel is used in learning machines to predict binding affinities of peptides to human leukocyte antigens DR (HLA-DR) molecules. On both fixed allele (Nielsen and Lund 2009) and pan-allele (Nielsen et.al. 2010) benchmark databases, our algorithm achieves the state-of-the-art performance. The kernel is also used to define a distance on an HLA-DR allele set based on which a clustering analysis precisely recovers the serotype classifications assigned by WHO (Nielsen and Lund 2009, and Marsh et.al. 2010). These results suggest that our kernel relates well the chain structure of both peptides and HLA-DR molecules to their biological functions, and that it offers a simple, powerful and promising methodology to immunology and amino acid chain studies.
Resolving the exploration-exploitation trade-off remains a fundamental problem in the design and implementation of reinforcement learning (RL) algorithms. In this paper, we focus on model-free RL using the epsilon-greedy exploration policy, which despite its simplicity, remains one of the most frequently used forms of exploration. However, a key limitation of this policy is the specification of $\varepsilon$. In this paper, we provide a novel Bayesian perspective of $\varepsilon$ as a measure of the uniformity of the Q-value function. We introduce a closed-form Bayesian model update based on Bayesian model combination (BMC), based on this new perspective, which allows us to adapt $\varepsilon$ using experiences from the environment in constant time with monotone convergence guarantees. We demonstrate that our proposed algorithm, $\varepsilon$-\texttt{BMC}, efficiently balances exploration and exploitation on different problems, performing comparably or outperforming the best tuned fixed annealing schedules and an alternative data-dependent $\varepsilon$ adaptation scheme proposed in the literature.
The recent advances in cancer immunotherapy boosted the development of tumor-immune system models aiming to provide mechanistic understanding and indicate more efficient treatment regimes. However, the complexity of such models, their multi-scale dynamics and their overparameterized character renders them inaccessible for wide utilization. In this work, the dynamics of a fundamental model formulating the interactions of tumor cells with natural killer cells, CD8$^+$ T cells and circulating lymphocytes is examined. It is first shown that the long-term evolution of the system towards high-tumor or tumor-free equilibria is determined by the dynamics of an initial \emph{explosive stage} of tumor progression. Focusing on this stage, the algorithmic Computational Singular Perturbation methodology is employed to identify the underlying mechanisms confining the system's evolution towards the equilibrium and the governing slow dynamics along them. It is shown that these insights are preserved along different tumor-immune system and patient-dependent realizations. Utilizing the obtained mechanistic understanding, a novel reduced model is constructed in an algorithmic fashion, which accuratel
The opioid crisis remains one of the most daunting and complex public health problems in the United States. This study investigates the national epidemic by analyzing vulnerability profiles of three key factors: opioid-related mortality rates, opioid prescription dispensing rates, and disability rank ordered rates. This study utilizes county level data, spanning the years 2014 through 2020, on the rates of opioid-related mortality, opioid prescription dispensing, and disability. To successfully estimate and predict trends in these opioid-related factors, we augment the Kalman Filter with a novel spatial component. To define opioid vulnerability profiles, we create heat maps of our filter's predicted rates across the nation's counties and identify the hotspots. In this context, hotspots are defined on a year-by-year basis as counties with rates in the top 5 percent nationally. Our spatial Kalman filter demonstrates strong predictive performance. From 2014 to 2018, these predictions highlight consistent spatiotemporal patterns across all three factors, with Appalachia distinguished as the nation's most vulnerable region. Starting in 2019 however, the dispensing rate profiles undergo
The immune system provides an ideal metaphor for anomaly detection in general and computer security in particular. Based on this idea, artificial immune systems have been used for a number of years for intrusion detection, unfortunately so far with little success. However, these previous systems were largely based on immunological theory from the 1970s and 1980s and over the last decade our understanding of immunological processes has vastly improved. In this paper we present two new immune inspired algorithms based on the latest immunological discoveries, such as the behaviour of Dendritic Cells. The resultant algorithms are applied to real world intrusion problems and show encouraging results. Overall, we believe there is a bright future for these next generation artificial immune algorithms.
The immune system is a cognitive system of complexity comparable to the brain and its computational algorithms suggest new solutions to engineering problems or new ways of looking at these problems. Using immunological principles, a two (or three-) module algorithm is developed which is capable of launching a specific response to an anomalous situation. Applications are being developed for electromechanical drives and network power transformers. Experimental results illustrate an application to fault detection in squirrel-cage electric motors.
First, under a geometric ergodicity assumption, we provide some limit theorems and some probability inequalities for the bifurcating Markov chains (BMC). The BMC model was introduced by Guyon to detect cellular aging from cell lineage, and our aim is thus to complete his asymptotic results. The deviation inequalities are then applied to derive first result on the moderate deviation principle (MDP) for a functional of the BMC with a restricted range of speed, but with a function which can be unbounded. Next, under a uniform geometric ergodicity assumption, we provide deviation inequalities for the BMC and apply them to derive a second result on the MDP for a bounded functional of the BMC with a larger range of speed. As statistical applications, we provide superexponential convergence in probability and deviation inequalities (for either the Gaussian setting or the bounded setting), and the MDP for least square estimators of the parameters of a first-order bifurcating autoregressive process.