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The diagnostic assessment of thyroid nodules is hampered by the persistence of uncertainty in borderline cases and further complicated by the inclusion of noninvasive follicular tumor with papillary-like nuclear features (NIFTP) as a less aggressive alternative to papillary thyroid carcinoma (PTC). In this setting, computational methods might facilitate the diagnostic process by unmasking key nuclear characteristics of NIFTP. The main aims of this work were to (1) identify morphometric features of NIFTP and PTC that are interpretable for the human eye and (2) develop a deep learning model for multiclass segmentation as a support tool to reduce diagnostic variability. Our findings confirmed that nuclei in NIFTP and PTC share multiple characteristics, setting them apart from hyperplastic nodules (HP). The morphometric analysis identified 15 features that can be translated into nuclear alterations readily understandable by pathologists, such as a remarkable internuclear homogeneity for HP in contrast to a major complexity in the chromatin texture of NIFTP and to the peculiar pattern of nuclear texture variability of PTC. A few NIFTP cases with available next-generation sequencing data were also analyzed to initially explore the impact of RAS-related mutations on nuclear morphometry. Finally, a pixel-based deep learning model was trained and tested on whole-slide images of NIFTP, PTC, and HP cases. The model, named NUTSHELL (NUclei from Thyroid tumors Segmentation to Highlight Encapsulated Low-malignant Lesions), successfully detected and classified the majority of nuclei in all whole-slide image tiles, showing comparable results with already well-established pathology nuclear scores. NUTSHELL provides an immediate overview of NIFTP areas and can be used to detect microfoci of PTC within extensive glandular samples or identify lymph node metastases. NUTSHELL can be run inside WSInfer with an easy rendering in QuPath, thus facilitating the democratization of digital pathology., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

During long-distance migrations, some bird species make use of in-wake flying, which should allow them to profit from the upwash produced by another bird. While indirect evidence supports energy saving as the primary benefit of in-wake flying, measurements are still missing. We equipped migrating northern bald ibises ( Geronticus eremita ) with high-precision global navigation satellite system data loggers to track their position in the flock. We estimated birds' energy expenditure through different proxies, namely dynamic body acceleration (DBA), heart rate and effective wingbeat frequency. During active flapping flight, DBA estimates dropped off when in-wake compared with when not-in-wake. In addition, effective wingbeat frequency decreased, suggesting an increased use of intermittent gliding flight during in-wake periods. Heart rate varied greatly among individuals, with a clear decrease during gliding-corroborating its energy-saving function. Furthermore, we found consistent proof for decreased heart rate during in-wake flying, by up to 4.2%. Hence, we have shown that flying in the wake of another individual reduces birds' DBA, heart rate and effective wingbeat frequency, which could reflect reduced energy requirement.

Fuzzy logic is useful tool to describe and represent biological or medical scenarios, where often states and outcomes are not only completely true or completely false, but rather partially true or partially false. Despite its usefulness and spread, fuzzy logic modeling might easily be done in the wrong way, especially by beginners and unexperienced researchers, who might overlook some important aspects or might make common mistakes. Malpractices and pitfalls, in turn, can lead to wrong or overoptimistic, inflated results, with negative consequences to the biomedical research community trying to comprehend a particular phenomenon, or even to patients suffering from the investigated disease. To avoid common mistakes, we present here a list of quick tips for fuzzy logic modeling any biomedical scenario: some guidelines which should be taken into account by any fuzzy logic practitioner, including experts. We believe our best practices can have a strong impact in the scientific community, allowing researchers who follow them to obtain better, more reliable results and outcomes in biomedical contexts., Competing Interests: The authors SS and MSN are among the developers of the Simpful and pyFUME software packages mentioned in this study., (Copyright: © 2023 Chicco et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Tumor recognition by T cells is essential for antitumor immunity. A comprehensive characterization of T cell diversity may be key to understanding the success of immunomodulatory drugs and failure of PD-1 blockade in tumors such as multiple myeloma (MM). Here, we use single-cell RNA and T cell receptor sequencing to characterize bone marrow T cells from healthy adults (n = 4) and patients with precursor (n = 8) and full-blown MM (n = 10). Large T cell clones from patients with MM expressed multiple immune checkpoints, suggesting a potentially dysfunctional phenotype. Dual targeting of PD-1 + LAG3 or PD-1 + TIGIT partially restored their function in mice with MM. We identify phenotypic hallmarks of large intratumoral T cell clones, and demonstrate that the CD27 - and CD27 + T cell ratio, measured by flow cytometry, may serve as a surrogate of clonal T cell expansions and an independent prognostic factor in 543 patients with MM treated with lenalidomide-based treatment combinations., (© 2023. Springer Nature Limited.)

Purpose: Congenital myopathies are a heterogeneous group of diseases affecting the skeletal muscles and characterized by high clinical, genetic, and histological variability. Magnetic Resonance (MR) is a valuable tool for the assessment of involved muscles (i.e., fatty replacement and oedema) and disease progression. Machine Learning is becoming increasingly applied for diagnostic purposes, but to our knowledge, Self-Organizing Maps (SOMs) have never been used for the identification of the patterns in these diseases. The aim of this study is to evaluate if SOMs may discriminate between muscles with fatty replacement (S), oedema (E) or neither (N)., Methods: MR studies of a family affected by tubular aggregates myopathy (TAM) with the histologically proven autosomal dominant mutation of the STIM1 gene, were examined: for each patient, in two MR assessments (i.e., t0 and t1, the latter after 5 years), fifty-three muscles were evaluated for muscular fatty replacement on the T1w images, and for oedema on the STIR images, for reference. Sixty radiomic features were collected from each muscle at t0 and t1 MR assessment using 3DSlicer software, in order to obtain data from images. A SOM was created to analyze all datasets using three clusters (i.e., 0, 1 and 2) and results were compared with radiological evaluation., Results: Six patients with TAM STIM1-mutation were included. At t0 MR assessments, all patients showed widespread fatty replacement that intensifies at t1, while oedema mainly affected the muscles of the legs and appears stable at follow-up. All muscles with oedema showed fatty replacement, too. At t0 SOM grid clustering shows almost all N muscles in Cluster 0 and most of the E muscles in Cluster 1; at t1 almost all E muscles appear in Cluster 1., Conclusion: Our unsupervised learning model appears to be able to recognize muscles altered by the presence of edema and fatty replacement., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Lupi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Oxford Nanopore Technologies (ONT) is a third generation sequencing approach that allows the analysis of individual, full-length nucleic acids. ONT records the alterations of an ionic current flowing across a nano-scaled pore while a DNA or RNA strand is threading through the pore. Basecalling methods are then leveraged to translate the recorded signal back to the nucleic acid sequence. However, basecall generally introduces errors that hinder the process of barcode demultiplexing, a pivotal task in single-cell RNA sequencing that allows for separating the sequenced transcripts on the basis of their cell of origin. Methods: To solve this issue, we present a novel framework, called UNPLEX, designed to tackle the barcode demultiplexing problem by operating directly on the recorded signals. UNPLEX combines two unsupervised machine learning methods: autoencoders and self-organizing maps (SOM). The autoencoders extract compact, latent representations of the recorded signals that are then clustered by the SOM. Results and Discussion: Our results, obtained on two datasets composed of in silico generated ONT-like signals, show that UNPLEX represents a promising starting point for the development of effective tools to cluster the signals corresponding to the same cell., Competing Interests: TL received reimbursement of expenses from ONT to speak at an event. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Papetti, Spolaor, Nazari, Tirelli, Leonardi, Caprioli, Besozzi, Vlachou, Pelicci, Cazzaniga and Nobile.)

Background and Objectives: Myocardial infarction scar (MIS) assessment by cardiac magnetic resonance provides prognostic information and guides patients' clinical management. However, MIS segmentation is time-consuming and not performed routinely. This study presents a deep-learning-based computational workflow for the segmentation of left ventricular (LV) MIS, for the first time performed on state-of-the-art dark-blood late gadolinium enhancement (DB-LGE) images, and the computation of MIS transmurality and extent., Methods: DB-LGE short-axis images of consecutive patients with myocardial infarction were acquired at 1.5T in two centres between Jan 1, 2019, and June 1, 2021. Two convolutional neural network (CNN) models based on the U-Net architecture were trained to sequentially segment the LV and MIS, by processing an incoming series of DB-LGE images. A 5-fold cross-validation was performed to assess the performance of the models. Model outputs were compared respectively with manual (LV endo- and epicardial border) and semi-automated (MIS, 4-Standard Deviation technique) ground truth to assess the accuracy of the segmentation. An automated post-processing and reporting tool was developed, computing MIS extent (expressed as relative infarcted mass) and transmurality., Results: The dataset included 1355 DB-LGE short-axis images from 144 patients (MIS in 942 images). High performance (> 0.85) as measured by the Intersection over Union metric was obtained for both the LV and MIS segmentations on the training sets. The performance for both LV and MIS segmentations was 0.83 on the test sets. Compared to the 4-Standard Deviation segmentation technique, our system was five times quicker (<1 min versus 7 ± 3 min), and required minimal user interaction., Conclusions: Our solution successfully addresses different issues related to automatic MIS segmentation, including accuracy, time-effectiveness, and the automatic generation of a clinical report., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

The investigation of the emergent collective behaviour in flying birds is a challenging task, yet it has always fascinated scientists from different disciplines. In the attempt of studying and modelling line formation, we collected high-precision position data of 29 free-flying northern bald ibises ( Geronticus eremita ) using Global Navigation Satellite System loggers, to investigate whether the spatial relationships within a flock can be explained by birds maintaining energetically advantageous positions. Specifically, we exploited domain knowledge and available literature information to model by means of fuzzy logic where the air vortices lie behind a flying bird. This allowed us to determine when a leading bird provides the upwash to a following bird, reducing its overall effort. Our results show that the fuzzy model allows to easily distinguish which bird is flying in the wake of another individual, provides a clear indication about flying flock dynamics and also gives a hint about birds' social relationships.

Calcium homeostasis and signaling processes in Saccharomyces cerevisiae , as well as in any eukaryotic organism, depend on various transporters and channels located on both the plasma and intracellular membranes. The activity of these proteins is regulated by a number of feedback mechanisms that act through the calmodulin-calcineurin pathway. When exposed to hypotonic shock (HTS), yeast cells respond with an increased cytosolic calcium transient, which seems to be conditioned by the opening of stretch-activated channels. To better understand the role of each channel and transporter involved in the generation and recovery of the calcium transient-and of their feedback regulations-we defined and analyzed a mathematical model of the calcium signaling response to HTS in yeast cells. The model was validated by comparing the simulation outcomes with calcium concentration variations before and during the HTS response, which were observed experimentally in both wild-type and mutant strains. Our results show that calcium normally enters the cell through the High Affinity Calcium influx System and mechanosensitive channels. The increase of the plasma membrane tension, caused by HTS, boosts the opening probability of mechanosensitive channels. This event causes a sudden calcium pulse that is rapidly dissipated by the activity of the vacuolar transporter Pmc1. According to model simulations, the role of another vacuolar transporter, Vcx1, is instead marginal, unless calcineurin is inhibited or removed. Our results also suggest that the mechanosensitive channels are subject to a calcium-dependent feedback inhibition, possibly involving calmodulin. Noteworthy, the model predictions are in accordance with literature results concerning some aspects of calcium homeostasis and signaling that were not specifically addressed within the model itself, suggesting that it actually depicts all the main cellular components and interactions that constitute the HTS calcium pathway, and thus can correctly reproduce the shaping of the calcium signature by calmodulin- and calcineurin-dependent complex regulations. The model predictions also allowed to provide an interpretation of different regulatory schemes involved in calcium handling in both wild-type and mutants yeast strains. The model could be easily extended to represent different calcium signals in other eukaryotic cells., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Spolaor, Rovetta, Nobile, Cazzaniga, Tisi and Besozzi.)

Mathematical models of biochemical networks can largely facilitate the comprehension of the mechanisms at the basis of cellular processes, as well as the formulation of hypotheses that can be tested by means of targeted laboratory experiments. However, two issues might hamper the achievement of fruitful outcomes. On the one hand, detailed mechanistic models can involve hundreds or thousands of molecular species and their intermediate complexes, as well as hundreds or thousands of chemical reactions, a situation generally occurring in rule-based modeling. On the other hand, the computational analysis of a model typically requires the execution of a large number of simulations for its calibration, or to test the effect of perturbations. As a consequence, the computational capabilities of modern Central Processing Units can be easily overtaken, possibly making the modeling of biochemical networks a worthless or ineffective effort. To the aim of overcoming the limitations of the current state-of-the-art simulation approaches, we present in this paper FiCoS, a novel "black-box" deterministic simulator that effectively realizes both a fine-grained and a coarse-grained parallelization on Graphics Processing Units. In particular, FiCoS exploits two different integration methods, namely, the Dormand-Prince and the Radau IIA, to efficiently solve both non-stiff and stiff systems of coupled Ordinary Differential Equations. We tested the performance of FiCoS against different deterministic simulators, by considering models of increasing size and by running analyses with increasing computational demands. FiCoS was able to dramatically speedup the computations up to 855×, showing to be a promising solution for the simulation and analysis of large-scale models of complex biological processes., Competing Interests: The authors have declared that no competing interests exist.

Background: Tremor severity assessment is an important step for the diagnosis and treatment decision-making of essential tremor (ET) patients. Traditionally, tremor severity is assessed by using questionnaires (e.g., ETRS and QUEST surveys). In this work we assume the possibility of assessing tremor severity using sensor data and computerized analyses. The goal of this work is to assess severity of tremor objectively, to be better able to asses improvement in ET patients due to deep brain stimulation or other treatments., Methods: We collect tremor data by strapping smartphones to the wrists of ET patients. The resulting raw sensor data is then pre-processed to remove any artifact due to patient's intentional movement. Finally, this data is exploited to automatically build a transparent, interpretable, and succinct fuzzy model for the severity assessment of ET. For this purpose, we exploit pyFUME, a tool for the data-driven estimation of fuzzy models. It leverages the FST-PSO swarm intelligence meta-heuristic to identify optimal clusters in data, reducing the possibility of a premature convergence in local minima which would result in a sub-optimal model. pyFUME was also combined with GRABS, a novel methodology for the automatic simplification of fuzzy rules., Results: Our model is able to assess tremor severity of patients suffering from Essential Tremor, notably without the need for subjective questionnaires nor interviews. The fuzzy model improves the mean absolute error (MAE) metric by 78-81% compared to linear models and by 71-74% compared to a model based on decision trees., Conclusion: This study confirms that tremor data gathered using the smartphones is useful for the constructing of machine learning models that can be used to support the diagnosis and monitoring of patients who suffer from Essential Tremor. The model produced by our methodology is easy to inspect and, notably, characterized by a lower error with respect to approaches based on linear models or decision trees.

Background: Genome-wide reconstructions of metabolism opened the way to thorough investigations of cell metabolism for health care and industrial purposes. However, the predictions offered by Flux Balance Analysis (FBA) can be strongly affected by the choice of flux boundaries, with particular regard to the flux of reactions that sink nutrients into the system. To mitigate possible errors introduced by a poor selection of such boundaries, a rational approach suggests to focus the modeling efforts on the pivotal ones., Methods: In this work, we present a methodology for the automatic identification of the key fluxes in genome-wide constraint-based models, by means of variance-based sensitivity analysis. The goal is to identify the parameters for which a small perturbation entails a large variation of the model outcomes, also referred to as sensitive parameters. Due to the high number of FBA simulations that are necessary to assess sensitivity coefficients on genome-wide models, our method exploits a master-slave methodology that distributes the computation on massively multi-core architectures. We performed the following steps: (1) we determined the putative parameterizations of the genome-wide metabolic constraint-based model, using Saltelli's method; (2) we applied FBA to each parameterized model, distributing the massive amount of calculations over multiple nodes by means of MPI; (3) we then recollected and exploited the results of all FBA runs to assess a global sensitivity analysis., Results: We show a proof-of-concept of our approach on latest genome-wide reconstructions of human metabolism Recon2.2 and Recon3D. We report that most sensitive parameters are mainly associated with the intake of essential amino acids in Recon2.2, whereas in Recon 3D they are associated largely with phospholipids. We also illustrate that in most cases there is a significant contribution of higher order effects., Conclusion: Our results indicate that interaction effects between different model parameters exist, which should be taken into account especially at the stage of calibration of genome-wide models, supporting the importance of a global strategy of sensitivity analysis.

Self-assembling processes are ubiquitous phenomena that drive the organization and the hierarchical formation of complex molecular systems. The investigation of assembling dynamics, emerging from the interactions among biomolecules like amino-acids and polypeptides, is fundamental to determine how a mixture of simple objects can yield a complex structure at the nano-scale level. In this paper we present HyperBeta, a novel open-source software that exploits an innovative algorithm based on hyper-graphs to efficiently identify and graphically represent the dynamics of [Formula: see text]-sheets formation. Differently from the existing tools, HyperBeta directly manipulates data generated by means of coarse-grained molecular dynamics simulation tools (GROMACS), performed using the MARTINI force field. Coarse-grained molecular structures are visualized using HyperBeta 's proprietary real-time high-quality 3D engine, which provides a plethora of analysis tools and statistical information, controlled by means of an intuitive event-based graphical user interface. The high-quality renderer relies on a variety of visual cues to improve the readability and interpretability of distance and depth relationships between peptides. We show that HyperBeta is able to track the [Formula: see text]-sheets formation in coarse-grained molecular dynamics simulations, and provides a completely new and efficient mean for the investigation of the kinetics of these nano-structures. HyperBeta will therefore facilitate biotechnological and medical research where these structural elements play a crucial role, such as the development of novel high-performance biomaterials in tissue engineering, or a better comprehension of the molecular mechanisms at the basis of complex pathologies like Alzheimer's disease.

Combination therapies proved to be a valuable strategy in the fight against cancer, thanks to their increased efficacy in inducing tumor cell death and in reducing tumor growth, metastatic potential, and the risk of developing drug resistance. The identification of effective combinations of drug targets generally relies on costly and time consuming processes based on in vitro experiments. Here, we present a novel computational approach that, by integrating dynamic fuzzy modeling with multi-objective optimization, allows to efficiently identify novel combination cancer therapies, with a relevant saving in working time and costs. We tested this approach on a model of oncogenic K-ras cancer cells characterized by a marked Warburg effect. The computational approach was validated by its capability in finding out therapies already known in the literature for this type of cancer cell. More importantly, our results show that this method can suggest potential therapies consisting in a small number of molecular targets. In the model of oncogenic K-ras cancer cells, for instance, we identified combination of up to three targets, which affect different cellular pathways that are crucial for cancer proliferation and survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Spolaor, Scheve, Firat, Cazzaniga, Besozzi and Nobile.)

Ras oncoproteins play a crucial role in the onset, maintenance, and progression of the most common and deadly human cancers. Despite extensive research efforts, only a few mutant-specific Ras inhibitors have been reported. We show that cmp4-previously identified as a water-soluble Ras inhibitor- targets multiple steps in the activation and downstream signaling of different Ras mutants and isoforms. Binding of this pan-Ras inhibitor to an extended Switch II pocket on HRas and KRas proteins induces a conformational change that down-regulates intrinsic and GEF-mediated nucleotide dissociation and exchange and effector binding. A mathematical model of the Ras activation cycle predicts that the inhibitor severely reduces the proliferation of different Ras-driven cancer cells, effectively cooperating with Cetuximab to reduce proliferation even of Cetuximab-resistant cancer cell lines. Experimental data confirm the model prediction, indicating that the pan-Ras inhibitor is an appropriate candidate for medicinal chemistry efforts tailored at improving its currently unsatisfactory affinity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tisi, Spinelli, Palmioli, Airoldi, Cazzaniga, Besozzi, Nobile, Mazzoleni, Arnhold, De Gioia, Grandori, Peri, Vanoni and Sacco.)

Acute myeloid leukemia (AML) is a highly frequent hematological malignancy, characterized by clinical and biological diversity, along with high relapse and mortality rates. The inherent functional and genetic intra-tumor heterogeneity in AML is thought to play an important role in disease recurrence and resistance to chemotherapy. Patient-derived xenograft (PDX) models preserve important features of the original tumor, allowing, at the same time, experimental manipulation and in vivo amplification of the human cells. Here we present a detailed protocol for the generation of fluorescently labeled AML PDX models to monitor cell proliferation kinetics in vivo, at the single-cell level. Although experimental protocols for cell proliferation studies are well established and widespread, they are not easily applicable to in vivo contexts, and the analysis of related time-series data is often complex to achieve. To overcome these limitations, model-driven approaches can be exploited to investigate different aspects of cell population dynamics. Among the existing approaches, the ProCell framework is able to perform detailed and accurate stochastic simulations of cell proliferation, relying on flow cytometry data. In particular, by providing an initial and a target fluorescence histogram, ProCell automatically assesses the validity of any user-defined scenario of intra-tumor heterogeneity, that is, it is able to infer the proportion of various cell subpopulations (including quiescent cells) and the division interval of proliferating cells. Here we explain the protocol in detail, providing a description of our methodology for the conditional expression of H2B-GFP in human AML xenografts, data processing by flow cytometry, and the final elaboration in ProCell.

The investigation of cell proliferation can provide useful insights for the comprehension of cancer progression, resistance to chemotherapy and relapse. To this aim, computational methods and experimental measurements based on in vivo label-retaining assays can be coupled to explore the dynamic behavior of tumoral cells. ProCell is a software that exploits flow cytometry data to model and simulate the kinetics of fluorescence loss that is due to stochastic events of cell division. Since the rate of cell division is not known, ProCell embeds a calibration process that might require thousands of stochastic simulations to properly infer the parameterization of cell proliferation models. To mitigate the high computational costs, in this paper we introduce a parallel implementation of ProCell's simulation algorithm, named cuProCell, which leverages Graphics Processing Units (GPUs). Dynamic Parallelism was used to efficiently manage the cell duplication events, in a radically different way with respect to common computing architectures. We present the advantages of cuProCell for the analysis of different models of cell proliferation in Acute Myeloid Leukemia (AML), using data collected from the spleen of human xenografts in mice. We show that, by exploiting GPUs, our method is able to not only automatically infer the models' parameterization, but it is also 237× faster than the sequential implementation. This study highlights the presence of a relevant percentage of quiescent and potentially chemoresistant cells in AML in vivo, and suggests that maintaining a dynamic equilibrium among the different proliferating cell populations might play an important role in disease progression.

Advances in microscopy imaging technologies have enabled the visualization of live-cell dynamic processes using time-lapse microscopy imaging. However, modern methods exhibit several limitations related to the training phases and to time constraints, hindering their application in the laboratory practice. In this work, we present a novel method, named Automated Cell Detection and Counting (ACDC), designed for activity detection of fluorescent labeled cell nuclei in time-lapse microscopy. ACDC overcomes the limitations of the literature methods, by first applying bilateral filtering on the original image to smooth the input cell images while preserving edge sharpness, and then by exploiting the watershed transform and morphological filtering. Moreover, ACDC represents a feasible solution for the laboratory practice, as it can leverage multi-core architectures in computer clusters to efficiently handle large-scale imaging datasets. Indeed, our Parent-Workers implementation of ACDC allows to obtain up to a 3.7× speed-up compared to the sequential counterpart. ACDC was tested on two distinct cell imaging datasets to assess its accuracy and effectiveness on images with different characteristics. We achieved an accurate cell-count and nuclei segmentation without relying on large-scale annotated datasets, a result confirmed by the average Dice Similarity Coefficients of 76.84 and 88.64 and the Pearson coefficients of 0.99 and 0.96, calculated against the manual cell counting, on the two tested datasets., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

Motivation: The elucidation of dysfunctional cellular processes that can induce the onset of a disease is a challenging issue from both the experimental and computational perspectives. Here we introduce a novel computational method based on the coupling between fuzzy logic modeling and a global optimization algorithm, whose aims are to (1) predict the emergent dynamical behaviors of highly heterogeneous systems in unperturbed and perturbed conditions, regardless of the availability of quantitative parameters, and (2) determine a minimal set of system components whose perturbation can lead to a desired system response, therefore facilitating the design of a more appropriate experimental strategy., Results: We applied this method to investigate what drives K-ras-induced cancer cells, displaying the typical Warburg effect, to death or survival upon progressive glucose depletion. The optimization analysis allowed to identify new combinations of stimuli that maximize pro-apoptotic processes. Namely, our results provide different evidences of an important protective role for protein kinase A in cancer cells under several cellular stress conditions mimicking tumor behavior. The predictive power of this method could facilitate the assessment of the response of other complex heterogeneous systems to drugs or mutations in fields as medicine and pharmacology, therefore paving the way for the development of novel therapeutic treatments., Availability and Implementation: The source code of FUMOSO is available under the GPL 2.0 license on GitHub at the following URL: https://github.com/aresio/FUMOSO., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2019. Published by Oxford University Press.)

Surfing in rough waters is not always as fun as wave riding the "big one". Similarly, in optimization problems, fitness landscapes with a huge number of local optima make the search for the global optimum a hard and generally annoying game. Computational Intelligence optimization metaheuristics use a set of individuals that "surf" across the fitness landscape, sharing and exploiting pieces of information about local fitness values in a joint effort to find out the global optimum. In this context, we designed surF, a novel surrogate modeling technique that leverages the discrete Fourier transform to generate a smoother, and possibly easier to explore, fitness landscape. The rationale behind this idea is that filtering out the high frequencies of the fitness function and keeping only its partial information (i.e., the low frequencies) can actually be beneficial in the optimization process. We prove our theory by combining surF with a settings free variant of Particle Swarm Optimization (PSO) based on Fuzzy Logic, called Fuzzy Self-Tuning PSO. Specifically, we introduce a new algorithm, named F3ST-PSO, which performs a preliminary exploration on the surrogate model followed by a second optimization using the actual fitness function. We show that F3ST-PSO can lead to improved performances, notably using the same budget of fitness evaluations.