Volumetric additive manufacturing promises near-instantaneous fabrication of 3D objects, yet achieving high fidelity at the micro-scale remains challenging due to the complex interplay between optical diffraction and chemical effects. We present Single-View Holographic Volumetric Additive Manufacturing (SHVAM), a mechanically static system that shapes volumetric dose distributions using time-multiplexed, phase-only holograms projected from a single optical axis. To achieve high resolution with SHVAM, we formulate hologram synthesis as a coupled inverse problem, integrating a differentiable wave-optical forward model with a simplified photochemical model that explicitly captures inhibitor diffusion and non-linear dose response. Optimizing hologram sequences under these coupled constraints allows us to pre-compensate for chemical blur, yielding higher print fidelity than optical-only optimization. We demonstrate the efficacy of SHVAM by fabricating simple 2D and 3D structures with lateral feature sizes of approximately 10 μm within a 0.8 mm × 0.8 mm × 3 mm volume in seconds.

Glioblastoma treatment response assessment is a critical component of tertiary prevention, in which the disease has already manifested, and the primary goal is to accurately monitor tumor evolution to guide therapeutic decisions and optimize ongoing patient management. In this context, this paper proposes a novel deep learning framework that integrates multimodal magnetic resonance imaging with radiomic features to automatically classify glioblastoma treatment response according to the Response Assessment in Neuro-Oncology (RANO) criteria. The proposed approach combines a preprocessing pipeline that ensures spatial standardization and skull stripping, automatic tumor segmentation using state-of-the-art deep learning models, and the extraction of handcrafted radiomic features capturing intensity, texture, and shape information. These features are aggregated and fed into predictive models for both binary (progressive vs. non-progressive disease) and multiclass (CR, PR, SD, PD) classification tasks. An experimental evaluation on the LUMIERE dataset demonstrates that the proposed method outperforms existing baselines while effectively leveraging the complementary strengths of deep and radiomic features. These results highlight the potential of combining deep learning and radiomics for automated, robust, and interpretable assessment of glioblastoma treatment response, ultimately supporting improved clinical decision-making in the advanced phases of disease management and contributing to more effective tertiary prevention, where timely and accurate evaluation of treatment efficacy is essential to guide the continuation or adjustment of therapeutic interventions.

This supplement contains seven revised and extended papers selected from CIBB 2018 and CIBB 2019, the 15th and 16th editions of the international conference on Computational Intelligence Methods for Bioinformatics and Biostatistics. CIBB is a venue that embraces researchers with different backgrounds, ranging from mathematics to computer science, from materials science to medicine, and from engineering to biology, all interested in the investigation and application of computational intelligence methods to open problems in bioinformatics, biostatistics, systems biology, synthetic biology, and medical informatics.

BACKGROUND: Nucleosomes wrap the DNA into the nucleus of the Eukaryote cell and regulate its transcription phase. Several studies indicate that nucleosomes are determined by the combined effects of several factors, including DNA sequence organization. Interestingly, the identification of nucleosomes on a genomic scale has been successfully performed by computational methods using DNA sequence as input data. RESULTS: In this work, we propose CORENup, a deep learning model for nucleosome identification. CORENup processes a DNA sequence as input using one-hot representation and combines in a parallel fashion a fully convolutional neural network and a recurrent layer. These two parallel levels are devoted to catching both non periodic and periodic DNA string features. A dense layer is devoted to their combination to give a final classification. CONCLUSIONS: Results computed on public data sets of different organisms show that CORENup is a state of the art methodology for nucleosome positioning identification based on a Deep Neural Network architecture. The comparisons have been carried out using two groups of datasets, currently adopted by the best performing methods, and CORENup has shown top performance both in terms of classification metrics and elapsed computation time.

Abstract Background Non-coding RNAs include different classes of molecules with regulatory functions. The most studied are microRNAs (miRNAs) that act directly inhibiting mRNA expression or protein translation through the interaction with a miRNAs-response element. Other RNA molecules participate in the complex network of gene regulation. They behave as competitive endogenous RNA (ceRNA), acting as natural miRNA sponges to inhibit miRNA functions and modulate the expression of RNA messenger (mRNA). It became evident that understanding the ceRNA–miRNA–mRNA crosstalk would increase the functional information across the transcriptome, contributing to identify new potential biomarkers for translational medicine. Results We present miRTissue ce, an improvement of our original miRTissue web service. By introducing a novel computational pipeline, miRTissue ce provides an easy way to search for ceRNA interactions in several cancer tissue types. Moreover it extends the functionalities of previous miRTissue release about miRNA-target interaction in order to provide a complete insight about miRNA mediated regulation processes. miRTissue ce is freely available at http://tblab.pa.icar.cnr.it/mirtissue.html . Conclusions The study of ceRNA networks and its dynamics in cancer tissue could be applied in many fields of translational biology, as the investigation of new cancer biomarker, both diagnostic and prognostic, and also in the investigation of new therapeutic strategies of intervention. In this scenario, miRTissue ce can offer a powerful instrument for the analysis and characterization of ceRNA-ceRNA interactions in different tissue types, representing a fundamental step in order to understand more complex regulation mechanisms.

The 16th Annual Meeting of the Bioinformatics Italian Society was held in Palermo, Italy, on June 26-28, 2019. More than 80 scientific contributions were presented, including 4 keynote lectures, 31 oral communications and 49 posters. Also, three workshops were organised before and during the meeting. Full papers from some of the works presented in Palermo were submitted for this Supplement of BMC Bioinformatics. Here, we provide an overview of meeting aims and scope. We also shortly introduce selected papers that have been accepted for publication in this Supplement, for a complete presentation of the outcomes of the meeting.

BACKGROUND: In silico experiments, with the aid of computer simulation, speed up the process of in vitro or in vivo experiments. Cancer therapy design is often based on signalling pathway. MicroRNAs (miRNA) are small non-coding RNA molecules. In several kinds of diseases, including cancer, hepatitis and cardiovascular diseases, they are often deregulated, acting as oncogenes or tumor suppressors. miRNA therapeutics is based on two main kinds of molecules injection: miRNA mimics, which consists of injection of molecules that mimic the targeted miRNA, and antagomiR, which consists of injection of molecules inhibiting the targeted miRNA. Nowadays, the research is focused on miRNA therapeutics. This paper addresses cancer related signalling pathways to investigate miRNA therapeutics. RESULTS: In order to prove our approach, we present two different case studies: non-small cell lung cancer and melanoma. KEGG signalling pathways are modelled by a digital circuit. A logic value of 1 is linked to the expression of the corresponding gene. A logic value of 0 is linked to the absence (not expressed) gene. All possible relationships provided by a signalling pathway are modelled by logic gates. Mutations, derived according to the literature, are introduced and modelled as well. The modelling approach and analysis are widely discussed within the paper. MiRNA therapeutics is investigated by the digital circuit analysis. The most effective miRNA and combination of miRNAs, in terms of reduction of pathogenic conditions, are obtained. A discussion of obtained results in comparison with literature data is provided. Results are confirmed by existing data. CONCLUSIONS: The proposed study is based on drug discovery and miRNA therapeutics and uses a digital circuit simulation of a cancer pathway. Using this simulation, the most effective combination of drugs and miRNAs for mutated cancer therapy design are obtained and these results were validated by the literature. The proposed modelling and analysis approach can be applied to each human disease, starting from the corresponding signalling pathway.

The 17th International NETTAB workshop was held in Palermo, Italy, on October 16-18, 2017. The special topic for the meeting was "Methods, tools and platforms for Personalised Medicine in the Big Data Era", but the traditional topics of the meeting series were also included in the event. About 40 scientific contributions were presented, including four keynote lectures, five guest lectures, and many oral communications and posters. Also, three tutorials were organised before and after the workshop. Full papers from some of the best works presented in Palermo were submitted for this Supplement of BMC Bioinformatics. Here, we provide an overview of meeting aims and scope. We also shortly introduce selected papers that have been accepted for publication in this Supplement, for a complete presentation of the outcomes of the meeting.

This BMC special issue collects a selection of eleven revised and extended papers presented at, or originated from, the 2015 and 2016 editions of the international meeting on Computational Intelligence methods for Bioinformatics and Biostatistics, CIBB2015 and CIBB2016, respectively.The CIBB conference series provides a multidisciplinary forum open to researchers interested in the application of computational intelligence, in a broad sense, to open problems in bioinformatics, biostatistics, systems and synthetic biology, medical informatics, as well as computational approaches to life sciences in general.In line with the spirit of CIBB, the 2015 and 2016 meetings brought together researchers from different communities who address problems from different, but connected and often overlapping, perspectives.CIBB provides them a venue to discuss cutting-edge methodologies and accelerate life science discoveries.More than 80 researchers from Europe, Asia, USA and Africa attended each the two editions, with many researchers attending both of them.Six keynote speakers, prominent scholars in their fields, were invited to present the latest advances of their research in each edition, providing insights into open problems and future directions of general interest for the field.Overall, more than 110 papers were submitted to the two editions, about 50 at CIBB2015 and 60 at CIBB2016, a positive trend confirming the interest and maturity of the CIBB series.

BACKGROUND: An open challenge in translational bioinformatics is the analysis of sequenced metagenomes from various environmental samples. Of course, several studies demonstrated the 16S ribosomal RNA could be considered as a barcode for bacteria classification at the genus level, but till now it is hard to identify the correct composition of metagenomic data from RNA-seq short-read data. 16S short-read data are generated using two next generation sequencing technologies, i.e. whole genome shotgun (WGS) and amplicon (AMP); typically, the former is filtered to obtain short-reads belonging to a 16S shotgun (SG), whereas the latter take into account only some specific 16S hypervariable regions. The above mentioned two sequencing technologies, SG and AMP, are used alternatively, for this reason in this work we propose a deep learning approach for taxonomic classification of metagenomic data, that can be employed for both of them. RESULTS: To test the proposed pipeline, we simulated both SG and AMP short-reads, from 1000 16S full-length sequences. Then, we adopted a k-mer representation to map sequences as vectors into a numerical space. Finally, we trained two different deep learning architecture, i.e., convolutional neural network (CNN) and deep belief network (DBN), obtaining a trained model for each taxon. We tested our proposed methodology to find the best parameters configuration, and we compared our results against the classification performances provided by a reference classifier for bacteria identification, known as RDP classifier. We outperformed the RDP classifier at each taxonomic level with both architectures. For instance, at the genus level, both CNN and DBN reached 91.3% of accuracy with AMP short-reads, whereas RDP classifier obtained 83.8% with the same data. CONCLUSIONS: In this work, we proposed a 16S short-read sequences classification technique based on k-mer representation and deep learning architecture, in which each taxon (from phylum to genus) generates a classification model. Experimental results confirm the proposed pipeline as a valid approach for classifying bacteria sequences; for this reason, our approach could be integrated into the most common tools for metagenomic analysis. According to obtained results, it can be successfully used for classifying both SG and AMP data.

BACKGROUND: Nucleosomes are DNA-histone complex, each wrapping about 150 pairs of double-stranded DNA. Their function is fundamental for one of the primary functions of Chromatin i.e. packing the DNA into the nucleus of the Eukaryote cells. Several biological studies have shown that the nucleosome positioning influences the regulation of cell type-specific gene activities. Moreover, computational studies have shown evidence of sequence specificity concerning the DNA fragment wrapped into nucleosomes, clearly underlined by the organization of particular DNA substrings. As the main consequence, the identification of nucleosomes on a genomic scale has been successfully performed by computational methods using a sequence features representation. RESULTS: In this work, we propose a deep learning model for nucleosome identification. Our model stacks convolutional layers and Long Short-term Memories to automatically extract features from short- and long-range dependencies in a sequence. Using this model we are able to avoid the feature extraction and selection steps while improving the classification performances. CONCLUSIONS: Results computed on eleven data sets of five different organisms, from Yeast to Human, show the superiority of the proposed method with respect to the state of the art recently presented in the literature.

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNA sequences with regulatory functions to post-transcriptional level for several biological processes, such as cell disease progression and metastasis. MiRNAs interact with target messenger RNA (mRNA) genes by base pairing. Experimental identification of miRNA target is one of the major challenges in cancer biology because miRNAs can act as tumour suppressors or oncogenes by targeting different type of targets. The use of machine learning methods for the prediction of the target genes is considered a valid support to investigate miRNA functions and to guide related wet-lab experiments. In this paper we propose the miRNA Target Interaction Predictor (miRNATIP) algorithm, a Self-Organizing Map (SOM) based method for the miRNA target prediction. SOM is trained with the seed region of the miRNA sequences and then the mRNA sequences are projected into the SOM lattice in order to find putative interactions with miRNAs. These interactions will be filtered considering the remaining part of the miRNA sequences and estimating the free-energy necessary for duplex stability. RESULTS: We tested the proposed method by predicting the miRNA target interactions of both the Homo sapiens and the Caenorhbditis elegans species; then, taking into account validated target (positive) and non-target (negative) interactions, we compared our results with other target predictors, namely miRanda, PITA, PicTar, mirSOM, TargetScan and DIANA-microT, in terms of the most used statistical measures. We demonstrate that our method produces the greatest number of predictions with respect to the other ones, exhibiting good results for both species, reaching the for example the highest percentage of sensitivity of 31 and 30.5 %, respectively for Homo sapiens and for C. elegans. All the predicted interaction are freely available at the following url: http://tblab.pa.icar.cnr.it/public/miRNATIP/ . CONCLUSIONS: Results state miRNATIP outperforms or is comparable to the other six state-of-the-art methods, in terms of validated target and non-target interactions, respectively.

BACKGROUND: MicroRNAs (miRNAs) are important key regulators in multiple cellular functions, due to their a crucial role in different physiological processes. MiRNAs are differentially expressed in specific tissues, during specific cell status, or in different diseases as tumours. RNA sequencing (RNA-seq) is a Next Generation Sequencing (NGS) method for the analysis of differential gene expression. Using machine learning algorithms, it is possible to improve the functional significance interpretation of miRNA in the analysis and interpretation of data from RNA-seq. Furthermore, we tried to identify some patterns of deregulated miRNA in human breast cancer (BC), in order to give a contribution in the understanding of this type of cancer at the molecular level. RESULTS: We adopted a biclustering approach, using the Iterative Signature Algorithm (ISA) algorithm, in order to evaluate miRNA deregulation in the context of miRNA abundance and tissue heterogeneity. These are important elements to identify miRNAs that would be useful as prognostic and diagnostic markers. Considering a real word breast cancer dataset, the evaluation of miRNA differential expressions in tumours versus healthy tissues evidenced 12 different miRNA clusters, associated to specific groups of patients. The identified miRNAs were deregulated in breast tumours compared to healthy controls. Our approach has shown the association between specific sub-class of tumour samples having the same immuno-histo-chemical and/or histological features. Biclusters have been validated by means of two online repositories, MetaMirClust database and UCSC Genome Browser, and using another biclustering algorithm. CONCLUSIONS: The obtained results with biclustering algorithm aimed first of all to give a contribute in the differential expression analysis in a cohort of BC patients and secondly to support the potential role that these non-coding RNA molecules could play in the clinical practice, in terms of prognosis, evolution of tumour and treatment response.

BACKGROUND: Studies on genomic sequences for classification and taxonomic identification have a leading role in the biomedical field and in the analysis of biodiversity. These studies are focusing on the so-called barcode genes, representing a well defined region of the whole genome. Recently, alignment-free techniques are gaining more importance because they are able to overcome the drawbacks of sequence alignment techniques. In this paper a new alignment-free method for DNA sequences clustering and classification is proposed. The method is based on k-mers representation and text mining techniques. METHODS: The presented method is based on Probabilistic Topic Modeling, a statistical technique originally proposed for text documents. Probabilistic topic models are able to find in a document corpus the topics (recurrent themes) characterizing classes of documents. This technique, applied on DNA sequences representing the documents, exploits the frequency of fixed-length k-mers and builds a generative model for a training group of sequences. This generative model, obtained through the Latent Dirichlet Allocation (LDA) algorithm, is then used to classify a large set of genomic sequences. RESULTS AND CONCLUSIONS: We performed classification of over 7000 16S DNA barcode sequences taken from Ribosomal Database Project (RDP) repository, training probabilistic topic models. The proposed method is compared to the RDP tool and Support Vector Machine (SVM) classification algorithm in a extensive set of trials using both complete sequences and short sequence snippets (from 400 bp to 25 bp). Our method reaches very similar results to RDP classifier and SVM for complete sequences. The most interesting results are obtained when short sequence snippets are considered. In these conditions the proposed method outperforms RDP and SVM with ultra short sequences and it exhibits a smooth decrease of performance, at every taxonomic level, when the sequence length is decreased.

BACKGROUND: We introduce a Knowledge-based Decision Support System (KDSS) in order to face the Protein Complex Extraction issue. Using a Knowledge Base (KB) coding the expertise about the proposed scenario, our KDSS is able to suggest both strategies and tools, according to the features of input dataset. Our system provides a navigable workflow for the current experiment and furthermore it offers support in the configuration and running of every processing component of that workflow. This last feature makes our system a crossover between classical DSS and Workflow Management Systems. RESULTS: We briefly present the KDSS' architecture and basic concepts used in the design of the knowledge base and the reasoning component. The system is then tested using a subset of Saccharomyces cerevisiae Protein-Protein interaction dataset. We used this subset because it has been well studied in literature by several research groups in the field of complex extraction: in this way we could easily compare the results obtained through our KDSS with theirs. Our system suggests both a preprocessing and a clustering strategy, and for each of them it proposes and eventually runs suited algorithms. Our system's final results are then composed of a workflow of tasks, that can be reused for other experiments, and the specific numerical results for that particular trial. CONCLUSIONS: The proposed approach, using the KDSS' knowledge base, provides a novel workflow that gives the best results with regard to the other workflows produced by the system. This workflow and its numeric results have been compared with other approaches about PPI network analysis found in literature, offering similar results.

BACKGROUND: The key idea of DNA barcode initiative is to identify, for each group of species belonging to different kingdoms of life, a short DNA sequence that can act as a true taxon barcode. DNA barcode represents a valuable type of information that can be integrated with ecological, genetic, and morphological data in order to obtain a more consistent taxonomy. Recent studies have shown that, for the animal kingdom, the mitochondrial gene cytochrome c oxidase I (COI), about 650 bp long, can be used as a barcode sequence for identification and taxonomic purposes of animals. In the present work we aims at introducing the use of an alignment-free approach in order to make taxonomic analysis of barcode sequences. Our approach is based on the use of two compression-based versions of non-computable Universal Similarity Metric (USM) class of distances. Our purpose is to justify the employ of USM also for the analysis of short DNA barcode sequences, showing how USM is able to correctly extract taxonomic information among those kind of sequences. RESULTS: We downloaded from Barcode of Life Data System (BOLD) database 30 datasets of barcode sequences belonging to different animal species. We built phylogenetic trees of every dataset, according to compression-based and classic evolutionary methods, and compared them in terms of topology preservation. In the experimental tests, we obtained scores with a percentage of similarity between evolutionary and compression-based trees between 80% and 100% for the most of datasets (94%). Moreover we carried out experimental tests using simulated barcode datasets composed of 100, 150, 200 and 500 sequences, each simulation replicated 25-fold. In this case, mean similarity scores between evolutionary and compression-based trees span between 83% and 99% for all simulated datasets. CONCLUSIONS: In the present work we aims at introducing the use of an alignment-free approach in order to make taxonomic analysis of barcode sequences. Our approach is based on the use of two compression-based versions of non-computable Universal Similarity Metric (USM) class of distances. This way we demonstrate the reliability of compression-based methods even for the analysis of short barcode sequences. Compression-based methods, with their strong theoretical assumptions, may then represent a valid alignment-free and parameter-free approach for barcode studies.

In this paper a new intelligent system designed to support the researcher in the development of a workflow for bio informatics experiments is presented. The proposed system is capable to suggest one or more strategies in order to resolve the selected problem and to support the user in the assembly of a workflow for complex experiments, using a a Knowledge base, representing the expertise about the application domain, and a Rule-Based system for decision-making activity. Moreover, the system can represent this workflow at different abstraction layers, freeing the user from implementation details and assisting him in the correct configuration of the algorithms. A sample workflow for protein complex extraction from protein-protein interaction network is presented in order to show the main features of the proposed workflow representation.

The paper describes a mechanism of introspection of a humanoid robot based on self observation of its running processes and sensory data. The robot builds is internal state representation by a suitable ontology: a working knowledge of its physical structure and functionalities, that it can exploit to interact with humans in order to describe, in natural language, his state and the manner in which it perceives. We report experiments performed on a humanoid robot, describing all the components necessary to implement the proposed architecture of introspection.

This paper presents a web based knowledge management system that supports information browsing using both semantic tagging and the Cyc knowledge base. Information contents are not linked each other, but tagged in a way that reflects the semantics of documents. The used tags are also related to concepts in the Cyc knowledge base. The relationships that connect these concepts are reported to the tags and to the information contents, building a huge set of dynamical links that support user's information navigation and sharing.

Visual exploration of scientific data in life science area is a growing research field due to the large amount of available data. The Kohonen's self organizing map (SOM) is a widely used tool for visualization of multidimensional data. In this paper we present a fast learning algorithm for SOMs that uses a simulated annealing method to adapt the learning parameters. The algorithm has been adopted in a data analysis framework for the generation of similarity maps. Such maps provide an effective tool for the visual exploration of large and multi-dimensional input spaces. The approach has been applied to data generated during the high throughput screening of molecular compounds; the generated maps allow a visual exploration of molecules with similar topological properties. The experimental analysis on real world data from the National Cancer Institute shows the speed up of the proposed SOM training process in comparison to a traditional approach. The resulting visual landscape groups molecules with similar chemical properties in densely connected regions.

Liquid state machine (LSM) is a neural system based on spiking neurons that implements a mapping between functions of time. A typical application of LSM is classification of time functions obtained observing the state of the liquid by using a memoryless readout circuit, usually implemented by a linear perceptron. Due to the high number of neurons in the liquid the training of the readout is difficult. In this paper we show that using the Spike-Timing-Dependent Plasticity (STDP) a single neuron with short training session can be used to recognize the state of the liquid due to an input signal. Using STDP it is possible to identify the spikes timing of the neurons in the liquid and this allows to correctly classify a large set of input signals, the method is also robust to noise and amplitude variations.

This correspondence proposes a complete framework for sign language recognition that integrates a commonsense engine in order to deal with sentence recognition. The proposed system is based on a multilevel architecture that allows modeling and managing of the knowledge of the recognition process in a simple and robust way. The final abstraction level of this architecture introduces the semantic context and the analysis of the correctness of a sentence given in a sequence of recognized signs. Experimentations are presented using a set of signs from the Italian sign language (LIS) for domotic applications. The implemented system maintains a high recognition rate when the set of signs grows, correcting erroneously recognized single signs using the sentence context.

In this paper we propose a three-layered neural network for binary pattern recognition and memorization. Unlike the classic approach to pattern recognition, our net works organizing itself in an unsupervised way, to distinguish beetween different patterns or to recognize similar ones. If we present a binary input to the first layer, after some time steps we could read the output of the net in the third layer, as one and only one neuron activating with high firing rate; the middle layer will act as a generalization layer, i.e. similar pattern will have similar (or the same) representation in the middle layer. We used learning algorithms inspired from other works or from biological data to achieve network stability and a correct pattern memorization. The network can be used for pattern recognition or generalization by selecting output signals from the selection layer or the generalization layer.

In this letter, a preliminary study of habituation in self-organizing networks is reported. The habituation model implemented allows us to obtain a faster learning process and better clustering performances. The habituable neuron is a generalization of the typical neuron and can be used in many self-organizing network models. The habituation mechanism is implemented in a SOM and the clustering performances of the network are compared to the conscience learning mechanism that follows roughly the same principle but is less sophisticated.

A large class of neural network models have their units organized in a lattice with fixed topology or generate their topology during the learning process. These network models can be used as neighborhood preserving map of the input manifold, but such a structure is difficult to manage since these maps are graphs with a number of nodes that is just one or two orders of magnitude less than the number of input points (i.e., the complexity of the map is comparable with the complexity of the manifold) and some hierarchical algorithms were proposed in order to obtain a high-level abstraction of these structures. In this paper a general structure capable to extract high order information from the graph generated by a large class of self-organizing networks is presented. This algorithm will allow to build a two layers hierarchical structure starting from the results obtained by using the suitable neural network for the distribution of the input data. Moreover the proposed algorithm is also capable to build a topology preserving map if it is trained using a graph that is also a topology preserving map.