Genome-wide search of nucleosome patterns using visual analytics.

MOTIVATION: The Burrows-Wheeler transform (BWT) is widely used for the fast alignment of high-throughput sequence data. This method also has potential applications in other areas of bioinformatics, and it can be specially useful for the fast searching of patterns on coverage data from different sources. RESULTS: We present a nucleosome pattern search method that converts levels of nucleosomal occupancy to a sequence-like format to which BWT searches can be applied. The method is embedded in a nucleosome map browser, 'Nucleosee', an interactive visual tool specifically designed to enhance BWT searches, giving them context and making them suitable for visual discourse analysis of the results. The proposed method is fast, flexible and sufficiently generic for the exploration of data in a broad and interactive way. AVAILABILITY AND IMPLEMENTATION: The proposed algorithm and visual browser are available for testing at http://cpg3.der.usal.es/nucleosee. The source code and installation packages are also available at https://github.com/rodrigoSantamaria/nucleosee. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

APID interactomes: providing proteome-based interactomes with controlled quality for multiple species and derived networks.

APID (Agile Protein Interactomes DataServer) is an interactive web server that provides unified generation and delivery of protein interactomes mapped to their respective proteomes. This resource is a new, fully redesigned server that includes a comprehensive collection of protein interactomes for more than 400 organisms (25 of which include more than 500 interactions) produced by the integration of only experimentally validated protein-protein physical interactions. For each protein-protein interaction (PPI) the server includes currently reported information about its experimental validation to allow selection and filtering at different quality levels. As a whole, it provides easy access to the interactomes from specific species and includes a global uniform compendium of 90,379 distinct proteins and 678,441 singular interactions. APID integrates and unifies PPIs from major primary databases of molecular interactions, from other specific repositories and also from experimentally resolved 3D structures of protein complexes where more than two proteins were identified. For this purpose, a collection of 8,388 structures were analyzed to identify specific PPIs. APID also includes a new graph tool (based on Cytoscape.js) for visualization and interactive analyses of PPI networks. The server does not require registration and it is freely available for use at http://apid.dep.usal.es.

BicOverlapper 2.0: visual analysis for gene expression.

MOTIVATION: Systems biology demands the use of several point of views to get a more comprehensive understanding of biological problems. This usually leads to take into account different data regarding the problem at hand, but it also has to do with using different perspectives of the same data. This multifaceted aspect of systems biology often requires the use of several tools, and it is often hard to get a seamless integration of all of them, which would help the analyst to have an interactive discourse with the data. RESULTS: Focusing on expression profiling, BicOverlapper 2.0 visualizes the most relevant aspects of the analysis, including expression data, profiling analysis results and functional annotation. It also integrates several state-of-the-art numerical methods, such as differential expression analysis, gene set enrichment or biclustering. AVAILABILITY AND IMPLEMENTATION: BicOverlapper 2.0 is available at: http://vis.usal.es/bicoverlapper2

Asymmetrical nucleosomal DNA signatures regulate transcriptional directionality.

Despite the symmetrical structure of nucleosomes, in vitro studies have shown that transcription proceeds with different efficiency depending on the orientation of the DNA sequence around them. However, it is unclear whether this functional asymmetry is present in vivo and whether it could regulate transcriptional directionality. Here, we report that the proximal and distal halves of nucleosomal DNA contribute differentially to nucleosome stability in the genome. In +1 nucleosomes, this asymmetry facilitates or hinders transcription depending on the orientation of its underlying DNA, and this difference is associated with an asymmetrical interaction between DNA and histones. These properties are encoded in the DNA signature of +1 nucleosomes, since its incorporation in the two orientations into downstream nucleosomes renders them asymmetrically accessible to MNase and inverts the balance between sense and antisense transcription. Altogether, our results show that nucleosomal DNA endows nucleosomes with asymmetrical properties that modulate the directionality of transcription.

Efficacy of a Rehabilitation Program Using Mirror Therapy and Cognitive Therapeutic Exercise on Upper Limb Functionality in Patients with Acute Stroke.

Applying evidence-based therapies in stroke rehabilitation plays a crucial role in this process, as they are supported by studies and results that demonstrate their effectiveness in improving functionality, such as mirror therapy (MT), cognitive therapeutic exercise (CTE), and task-oriented training. The aim of this study was to assess the effectiveness of MT and CTE combined with task-oriented training on the functionality, sensitivity, range, and pain of the affected upper limb in patients with acute stroke. A longitudinal multicenter study recruited a sample of 120 patients with acute stroke randomly and consecutively, meeting specific inclusion and exclusion criteria. They were randomly allocated into three groups: a control group only for task-oriented training (TOT) and two groups undergoing either MT or CTE, both combined with TOT. The overall functionality of the affected upper limb, specific functionality, sensitivity, range of motion, and pain were assessed using the Fugl-Meyer Assessment Upper Extremity (FMA-UE) scale validated for the Spanish population. An initial assessment was conducted before the intervention, a second assessment after completing the 20 sessions, and another three months later. ANCOVA analysis revealed statistically significant differences between the assessments and the experimental groups compared to the control group, indicating significant improvement in the overall functionality of the upper limb in these patients. However, no significant differences were observed between the two experimental groups. The conclusion drawn was that both therapeutic techniques are equally effective in treating functionality, sensitivity, range of motion, and pain in the upper limb following a stroke.

Voronto: mapper for expression data to ontologies.

MOTIVATION: Several techniques analyze gene expression data from the point of view of biological ontologies. These methods focus on statistical and numerical analyses, but there is an additional need for fast, global and interactive visualizations of gene expression data in the context of biological ontologies. RESULTS: Voronto addresses these needs with an easy to use integration of custom gene expression data with custom or public ontologies. In order to do that, it implements Voronoi diagrams where ontologies are mapped with gene expression, providing a quick hierarchy browsing and integration with ontology's resources. AVAILABILITY: The tool is available at http://vis.usal.es/voronto. Source code available at https:/github.com/rodrigoSantamaria/Voronto.

Low level genome mistranslations deregulate the transcriptome and translatome and generate proteotoxic stress in yeast.

BACKGROUND: Organisms use highly accurate molecular processes to transcribe their genes and a variety of mRNA quality control and ribosome proofreading mechanisms to maintain intact the fidelity of genetic information flow. Despite this, low level gene translational errors induced by mutations and environmental factors cause neurodegeneration and premature death in mice and mitochondrial disorders in humans. Paradoxically, such errors can generate advantageous phenotypic diversity in fungi and bacteria through poorly understood molecular processes. RESULTS: In order to clarify the biological relevance of gene translational errors we have engineered codon misreading in yeast and used profiling of total and polysome-associated mRNAs, molecular and biochemical tools to characterize the recombinant cells. We demonstrate here that gene translational errors, which have negligible impact on yeast growth rate down-regulate protein synthesis, activate the unfolded protein response and environmental stress response pathways, and down-regulate chaperones linked to ribosomes. CONCLUSIONS: We provide the first global view of transcriptional and post-transcriptional responses to global gene translational errors and we postulate that they cause gradual cell degeneration through synergistic effects of overloading protein quality control systems and deregulation of protein synthesis, but generate adaptive phenotypes in unicellular organisms through activation of stress cross-protection. We conclude that these genome wide gene translational infidelities can be degenerative or adaptive depending on cellular context and physiological condition.

Long COVID Symptomatology and Associated Factors in Primary Care Patients: The EPICOVID-AP21 Study.

Persistent COVID-19 condition includes a wide variety of symptoms and health problems of indeterminate duration. The present study examined the sociodemographic and clinical characteristics of the population with Long COVID seen in Primary Care using a questionnaire based on the existing scientific literature. It was an observational and descriptive study of the characteristics of the Spanish population with Long COVID over 14 years of age. The responses were analysed by means of a descriptive analysis of the variables recorded, in addition to a bivariate analysis to determine the existence of a relationship between persistent COVID-19 and variables such as gender, age, vaccination status or concomitant pathology. The results obtained clearly describe the sociodemographic characteristics of the population, highlighting the predominance of female gender and the prevalence of tiredness and fatigue. Furthermore, relevant information was obtained on the differences in symptomatology according to gender, age, previous pathologies and alterations derived from infection and/or vaccination. These data are important for better detection, diagnosis and treatment of Long COVID and the improvement of the quality of life of this population.

Functionality, physical activity, fatigue and quality of life in patients with acute COVID-19 and Long COVID infection.

A prominent feature of COVID-19, both in the short and long term, is the reduction in quality of life (QoL) due to low functionality scores and the presence of fatigue, which can hinder daily activities. The main objective of this study is to compare the functional status, level of physical activity, fatigue, and QoL of patients with Long COVID to other COVID-19 patients who did not develop persistent illness, and to determine whether there is a relationship between these variables and QoL. A cross-sectional study was conducted with 170 participants who had been infected with COVID-19 or had developed Long COVID. The main variables studied were functionality, physical activity, QoL and fatigue, measured using the PostCOVID-19 Functional Status Scale (PCFS), International Physical Activity Questionnaire (IPAQ), Short Form 12 (SF-12), and Fatigue Severity Scale (FSS). The main findings show a significant relationship (p < 0.001) between reduced functionality, lower physical activity levels, increased fatigue severity, and poorer QoL in Long COVID patients. Furthermore, these variables are also related to worse QoL, but only functional status predicts it. In conclusion, our results have shown highly significant correlations between the group with COVID-19 and Long COVID regarding functional status, level of physical activity, QoL, and fatigue.

Clinical and Epidemiological Profiles of Primary Healthcare Professionals with COVID-19 Infection and Long COVID: An Observational Study.

Health professionals have been one of the groups most affected by the SARS-CoV-2 virus. Currently, there is little scientific evidence on the similarities and differences between COVID-19 infection and the development of long COVID in primary care (PC) workers. Therefore, it is necessary to analyse their clinical and epidemiological profiles in depth. This study was observational and descriptive, including PC professionals who were divided into three comparison groups based on the diagnostic test for acute SARS-CoV-2 infection. The responses were analysed using descriptive and bivariate analysis to examinate the relationship between independent variables and the presence or not of long COVID. Binary logistic regression analysis was also conducted, with each symptom as the dependent variable and each group as the independent variable. The results describe the sociodemographic characteristics of these population groups, revealing that women in the health sector are the most affected by long COVID and that being in this group is associated with its development. Furthermore, individuals with long COVID exhibited the highest number of symptoms and pathologies. Certain symptoms were found to be associated with long COVID development in this population, including an altered sense of smell, pneumonia, fever, and sore throat, among others. Similarly, altered senses of smell and taste, chest tightness, and joint pain, among others, were found to be associated with acute COVID-19 infection. Additionally, patients with pre-existing overweight or obesity were more likely to experience acute COVID-19 and develop long COVID. The data obtained can be crucial for improving the detection, diagnosis, and treatment of long COVID patients, ultimately leading to an enhancement in their quality of life.

[Epidemiological characteristics and types of domestic and leisure accidents: sentinel health network of Castilla y León (2009)]. / Incidencia, características epidemiológicas y tipos de accidentes domésticos y de ocio. Red centinela sanitaria de Castilla y León (2009).

OBJECTIVES: To study incidence, epidemiological characteristics and types of domestic and leisure accidents in Castilla y León during 2009. DESIGN: A descriptive study using a prospective sample design. EMPLACEMENT: Health Primary Care Centres of Castilla y León. PARTICIPANTS: The Nurse Registry is made up of 130 nurses selected by conglomerates analysis. They cover 5% of the population. PRINCIPAL MEASUREMENTS: The information was obtained by means of an anonymous form. The studied variables were sex, age, type, place, type and origin of the accident. A descriptive analysis was performed using χ(2), Fischer, χ(2) of trends and t Student tests, with 95% confidence intervals. RESULTS: The annual cumulative incidence was 2651 cases/100000 inhabitants, there being slightly higher percentage of men (50.4%). The ≤ 15 and ≥ 65 years age groups had more accidents. The time of day of 49.2% of the accidents was during the morning and 71.7% were on a working day. The majority (57.1%) took place in the home, 16,8% in the street, and 7.3% in schools. The most common accidents types were falls to the same level (40.4%) and use of cutting and sharp objects (22.7%). CONCLUSIONS: Most accidents took place within the home, on a working day and by falls. The most affected were the ≤ 15 and ≥ 65 years old age groups.

Nitric Oxide Metabolism Affects Germination in Botrytiscinerea and Is Connected to Nitrate Assimilation.

Nitric oxide regulates numerous physiological processes in species from all taxonomic groups. Here, its role in the early developmental stages of the fungal necrotroph Botrytis cinerea was investigated. Pharmacological analysis demonstrated that NO modulated germination, germ tube elongation and nuclear division rate. Experimental evidence indicates that exogenous NO exerts an immediate but transitory negative effect, slowing down germination-associated processes, and that this effect is largely dependent on the flavohemoglobin BCFHG1. The fungus exhibited a "biphasic response" to NO, being more sensitive to low and high concentrations than to intermediate levels of the NO donor. Global gene expression analysis in the wild-type and ΔBcfhg1 strains indicated a situation of strong nitrosative and oxidative stress determined by exogenous NO, which was much more intense in the mutant strain, that the cells tried to alleviate by upregulating several defense mechanisms, including the simultaneous upregulation of the genes encoding the flavohemoglobin BCFHG1, a nitronate monooxygenase (NMO) and a cyanide hydratase. Genetic evidence suggests the coordinated expression of Bcfhg1 and the NMO coding gene, both adjacent and divergently arranged, in response to NO. Nitrate assimilation genes were upregulated upon exposure to NO, and BCFHG1 appeared to be the main enzymatic system involved in the generation of the signal triggering their induction. Comparative expression analysis also showed the influence of NO on other cellular processes, such as mitochondrial respiration or primary and secondary metabolism, whose response could have been mediated by NmrA-like domain proteins.

Hospital admission and vaccination as predictive factors of long COVID-19 symptoms.

Background: Since the beginning of the COVID-19 pandemic, a great variability of symptoms that affect all organs and systems of the body has been identified in patients with SARS-CoV-2 infection; this symptomatology can sometimes persist over time, giving rise to the so-called long COVID or post-COVID. The aim of this study is to delve into the clinical characterization of these patients, as well as to take into account the influence of factors such as hospitalization, admission to ICU, history of pneumonia, or vaccination status on the persistence of symptoms. Material and methods: An observational, descriptive, multicenter, and retrospective study was designed with a series of cases of people who presented long COVID, which includes univariate, bivariate, and multivariate analyses. Data were obtained from an online ad hoc questionnaire, and statistical analysis was performed using SPSS Software Version 25 (IBM-Inc., Chicago, IL, USA). Results: Hospitalization, ICU admission, history of pneumonia, and vaccination were predictive factors (positive or negative) for the following long-COVID symptoms: headache, menstrual disorders, joint pain, cough, chills, nasal congestion, back pain, abdominal pain, weight loss, eye discomfort, facial erythema, itching, tremors, dizziness, seizures, sleeping difficulty, dry eyes, palpitations, fatigue, paresthesia, dyspnea, aphonia, chest pain, high blood pressure, vomiting, memory loss, brain fog, hypothermia, low blood pressure, sputum or phlegm, lack of concentration, hair loss, and erectile dysfunction. Conclusion: This study provides evidence on the clinical characterization of patients suffering from long COVID in order to offer them the most appropriate treatments.

An evaluation study of biclusters visualization techniques of gene expression data.

Biclustering is a non-supervised data mining technique used to analyze gene expression data, it consists to classify subgroups of genes that have similar behavior under subgroups of conditions. The classified genes can have independent behavior under other subgroups of conditions. Discovering such co-expressed genes, called biclusters, can be helpful to find specific biological features such as gene interactions under different circumstances. Compared to clustering, biclustering has two main characteristics: bi-dimensionality which means grouping both genes and conditions simultaneously and overlapping which means allowing genes to be in more than one bicluster at the same time. Biclustering algorithms, which continue to be developed at a constant pace, give as output a large number of overlapping biclusters. Visualizing groups of biclusters is still a non-trivial task due to their overlapping. In this paper, we present the most interesting techniques to visualize groups of biclusters and evaluate them.

Treevolution: visual analysis of phylogenetic trees.

SUMMARY: Treevolution is a tool for the representation and exploration of phylogenetic trees that facilitates visual analysis. There are several useful tools to visualize phylogenetic trees, but their level of interaction is usually low, especially in the case of radial representations. Highly interactive visualizations can improve the exploration and understanding of phylogenetic trees. Treevolution implements strategies to interact with phylogenetic trees in order to allow a more thorough analysis by users. AVAILABILITY: Treevolution is available at http://vis.usal.es/treevolution. Additional figures, a user's guide, a video demo and some examples are available at the same site. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

VisBicluster: A Matrix-Based Bicluster Visualization of Expression Data.

One of the main methods to analyze gene expression data is biclustering, a nonsupervised technique, which consists of selection subgroups of genes that co-expressed under subgroups of experimental conditions. A large number of biclustering algorithms have been developed to classify gene expression data. These algorithms can give as output a large number of overlapped biclusters, whose visualization still requires deeper studies. We present VisBicluster, a web-based interactive visualization tool for displaying biclustering results. The developed visualization technique consists of laying out the generated biclusters in a two-dimensional matrix where each bicluster is represented as a column and each overlap between a set of biclusters is represented as a row. A search interface for the user is developed to query the matrix of bicluster intersection and visualize the results matching the queries. Our tool supports many interactive features such as sorting, zooming, and details-on-demand. We proved the usefulness of VisBicluster with biclustering results from real and synthetic datasets. Besides, we performed a user study with 14 participants to illustrate the clarity and simplicity of overlap representation with our tool.

BicOverlapper: a tool for bicluster visualization.

UNLABELLED: BicOverlapper is a tool to visualize biclusters from gene-expression matrices in a way that helps to compare biclustering methods, to unravel trends and to highlight relevant genes and conditions. A visual approach can complement biological and statistical analysis and reduce the time spent by specialists interpreting the results of biclustering algorithms. The technique is based on a force-directed graph where biclusters are represented as flexible overlapped groups of genes and conditions. AVAILABILITY: The BicOverlapper software and supplementary material are available at http://vis.usal.es/bicoverlapper

A visual analytics approach for understanding biclustering results from microarray data.

BACKGROUND: Microarray analysis is an important area of bioinformatics. In the last few years, biclustering has become one of the most popular methods for classifying data from microarrays. Although biclustering can be used in any kind of classification problem, nowadays it is mostly used for microarray data classification. A large number of biclustering algorithms have been developed over the years, however little effort has been devoted to the representation of the results. RESULTS: We present an interactive framework that helps to infer differences or similarities between biclustering results, to unravel trends and to highlight robust groupings of genes and conditions. These linked representations of biclusters can complement biological analysis and reduce the time spent by specialists on interpreting the results. Within the framework, besides other standard representations, a visualization technique is presented which is based on a force-directed graph where biclusters are represented as flexible overlapped groups of genes and conditions. This microarray analysis framework (BicOverlapper), is available at http://vis.usal.es/bicoverlapper CONCLUSION: The main visualization technique, tested with different biclustering results on a real dataset, allows researchers to extract interesting features of the biclustering results, especially the highlighting of overlapping zones that usually represent robust groups of genes and/or conditions. The visual analytics methodology will permit biology experts to study biclustering results without inspecting an overwhelming number of biclusters individually.

Adaptive Mistranslation Accelerates the Evolution of Fluconazole Resistance and Induces Major Genomic and Gene Expression Alterations in Candida albicans.

Regulated erroneous protein translation (adaptive mistranslation) increases proteome diversity and produces advantageous phenotypic variability in the human pathogen Candida albicans. It also increases fitness in the presence of fluconazole, but the underlying molecular mechanism is not understood. To address this question, we evolved hypermistranslating and wild-type strains in the absence and presence of fluconazole and compared their fluconazole tolerance and resistance trajectories during evolution. The data show that mistranslation increases tolerance and accelerates the acquisition of resistance to fluconazole. Genome sequencing, array-based comparative genome analysis, and gene expression profiling revealed that during the course of evolution in fluconazole, the range of mutational and gene deregulation differences was distinctively different and broader in the hypermistranslating strain, including multiple chromosome duplications, partial chromosome deletions, and polyploidy. Especially, the increased accumulation of loss-of-heterozygosity events, aneuploidy, translational and cell surface modifications, and differences in drug efflux seem to mediate more rapid drug resistance acquisition under mistranslation. Our observations support a pivotal role for adaptive mistranslation in the evolution of drug resistance in C. albicans. IMPORTANCE Infectious diseases caused by drug-resistant fungi are an increasing threat to public health because of the high mortality rates and high costs associated with treatment. Thus, understanding of the molecular mechanisms of drug resistance is of crucial interest for the medical community. Here we investigated the role of regulated protein mistranslation, a characteristic mechanism used by C. albicans to diversify its proteome, in the evolution of fluconazole resistance. Such codon ambiguity is usually considered highly deleterious, yet recent studies found that mistranslation can boost adaptation in stressful environments. Our data reveal that CUG ambiguity diversifies the genome in multiple ways and that the full spectrum of drug resistance mechanisms in C. albicans goes beyond the traditional pathways that either regulate drug efflux or alter the interactions of drugs with their targets. The present work opens new avenues to understand the molecular and genetic basis of microbial drug resistance.

RUN and FYVE domain-containing protein 4 enhances autophagy and lysosome tethering in response to Interleukin-4.

Autophagy is a key degradative pathway coordinated by external cues, including starvation, oxidative stress, or pathogen detection. Rare are the molecules known to contribute mechanistically to the regulation of autophagy and expressed specifically in particular environmental contexts or in distinct cell types. Here, we unravel the role of RUN and FYVE domain-containing protein 4 (RUFY4) as a positive molecular regulator of macroautophagy in primary dendritic cells (DCs). We show that exposure to interleukin-4 (IL-4) during DC differentiation enhances autophagy flux through mTORC1 regulation and RUFY4 induction, which in turn actively promote LC3 degradation, Syntaxin 17-positive autophagosome formation, and lysosome tethering. Enhanced autophagy boosts endogenous antigen presentation by MHC II and allows host control of Brucella abortus replication in IL-4-treated DCs and in RUFY4-expressing cells. RUFY4 is therefore the first molecule characterized to date that promotes autophagy and influences endosome dynamics in a subset of immune cells.