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Understanding the interactions between microorganisms and their impact on bacterial behavior at the community level is a key research topic in microbiology. Different methods, relying on experimental or mathematical approaches based on the diverse properties of bacteria, are currently employed to study these interactions. Recently, the use of metabolic networks to understand the interactions between bacterial pairs has increased, highlighting the relevance of this approach in characterizing bacteria. In this study, we leverage the representation of bacteria through their metabolic networks to build a predictive model aimed at reducing the number of experimental assays required for designing bacterial consortia with specific behaviors. Our novel method for predicting cross-feeding or competition interactions between pairs of microorganisms utilizes metabolic network features. Machine learning classifiers are employed to determine the type of interaction from automatically reconstructed metabolic networks. Several algorithms were assessed and selected based on comprehensive testing and careful separation of manually compiled data sets obtained from literature sources. We used different classification algorithms, including K Nearest Neighbors, XGBoost, Support Vector Machine, and Random Forest, tested different parameter values, and implemented several data curation approaches to reduce the biological bias associated with our data set, ultimately achieving an accuracy of over 0.9. Our method holds substantial potential to advance the understanding of community behavior and contribute to the development of more effective approaches for consortia design.IMPORTANCEUnderstanding bacterial interactions at the community level is critical for microbiology, and leveraging metabolic networks presents an efficient and effective approach. The introduction of this novel method for predicting interactions through machine learning classifiers has the potential to advance the field by reducing the number of experimental assays required and contributing to the development of more effective bacterial consortia., Competing Interests: The authors declare no conflict of interest.

Periodontitis is a chronic inflammatory disease characterized by the progressive and irreversible destruction of the periodontium. Its aetiopathogenesis lies in the constant challenge of the dysbiotic biofilm, which triggers a deregulated immune response responsible for the disease phenotype. Although the molecular mechanisms underlying periodontitis have been extensively studied, the regulatory mechanisms at the transcriptional level remain unclear. To generate transcriptomic data, we performed RNA shotgun sequencing of the oral mucosa of periodontitis-affected mice. Since genes are not expressed in isolation during pathological processes, we disclose here the complete repertoire of differentially expressed genes (DEG) and co-expressed modules to build Gene Regulatory Networks (GRNs) and identify the Master Transcriptional Regulators of periodontitis. The transcriptional changes revealed 366 protein-coding genes and 42 non-coding genes differentially expressed and enriched in the immune response. Furthermore, we found 13 co-expression modules with different representation degrees and gene expression levels. Our GRN comprises genes from 12 gene clusters, 166 nodes, of which 33 encode Transcription Factors, and 201 connections. Finally, using these strategies, 26 master regulators of periodontitis were identified. In conclusion, combining the transcriptomic analyses with the regulatory network construction represents a powerful and efficient strategy for identifying potential periodontitis-therapeutic targets.

This perspective highlights the potential of individualized networks as a novel strategy for studying complex diseases through patient stratification, enabling advancements in precision medicine. We emphasize the impact of interpatient heterogeneity resulting from genetic and environmental factors and discuss how individualized networks improve our ability to develop treatments and enhance diagnostics. Integrating system biology, combining multimodal information such as genomic and clinical data has reached a tipping point, allowing the inference of biological networks at a single-individual resolution. This approach generates a specific biological network per sample, representing the individual from which the sample originated. The availability of individualized networks enables applications in personalized medicine, such as identifying malfunctions and selecting tailored treatments. In essence, reliable, individualized networks can expedite research progress in understanding drug response variability by modeling heterogeneity among individuals and enabling the personalized selection of pharmacological targets for treatment. Therefore, developing diverse and cost-effective approaches for generating these networks is crucial for widespread application in clinical services., 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 © 2023 Latapiat, Saez, Pedroso and Martin.)

Insect pollinators provide an important ecosystem service that supports global biodiversity and environmental health. The study investigates the effects of the environmental matrix on six oxidative stress biomarkers in the honey bee Apis mellifera . Thirty-five apiaries located in urban, forested, and agricultural areas in Central Italy were sampled during the summer season. Enzyme activities in forager bees were analyzed using an artificial neural network, allowing the identification and representation of the apiary patterns in a Self-Organizing Map. The SOM nodes were correlated with the environmental parameters and tissue levels of eight heavy metals. The results indicated that the apiaries were not clustered according to their spatial distribution. Superoxide dismutase expressed a positive correlation with Cr and Mn concentrations; catalase with Zn, Mn, Fe, and daily maximum air temperature; glutathione S-transferase with Cr, Fe, and daily maximal air temperature; and glutathione reductase showed a negative correlation to Ni and Fe exposure. This study highlights the importance of exploring how environmental stressors affect these insects and the role of oxidative stress biomarkers. Artificial neural networks proved to be a powerful approach to untangle the complex relationships between the environment and oxidative stress biomarkers in honey bees. The application of SOM modeling offers a valuable means of assessing the potential effects of environmental pressures on honey bee populations.

Background: The Andean condor ( Vultur gryphus ) is the largest scavenger in South America. This predatory bird plays a crucial role in their ecological niche by removing carcasses. We report the first metagenomic analysis of the Andean condor gut microbiome., Methods: This work analyzed shotgun metagenomics data from a mixture of fifteen captive Chilean Andean condors. To filter eukaryote contamination, we employed BWA-MEM v0.7. Taxonomy assignment was performed using Kraken2 and MetaPhlAn v2.0 and all filtered reads were assembled using IDBA-UD v1.1.3. The two most abundant species were used to perform a genome reference-guided assembly using MetaCompass. Finally, we performed a gene prediction using Prodigal and each gene predicted was functionally annotated. InterproScan v5.31-70.0 was additionally used to detect homology based on protein domains and KEGG mapper software for reconstructing metabolic pathways., Results: Our results demonstrate concordance with the other gut microbiome data from New World vultures. In the Andean condor, Firmicutes was the most abundant phylum present, with Clostridium perfringens , a potentially pathogenic bacterium for other animals, as dominating species in the gut microbiome. We assembled all reads corresponding to the top two species found in the condor gut microbiome, finding between 94% to 98% of completeness for Clostridium perfringens and Plesiomonas shigelloides , respectively. Our work highlights the ability of the Andean condor to act as an environmental reservoir and potential vector for critical priority pathogens which contain relevant genetic elements. Among these genetic elements, we found 71 antimicrobial resistance genes and 1,786 virulence factors that we associated with several adaptation processes., Competing Interests: The authors declare that they have no competing interests., (© 2023 Martinez-Hernandez et al.)

Huntington's disease (HD) is a disorder caused by an abnormal expansion of trinucleotide CAG repeats within the huntingtin (Htt) gene. Under normal conditions, the CREB Binding Protein interacts with CREB elements and acetylates Lysine 27 of Histone 3 to direct the expression of several genes. However, mutant Htt causes depletion of CBP, which in turn induces altered histone acetylation patterns and transcriptional deregulation. Here, we have studied a differential expression analysis and H3K27ac variation in 4- and 6-week-old R6/2 mice as a model of juvenile HD. The analysis of differential gene expression and acetylation levels were integrated into Gene Regulatory Networks revealing key regulators involved in the altered transcription cascade. Our results show changes in acetylation and gene expression levels that are related to impaired neuronal development, and key regulators clearly defined in 6-week-old mice are proposed to drive the downstream regulatory cascade in HD. Here, we describe the first approach to determine the relationship among epigenetic changes in the early stages of HD. We determined the existence of changes in pre-symptomatic stages of HD as a starting point for early onset indicators of the progression of this disease.

Introduction: Gut microbiota plays a critical role in the regulation of immune homeostasis. Accordingly, several autoimmune disorders have been associated with dysbiosis in the gut microbiota. Notably, the dysbiosis associated with central nervous system (CNS) autoimmunity involves a substantial reduction of bacteria belonging to Clostridia clusters IV and XIVa, which constitute major producers of short-chain fatty acids (SCFAs). Here we addressed the role of the surface receptor-mediated effects of SCFAs on mucosal T-cells in the development of CNS autoimmunity., Methods: To induce CNS autoimmunity, we used the mouse model of experimental autoimmune encephalomyelitis (EAE) induced by immunization with the myelin oligodendrocyte glycoprotein (MOG)-derived peptide (MOG 35-55 peptide). To address the effects of GPR43 stimulation on colonic TCRαβ + T-cells upon CNS autoimmunity, mucosal lymphocytes were isolated and stimulated with a selective GPR43 agonist ex vivo and then transferred into congenic mice undergoing EAE. Several subsets of lymphocytes infiltrating the CNS or those present in the gut epithelium and gut lamina propria were analysed by flow cytometry. In vitro migration assays were conducted with mucosal T-cells using transwells., Results: Our results show a sharp and selective reduction of intestinal propionate at the peak of EAE development, accompanied by increased IFN-γ and decreased IL-22 in the colonic mucosa. Further analyses indicated that GPR43 was the primary SCFAs receptor expressed on T-cells, which was downregulated on colonic TCRαβ + T-cells upon CNS autoimmunity. The pharmacologic stimulation of GPR43 increased the anti-inflammatory function and reduced the pro-inflammatory features in several TCRαβ + T-cell subsets in the colonic mucosa upon EAE development. Furthermore, GPR43 stimulation induced the arrest of CNS-autoreactive T-cells in the colonic lamina propria, thus avoiding their infiltration into the CNS and dampening the disease development. Mechanistic analyses revealed that GPR43-stimulation on mucosal TCRαβ + T-cells inhibits their CXCR3-mediated migration towards CXCL11, which is released from the CNS upon neuroinflammation., Conclusions: These findings provide a novel mechanism involved in the gut-brain axis by which bacterial-derived products secreted in the gut mucosa might control the CNS tropism of autoreactive T-cells. Moreover, this study shows GPR43 expressed on T-cells as a promising therapeutic target for CNS autoimmunity., (© 2023. The Author(s).)

Motivation: One of the most relevant mechanisms involved in the determination of chromatin structure is the formation of structural loops that are also related with the conservation of chromatin states. Many of these loops are stabilized by CCCTC-binding factor (CTCF) proteins at their base. Despite the relevance of chromatin structure and the key role of CTCF, the role of the epigenetic factors that are involved in the regulation of CTCF binding, and thus, in the formation of structural loops in the chromatin, is not thoroughly understood., Results: Here we describe a CTCF binding predictor based on Random Forest that employs different epigenetic data and genomic features. Importantly, given the ability of Random Forests to determine the relevance of features for the prediction, our approach also shows how the different types of descriptors impact the binding of CTCF, confirming previous knowledge on the relevance of chromatin accessibility and DNA methylation, but demonstrating the effect of epigenetic modifications on the activity of CTCF. We compared our approach against other predictors and found improved performance in terms of areas under PR and ROC curves (PRAUC-ROCAUC), outperforming current state-of-the-art methods., Competing Interests: None declared., (© 2023 The Authors.)

The human gut is home to trillions of microorganisms that influence several aspects of our health. This dense microbial community targets almost all dietary polysaccharides and releases multiple metabolites, some of which have physiological effects on the host. A healthy equilibrium between members of the gut microbiota, its microbial diversity, and their metabolites is required for intestinal health, promoting regulatory or anti-inflammatory immune responses. In contrast, the loss of this equilibrium due to antibiotics, low fiber intake, or other conditions results in alterations in gut microbiota composition, a term known as gut dysbiosis. This dysbiosis can be characterized by a reduction in health-associated microorganisms, such as butyrate-producing bacteria, enrichment of a small number of opportunistic pathogens, or a reduction in microbial diversity. Bifidobacterium species are key species in the gut microbiome, serving as primary degraders and contributing to a balanced gut environment in various ways. Colonization resistance is a fundamental property of gut microbiota for the prevention and control of infections. This community competes strongly with foreign microorganisms, such as gastrointestinal pathogens, antibiotic-resistant bacteria, or even probiotics. Resistance to colonization is based on microbial interactions such as metabolic cross-feeding, competition for nutrients, or antimicrobial-based inhibition. These interactions are mediated by metabolites and metabolic pathways, representing the inner workings of the gut microbiota, and play a protective role through colonization resistance. This review presents a rationale for how microbial interactions provide resistance to colonization and gut dysbiosis, highlighting the protective role of Bifidobacterium species., Competing Interests: All authors declared that there are no conflicts of interest., (© The Author(s) 2023.)

The red swamp crayfish Procambarus clarkii is one of the most threatening freshwater species in the world. The aim of this study is to provide a better understanding of the phylogeography and the invasion routes of P. clarkii populations in the Italian Peninsula through the analysis of mitochondrial phylogeny. Mitochondrial control region and cytochrome c oxidase subunit I (COI) sequences of 153 samples collected from six Italian basins were analyzed and compared to worldwide data. Except for the lakes Bolsena and Posta Fibreno, a high genetic variability was found in the other basins. The mitochondrial DNA pattern of P. clarkii from the lakes Candia and Massaciuccoli confirmed the hypothesis of double introduction events. Another entry point could be represented by Lake Trasimeno, which shows haplotypes originating from Louisiana and not shared with other Italian basins. Moreover, unique lineages were also found in the Stella River, thus enhancing the hypothesis that multiple introductions of P. clarkii occurred in northern and Central Italy and strengthening the idea that knowledge about the dispersion routes of this alien species can be useful to predict its invasiveness and elaborate control strategies to preserve biodiversity.

Concentrations of essential metals (Cu, Co, Cr, Fe, Ni, Mn, and Zn) and non-essential and toxic metals (Ag, Cd, Hg, and Pb) were quantified in hepatopancreas and abdominal muscle for 73 specimens (37 males and 36 females) of Procambarus clarkii from Lake Trasimeno (Italy) in a year's campaign (July 2018 to June 2019). Elemental concentrations determined in crayfish differed in tissues, seasons, and gender. Both sexes showed lower concentrations in abdominal muscle than in hepatopancreas. Essential metals accumulated in higher concentrations in both tissues than non-essential elements, while associations between essential metals were stronger, especially for females; however, a strong correlation was also observed between Cu and Ag in both sexes. No significant differences in concentrations were recorded between sexes for all seasons; contrarily, significant differences among the total seasonal concentrations (males plus females) were observed only for essential metals and for Ag. Seasonal Toxic Contamination Index (TCI) for Cr, Ni, Cu, Zn, Cd, Pb, and Hg were calculated to assess the toxicity level of metals in the sediments. TCI higher than 1 was detected for Ni only in summer, confirming the close connection between the fluctuating hydrological levels of the shallow Lake Trasimeno, strongly dependent on precipitation, and the metal contamination levels of sediments., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Recently, the combination of chemotherapy plus nivolumab (chemo-immunotherapy) has become the standard of care for advanced-stage gastric cancer (GC) patients. However, despite its efficacy, up to 40% of patients do not respond to these treatments. Our study sought to identify variations in gene expression associated with primary resistance to chemo-immunotherapy. Diagnostic endoscopic biopsies were retrospectively obtained from advanced GC patients previously categorized as responders (R) or non-responders (NR). Thirty-four tumor biopsies (R: n = 16, NR: n = 18) were analyzed by 3′ massive analysis of cDNA ends (3′MACE). We found >30 differentially expressed genes between R and NRs. Subsequent pathway enrichment analyses demonstrated that angiogenesis and the Wnt-β-catenin signaling pathway were enriched in NRs. Concomitantly, we performed next generation sequencing (NGS) analyses in a subset of four NR patients that confirmed alterations in genes that belonged to the Wnt/β-catenin and the phosphoinositide 3-kinase (PI3K) pathways. We speculate that angiogenesis, the Wnt, and the PI3K pathways might offer actionable targets. We also discuss therapeutic alternatives for chemo-immunotherapy-resistant advanced-stage GC patients.

Gene regulation is a key process for all microorganisms, as it allows them to adapt to different environmental stimuli. However, despite the relevance of gene expression control, for only a handful of organisms is there related information about genome regulation. In this work, we inferred the gene regulatory networks (GRNs) of bacterial and archaeal genomes by comparisons with six organisms with well-known regulatory interactions. The references we used are: Escherichia coli K-12 MG1655, Bacillus subtilis 168, Mycobacterium tuberculosis , Pseudomonas aeruginosa PAO1, Salmonella enterica subsp. enterica serovar typhimurium LT2, and Staphylococcus aureus N315. To this end, the inferences were achieved in two steps. First, the six model organisms were contrasted in an all- vs -all comparison of known interactions based on Transcription Factor (TF)-Target Gene (TG) orthology relationships and Transcription Unit (TU) assignments. In the second step, we used a guilt-by-association approach to infer the GRNs for 12,230 bacterial and 649 archaeal genomes based on TF-TG orthology relationships of the six bacterial models determined in the first step. Finally, we discuss examples to show the most relevant results obtained from these inferences. A web server with all the predicted GRNs is available at https://regulatorynetworks.unam.mx/ or http://132.247.46.6/., 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 Romero, Contreras-Riquelme, Lira, Martin and Perez-Rueda.)

Biofouling is a costly burden for the shipping industry. Metal-based antifouling paints are widely used to protect submerged surfaces, but the release of metals from coatings and the recoating of hulls can leach large amounts of copper and zinc into aquatic environments, posing a risk for aquatic ecosystems and biodiversity. With this study, we studied the time-course metal accumulation and oxidative stress in the digestive gland and the gills of Hyriopsis bialatus, an Asian freshwater mussel, exposed to sublethal concentrations of cuprous chloride (50 and 5 µg/L) and zinc sulfate (1000 and 100 µg/L). Time-dependent accumulation was observed after exposure to copper, but zinc uptake was negligible. Integrated biomarker response (IBRv2) and statistical analysis of individual biomarker levels showed a greater biomarker response in the digestive gland and the gills after exposure to the higher concentration of CuCl and ZnSO 4 . Both compounds elicited a biochemical response, especially in the digestive gland. Glutathione peroxidase activity was increased after exposure to both metals at both concentrations, suggesting a powerful defense against lipid peroxidation. The biological impact of zinc was less than that of copper, suggesting mitigated ecological pressure., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Leishmania parasites are the causal agent of leishmaniasis, an endemic disease in more than 90 countries worldwide. Over the years, traditional approaches focused on the parasite when developing treatments against leishmaniasis. Despite numerous attempts, there is not yet a universal treatment, and those available have allowed for the appearance of resistance. Here, we propose and follow a host-directed approach that aims to overcome the current lack of treatment. Our approach identifies potential therapeutic targets in the host cell and proposes known drug interactions aiming to improve the immune response and to block the host machinery necessary for the survival of the parasite. We started analyzing transcription factor regulatory networks of macrophages infected with Leishmania major. Next, based on the regulatory dynamics of the infection and available gene expression profiles, we selected potential therapeutic target proteins. The function of these proteins was then analyzed following a multilayered network scheme in which we combined information on metabolic pathways with known drugs that have a direct connection with the activity carried out by these proteins. Using our approach, we were able to identify five host protein-coding gene products that are potential therapeutic targets for treating leishmaniasis. Moreover, from the 11 drugs known to interact with the function performed by these proteins, 3 have already been tested against this parasite, verifying in this way our novel methodology. More importantly, the remaining eight drugs previously employed to treat other diseases, remain as promising yet-untested antileishmanial therapies. IMPORTANCE This work opens a new path to fight parasites by targeting host molecular functions by repurposing available and approved drugs. We created a novel approach to identify key proteins involved in any biological process by combining gene regulatory networks and expression profiles. Once proteins have been selected, our approach employs a multilayered network methodology that relates proteins to functions to drugs that alter these functions. By applying our novel approach to macrophages during the Leishmania infection process, we both validated our work and found eight drugs already approved for use in humans that to the best of our knowledge were never employed to treat leishmaniasis, rendering our work as a new tool in the box available to the scientific community fighting parasites.

The deliberate or accidental introduction of invasive alien species (IAS) causes negative ecological and economic impacts altering ecosystem processes, imperiling native species and causing damage to human endeavors. A monthly monitoring program was performed in Lake Trasimeno (Central Italy) from July 2018 to July 2019 in order to provide an upgrade of the population ecology of Procambarus clarkii and to assess the genetic diversity by analyzing the relationships among mitochondrial DNA diversity. Our results confirmed that P. clarkii is well acclimatized in the lake, revealing a stable population structure favored by the resources and conditions typical of this ecosystem, which seem to be optimal for the maintenance of the species. Four distinct mitochondrial haplotypes were detected, but one of them was clearly overrepresented (76%), suggesting that a single predominant introduction event may have occurred in this area, likely followed by secondary events. The identification of the typical genetic variants provides a better understanding of the evolutionary scenarios of P. clarkii in this biotope and it can be helpful in management plans concerning the expanding populations of this invasive alien species.

Patients with cancer are at a high risk of symptomatic venous thromboembolism (VTE), which is a common cause of morbidity and mortality in this patient population. Increased risk of recurrent VTE and bleeding complications are two major challenges associated with therapeutic anticoagulation in these patients. Long-term therapy with low-molecular-weight heparins (LMWHs) has been the standard of care for the treatment of cancer-associated VTE given its favorable risk-benefit ratio in comparison with vitamin K antagonists. Direct oral anticoagulants (DOACs), which offer the convenience of oral administration and have a rapid onset of action, have recently emerged as a new treatment option for patients with cancer-associated thrombosis (CT). Randomized clinical trial data with head-to-head comparisons between DOACs and LMWHs showed that overall, DOACs have a similar efficacy profile but a higher risk of bleeding was observed in some of these studies. This review aims to identify unmet needs in the treatment of CT. We discuss important considerations for clinicians tailoring anticoagulation (1) drug-drug interactions, (2) risk of bleeding (e.g., gastrointestinal bleeding), (3) thrombocytopenia, hematological malignancies, (4) metastatic or primary brain tumors, and (5) renal impairment. Additional research is warranted in several clinical scenarios to help clinicians on the best therapeutic approach., Competing Interests: Conflicts of Interest Anna Falanga is a professor of Haematology at the University of Milano-Bicocca and Director of the Department of Immunohematology and Transfusion Medicine in Bergamo, Italy. She has received personal fees for participation in advisory boards and lectures from Instrumentation Laboratory, Stago, Bayer, Sanofi, ROVI Pharmaceuticals, and Leo Pharma. Grégoire Le Gal holds the Chair on Diagnosis of Venous Thromboembolism, Department of Medicine, University of Ottawa and has received a Mid-Career Clinician–Scientist Award from the Heart and Stroke Foundation of Canada. Marc Carrier has received funding for research from BMS, Pfizer, and Leo Pharma, and personal fees from Bayer, BMC, Pfizer, Sanofi, Servier, and Leo Pharma. Hikmat Abdel-Razeq has nothing to report. Cihan Ay has received honoraria/personal fees for lectures from Bayer, Daiichi-Sankyo, and BMS/Pfizer and participated in the advisory boards for Bayer, Sanofi, Daiichi Sankyo, and BMS/Pfizer. Andrés J. Muñoz Martin is Head of Cancer & Thrombosis Section of the Spanish Society of Medical Oncology (SEOM) and coordinator of the TESEO-SEOM registry of cancer-associated thrombosis. He has provided consultation and lectures and participated in advisory boards of Sanofi, Celgene, AstraZeneca, Roche, Leo Pharma, Servier, Pfizer, Bristol-Myers Squibb, Daiichi Sankyo, Bayer, Amgen, Rovi, Merck Sharp & Dohme, and Eli Lilly. He has also received funding for research from Sanofi, Leo Pharma, and Celgene. Travel and accommodations expenses have been borne by Roche, Merck Serono, Amgen, and Celgene. Inventor with Dr. José Manuel Soria: Genetic Risk Score in VTE and Cancer. Ana Thereza Rocha received personal fees for participation in advisory boards and for lectures from Bayer, Daiichi/Sankyo, Boehringer Ingelheim and Sanofi Giancarlo Agnelli reports personal fees from Bristol Myers Squibb, Pfizer, Bayer Healthcare, and Daiichi Sankyo outside the submitted work Ismail Elalamy has provided lectures and participated in advisory boards of Aspen, Sanofi, Bayer, Bristol-Myers Squibb, Pfizer, Leo Pharma, Rovi, and Boehringer Ingelheim. Benjamin Brenner has received honorarium for participation in advisory boards and lectures from Bayer, Sanofi, Rovi Pharmaceuticals, and Leo Pharma., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Gene Regulatory Networks (GRNs) allow the study of regulation of gene expression of whole genomes. Among the most relevant advantages of using networks to depict this key process, there is the visual representation of large amounts of information and the application of graph theory to generate new knowledge. Nonetheless, despite the many uses of GRNs, it is still difficult and expensive to assign Transcription Factors (TFs) to the regulation of specific genes. ChIP-Seq allows the determination of TF Binding Sites (TFBSs) over whole genomes, but it is still an expensive technique that can only be applied one TF at a time and requires replicates to reduce its noise. Once TFBSs are determined, the assignment of each TF and its binding sites to the regulation of specific genes is not trivial, and it is often performed by carrying out site-specific experiments that are unfeasible to perform in all possible binding sites. Here, we addressed these relevant issues with a two-step methodology using Drosophila melanogaster as a case study. First, our protocol starts by gathering all transcription factor binding sites (TFBSs) determined with ChIP-Seq experiments available at ENCODE and FlyBase. Then each TFBS is used to assign TFs to the regulation of likely target genes based on the TFBS proximity to the transcription start site of all genes. In the final step, to try to select the most likely regulatory TF from those previously assigned to each gene, we employ GENIE3, a random forest-based method, and more than 9,000 RNA-seq experiments from D. melanogaster . Following, we employed known TF protein-protein interactions to estimate the feasibility of regulatory events in our filtered networks. Finally, we show how known interactions between co-regulatory TFs of each gene increase after the second step of our approach, and thus, the consistency of the TF-gene assignment. Also, we employed our methodology to create a network centered on the Drosophila melanogaster gene Hr96 to demonstrate the role of this transcription factor on mitochondrial gene regulation., 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 Cuesta-Astroz, Gischkow Rucatti, Murgas, SanMartín, Sanhueza and Martin.)

Bronopol and Detarox® AP are broad spectrum antimicrobial biocides of growing interest for the aquaculture sector. While their effectiveness against aquatic pathogens has been demonstrated, toxicity data on wild or farmed species are still lacking, as is information on their potential environmental risk for aquatic ecosystems. With this study, we assessed the acute and sublethal toxicity of Bronopol and Detarox® AP in the freshwater bivalve Sinanodonta woodiana and their theoretical risk for aquatic ecosystem. The 96-h median lethal concentration (LC 50 ) was determined using the acute toxicity test, while for the sublethal toxicity test the bivalves were exposed to two concentrations for 14 days of Bronopol (2.5 and 50 mg/L) and Detarox® AP (1.11 and 22.26 mg/L) followed by a 14-day withdrawal period. Biocide-mediated oxidative processes were investigated via a panel of oxidative stress biomarkers (malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase, glutathione S-transferase). Theoretical environmental risk assessment of both biocides, with predicted concentration of no effect (PNEC), expected theoretical concentration (TEC) in the environment, and risk quotient (RQ) was performed. TEC was calculated using a model based on the size of the aquaculture facility and the receiving basin, the estimated quantity of biocide dissolved in water, and published data on biocide stability in water. Although the LC 50 was higher for Bronopol (2440 mg/L) than for Detarox® AP (126 mg/L), fluctuations in oxidative stress biomarkers levels indicated that both biocides exert a slight oxidative pressure on S. woodiana. Theoretical environmental risk assessment suggested a muted risk with Detarox® AP and greater eco-sustainability compared to Bronopol., 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 © 2021 Elsevier B.V. All rights reserved.)

Tributyltin-based (TBT) antifouling paints, widely used for the treatment of flooded surfaces, have been banned in 2008 for their high environmental persistence and bioaccumulation in aquatic organisms. Although it is still present in aquatic ecosystems, oxidative stress driven by TBT has been still poorly investigated in fish. The aim of the study was to examine the time-course stress responses in liver of rainbow trout that received a single intraperitoneal injection of tributyltin chloride (TBTC) or tributyltin ethoxide (TBTE), both at a dose of 0.05 and 0.5 mg/kg. Levels of metallothioneins, total glutathione, malondialdehyde, superoxide dismutase, catalase, glutathione peroxidase and glutathione S-transferase were evaluated at 3 and 6 days post-injection. Tin load was measured in the muscle of the same fish. Differences were observed in the time-course accumulation of tin with a clear dose-response relationship. Although individual oxidative stress biomarkers varied, the biomarker profile indicated different stress mechanisms caused by both TBTC and TBTE. The weak induction of metal-trapping metallothioneins and the changes of oxidative stress biomarkers suggested a stress-pressure in both TBT-treated trout, advising for an ecotoxicological risk for freshwater ecosystems., (© 2021. The Author(s).)

The regulation of gene expression is a key factor in the development and maintenance of life in all organisms. Even so, little is known at whole genome scale for most genes and contexts. We propose a method, Tool for Weighted Epigenomic Networks in Drosophila melanogaster (Fly T-WEoN), to generate context-specific gene regulatory networks starting from a reference network that contains all known gene regulations in the fly. Unlikely regulations are removed by applying a series of knowledge-based filters. Each of these filters is implemented as an independent module that considers a type of experimental evidence, including DNA methylation, chromatin accessibility, histone modifications and gene expression. Fly T-WEoN is based on heuristic rules that reflect current knowledge on gene regulation in D. melanogaster obtained from the literature. Experimental data files can be generated with several standard procedures and used solely when and if available. Fly T-WEoN is available as a Cytoscape application that permits integration with other tools and facilitates downstream network analysis. In this work, we first demonstrate the reliability of our method to then provide a relevant application case of our tool: early development of D. melanogaster . Fly T-WEoN together with its step-by-step guide is available at https://weon.readthedocs.io., (© 2021 The Authors.)

In the last two decades, pancreatic cancer has been undergoing important changes in its perioperative management due to the great interest in multidisciplinary management and preoperative multimodal therapy, which in numerous studies have shown promising clinical results. Although the standard of treatment for resectable pancreatic ductal adenocarcinoma (PDAC) today is surgery followed by adjuvant therapy, as it is a biologically aggressive disease, even with complete resection, it has high rates of local and distant relapse. Several retrospective and prospective phase I/II studies have opened the window for neoadjuvant therapy with chemotherapy (CT), chemoradiotherapy (CRT), or both, as an alternative treatment for resectable pancreatic cancer, with promising results. Neoadjuvant therapy could has some advantages, including early administration of systemic treatment, in vivo assessment of response to treatment, increase resectability rate in borderline patients, increase resection rate with negative margin and survival benefit. While it seems clear that even potentially resectable disease would benefit from preoperative multimodal therapy, the optimal neoadjuvant therapeutic strategy is still controversial and currently there are only recommendations for neoadjuvant treatment, in clinical guidelines such as the NCCN and ESMO, for borderline and/or locally advanced PDAC. This review provides an overview of recent studies available and how they relate to systemic treatment of resectable PDAC in the neoadjuvant setting.

Alteration to endoplasmic reticulum (ER) proteostasis is observed in a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR target genes. In this study, we designed an ATF6f/XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has a stronger effect in reducing the abnormal aggregation of mutant huntingtin and α-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson's disease and Huntington's disease. These results support the concept in which directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions., Competing Interests: Declarations of interest R.L.V. and C.H. protected the use of a gene therapy to deliver UPRplus into the brain to treat Parkinson’s disease and Huntington’s disease. UPRplus is a registered brand in Chile. The patent is licensed to Handl Biotech, Belgium (https://patents.google.com/patent/WO2017075729A1/es)., (Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

Motivation: Cells are complex systems composed of hundreds of genes whose products interact to produce elaborated behaviors. To control such behaviors, cells rely on transcription factors to regulate gene expression, and gene regulatory networks (GRNs) are employed to describe and understand such behavior. However, GRNs are static models, and dynamic models are difficult to obtain due to their size, complexity, stochastic dynamics and interactions with other cell processes., Results: We developed Atlas, a Python software that converts genome graphs and gene regulatory, interaction and metabolic networks into dynamic models. The software employs these biological networks to write rule-based models for the PySB framework. The underlying method is a divide-and-conquer strategy to obtain sub-models and combine them later into an ensemble model. To exemplify the utility of Atlas, we used networks of varying size and complexity of Escherichia coli and evaluated in silico modifications, such as gene knockouts and the insertion of promoters and terminators. Moreover, the methodology could be applied to the dynamic modeling of natural and synthetic networks of any bacteria., Availability and Implementation: Code, models and tutorials are available online (https://github.com/networkbiolab/atlas)., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2020. Published by Oxford University Press.)

Eighty-six samples belonging to five different species (crucian carp, Carassius carassius; European perch, Perca fluviatilis; tench, Tinca tinca; eel, Anguilla anguilla; red swamp crayfish, Procambarus clarkii) collected from Lake Trasimeno (Italy) were analyzed to assess polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecanes (HBCDs) contamination. The Trasimeno is the largest Italian peninsular lake located in Umbria (Central Italy), in a rural area with low anthropogenic impact. All the samples were analyzed by an in-house developed analytical procedure involving a single sample preparation with dual detection: Gas- and Liquid-Chromatography coupled to tandem Mass Spectrometry (GC-MS/MS for PBDEs and LC-MS/MS for HBCDs). BFRs levels in crucian carp, tench and European perch were negligible and mostly below quantification limits (LOQs). In eel, the species with the higher fat content, PBDE sum (15 congeners) ranged from 0.269 to 0.916 ng/g w.w. BDE-47, -100 and -154 accounted for roughly 57%, 16% and 11% of the PBDE sum, respectively, while BDE-99 (usually one of the most abundant congeners in biota), only for 3%. HBCDs (sum of α-, β-, γ-isomers) were found between 0.157 and 1.14 ng/g w.w. with α- as predominant isomer (92% of the sum), followed by γ- (5%) and β- (2%). Peculiar was the contamination in red swamp crayfish characterized by negligible PBDEs and very high HBCDs levels with a singular contamination pattern. In female pools (n = 9) the mean HBCDs sum was 0.150 ng/g w.w., while in males higher concentrations were measured (mean = 2.77 ng/g w.w.). A significant correlation seems to exist between the contamination level and the seasonal cycle only in male crayfish. Interestingly, among the HBCDs, the γ-isomer was the highest (67% of the total) while α- contributes only for 20%., 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 © 2020 Elsevier B.V. All rights reserved.)

Crassostrea gigas is a sentinel species along the Italian coast. In mussels, the levels of oxidative stress biomarkers can be modulated by several environmental pollutants or pathogens and also fluctuate in response to reproductive stages and seasonal changes. In this study, adult Crassostrea gigas were sampled during summer and autumn from two lagoon and two offshore sites along the Adriatic coast of Italy in order to investigate the influence of seasonality on oxidative stress biomarkers. Trace elements load of Al, As, Cd, Cr, Cu, Fe, Mn, Ni, Pb, Se and Zn suggests low contamination for lagoon and offshore sites. Levels of total glutathione, superoxide dismutase, catalase, glutathione peroxidases, glutathione reductase and glutathione S-transferase were analyzed in digestive gland and gills of the Pacific oysters in June, July, September and October. OsHV-1 and Vibrio aestuarianus were detected in lagoon sites, but both pathogens did not affect the biomarkers levels in both tissues. Although several biological responses were found different among the four sites in the same month, principal component analysis revealed similar trend in biomarkers levels between sites during the whole sampling period. On the other hand, a different biochemical pattern through the months emerged, suggesting that the level of oxidative stress biomarkers in both tissues may be related to seasonal progress and biological cycle of oysters sampled from the two lagoons and offshore sites along the Italian coasts of the Mediterranean Sea., 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 © 2020 Elsevier B.V. All rights reserved.)

High-mountain lakes are pristine ecosystems characterized by extreme environmental conditions. The atmospheric transport of pollutants from lowlands may add further stress to organisms inhabiting these environments. We investigated the environmental stress pressure on brook trout (Salvelinus fontinalis) from a high-mountain lake in the Cottian Alps (Piedmont, northwest Italy). To do this, males and females of brook trout were sampled from Balma Lake in summer (August) and autumn (October) 2017 in order to assess the influence of trace elements accumulation and environmental parameters (physicochemical parameters and nutrient characteristics of water) on oxidative stress biomarkers. Bioaccumulation of Al, As, Cd, Cr, Cu, Fe, Hg, Pb, Ni, Se, and Zn and metallothionein levels were measured in muscle tissue of males and females. Liver, gills, kidney, and spleen tissue samples were analyzed for superoxide dismutase, catalase, total glutathione peroxidase, selenium-dependent glutathione peroxidase, glutathione reductase, and glutathione S-transferase activity. Analysis of environmental parameters showed changes in biomarker levels with seasonal variations. Water temperature was significantly higher in summer than autumn (Wilcoxon test; p = .0078), while pH was significantly higher in autumn than in summer (Wilcoxon test; p = .0078). Sex-related differences in oxidative stress biomarkers in tissues were unremarkable, whereas seasonal variability of oxidative stress biomarkers was observed, with major differences occurred for liver in summer and for gills, kidney, spleen and muscle in autumn. Positive correlations between environmental parameters and biomarkers were noted. Major fluctuations in water temperature, pH, Cu, Pb and Hg produced changes in biomarker levels; however, increased food intake during the ice-free season was probably the main factor that influenced changes in oxidative stress biomarker levels in brook trout in this extreme ecosystem., 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 © 2020 Elsevier B.V. All rights reserved.)

The trial investigates if a highly defatted Hermetia illucens larva meal (H) at two dietary inclusion levels and a vegetable protein based diet (VEG) influences the normal gut and liver histology and the oxidative stress biomarkers in liver and kidney of Siberian sturgeon juveniles. Fish were fed four diets: one control diet (H0) containing 70% of fishmeal (FM), two diets including 18.5% (H185) and 37.5% (H375) of highly defatted H in substitution for 25% and 50% of FM, and one vegetable protein based diet (VEG). At the end of a growth trial, 12 fish per treatment were sacrificed by over-anaesthesia to collect 12 liver and 5 distal intestine samples for histological analyses, as well as 12 liver and kidney samples for biochemical analyses. The H and VEG diets did not significantly affect the histology of liver and distal intestine, but alterations of the oxidative stress biomarkers were detected at the highest inclusion level of H (37.5%). In order to avoid unfavorable effects on the fish health, an inclusion level up to 18.5% of H is recommended for Siberian sturgeon juveniles., Competing Interests: The authors declare no conflict of interest.

Mathematical models based on Ordinary Differential Equations (ODEs) are frequently used to describe and simulate biological systems. Nevertheless, such models are often difficult to understand. Unlike ODE models, Rule-Based Models (RBMs) utilise formal language to describe reactions as a cumulative number of statements that are easier to understand and correct. They are also gaining popularity because of their conciseness and simulation flexibility. However, RBMs generally lack tools to perform further analysis that requires simulation. This situation arises because exact and approximate simulations are computationally intensive. Translating RBMs into ODEs is commonly used to reduce simulation time, but this technique may be prohibitive due to combinatorial explosion. Here, we present the software called Pleione to calibrate RBMs. Parameter calibration is essential given the incomplete experimental determination of reaction rates and the goal of using models to reproduce experimental data. The software distributes stochastic simulations and calculations and incorporates equivalence tests to determine the fitness of RBMs compared with data. The primary features of Pleione were thoroughly tested on a model of gene regulation in Escherichia coli. Pleione yielded satisfactory results regarding calculation time and error reduction for multiple simulators, models, parameter search strategies, and computing infrastructures.

Background and Objectives: Post-traumatic stress disorder (PTSD) is a common psychiatric disorder resulting from a traumatic event, is manifested through hyperarousal, anxiety, depressive symptoms, and sleep disturbances. Despite several therapeutic approaches being available, both pharmacological and psychological, recently a growing interest has developed in using cannabis and synthetic cannabinoids stems from their consideration as more efficient and better tolerated alternatives for the treatment of this condition. The present paper aims to evaluate the clinical and therapeutic potentials of medical cannabis and synthetic cannabinoids in treating PTSD patients., Methods: A systematic electronic search was performed, including all papers published up to May 2019, using the following keywords (((cannabis[Title/Abstract]) OR (synthetic cannabinoids [Title/Abstract])) AND ((PTSD[Title/Abstract]) OR (Posttraumatic stress disorder[Title/Abstract]))) for the topics 'Cannabis', 'Synthetic Cannabinoids', 'PTSD', and MESH terms, on the PubMed, Cochrane Library, and Web of Science online databases. For data gathering purposes, PRISMA guidelines were followed. Results were organized into two groups, considering cannabis and synthetic cannabinoids as different therapeutic approaches for PTSD., Results: Present data show that cannabis and synthetic cannabinoids, both acting on the endocannabinoids system, may have a potential therapeutic use for improving PTSD symptoms, e.g., reducing anxiety, modulating memory-related processes, and improving sleep., Conclusions: Even though the current literature suggests that cannabis and synthetic cannabinoids may have a role in the treatment of PTSD, there is currently limited evidence regarding their safety and efficacy. Therefore, additional research is needed in order to better understand the effectiveness and therapeutic usage of these drug classes and monitor their safety., 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.

Farmed trout are commonly fed carotenoid-enriched diets during the finishing period to acquire typical red-to-pink flesh color in salmonid muscle. The aim of this study was to examine the effects of two xanthophylls, astaxanthin (Ax) or canthaxanthin (Cx), administered individually or in combination, on oxidative stress biomarkers in kidney and liver of rainbow trout. Specimens were fed Ax (75 mg/kg) or Cx (25 mg/kg) individually or in combination in the diets for 8 weeks. Changes in concentration of oxidative stress biomarkers, including total glutathione, superoxide dismutase, glutathione peroxidase, glutathione reductase, and glutathione S -transferase, were recorded in Ax- and Cx-dosed trout. These two carotenoids, predominantly Cx, initiated enzymatic responses in rainbow trout. It is noteworthy that lipid peroxidation processes were not apparent in all Ax or Cx-dosed trout. Further, both combined xanthophylls did not exert significant synergistic effects in liver and kidney. Biomarker responses were generally altered in both tissues through the 4 and 8 weeks suggesting that different time-dependent mechanisms led to enhanced antioxidant defense in Ax and/or Cx-fed trout. Data demonstrated that these two xanthophylls did not exert detrimental effects on rainbow trout.

Protein structure is not static; residues undergo conformational rearrangements and, in doing so, create, stabilize or break non-covalent interactions. Molecular dynamics (MD) is a technique used to simulate these movements with atomic resolution. However, given the data-intensive nature of the technique, gathering relevant information from MD simulations is a complex and time consuming process requiring several computational tools to perform these analyses. Among different approaches, the study of residue interaction networks (RINs) has proven to facilitate the study of protein structures. In a RIN, nodes represent amino-acid residues and the connections between them depict non-covalent interactions. Here, we describe residue interaction networks in protein molecular dynamics (RIP-MD), a visual molecular dynamics (VMD) plugin to facilitate the study of RINs using trajectories obtained from MD simulations of proteins. Our software generates RINs from MD trajectory files. The non-covalent interactions defined by RIP-MD include H-bonds, salt bridges, VdWs, cation-π, π-π, Arginine-Arginine, and Coulomb interactions. In addition, RIP-MD also computes interactions based on distances between C α s and disulfide bridges. The results of the analysis are shown in an user friendly interface. Moreover, the user can take advantage of the VMD visualization capacities, whereby through some effortless steps, it is possible to select and visualize interactions described for a single, several or all residues in a MD trajectory. Network and descriptive table files are also generated, allowing their further study in other specialized platforms. Our method was written in python in a parallelized fashion. This characteristic allows the analysis of large systems impossible to handle otherwise. RIP-MD is available at http://www.dlab.cl/ripmd., Competing Interests: Tomas Perez-Acle is an Academic Editor for PeerJ.

Background: The high-density lipoprotein receptor SR-B1 mediates cellular uptake of several lipid species, including cholesterol and vitamin E. During early mouse development, SR-B1 is located in the maternal-fetal interface, where it facilitates vitamin E transport towards the embryo. Consequently, mouse embryos lacking SR-B1 are vitamin E-deficient, and around half of them fail to close the neural tube and show cephalic neural tube defects (NTD). Here, we used transcriptomic profiling to identify the molecular determinants of this phenotypic difference between SR-B1 deficient embryos with normal morphology or with NTD., Results: We used RNA-Seq to compare the transcriptomic profile of three groups of embryos retrieved from SR-B1 heterozygous intercrosses: wild-type E9.5 embryos (WT), embryos lacking SR-B1 that are morphologically normal, without NTD (KO-N) and SR-B1 deficient embryos with this defect (KO-NTD). We identified over 1000 differentially expressed genes: down-regulated genes in KO-NTD embryos were enriched for functions associated to neural development, while up-regulated genes in KO-NTD embryos were enriched for functions related to lipid metabolism. Feeding pregnant dams a vitamin E-enriched diet, which prevents NTD in SR-B1 KO embryos, resulted in mRNA levels for those differentially expressed genes that were more similar to KO-N than to KO-NTD embryos. We used gene regulatory network analysis to identify putative transcriptional regulators driving the different embryonic expression profiles, and identified a regulatory circuit controlled by the androgen receptor that may contribute to this dichotomous expression profile in SR-B1 embryos. Supporting this possibility, the expression level of the androgen receptor correlated strongly with the expression of several genes involved in neural development and lipid metabolism., Conclusions: Our analysis shows that normal and defective embryos lacking SR-B1 have divergent expression profiles, explained by a defined set of transcription factors that may explain their divergent phenotype. We propose that distinct expression profiles may be relevant during early development to support embryonic nutrition and neural tube closure.

Computational simulation is a widely employed methodology to study the dynamic behavior of complex systems. Although common approaches are based either on ordinary differential equations or stochastic differential equations, these techniques make several assumptions which, when it comes to biological processes, could often lead to unrealistic models. Among others, model approaches based on differential equations entangle kinetics and causality, failing when complexity increases, separating knowledge from models, and assuming that the average behavior of the population encompasses any individual deviation. To overcome these limitations, simulations based on the Stochastic Simulation Algorithm (SSA) appear as a suitable approach to model complex biological systems. In this work, we review three different models executed in PISKaS: a rule-based framework to produce multiscale stochastic simulations of complex systems. These models span multiple time and spatial scales ranging from gene regulation up to Game Theory. In the first example, we describe a model of the core regulatory network of gene expression in Escherichia coli highlighting the continuous model improvement capacities of PISKaS. The second example describes a hypothetical outbreak of the Ebola virus occurring in a compartmentalized environment resembling cities and highways. Finally, in the last example, we illustrate a stochastic model for the prisoner's dilemma; a common approach from social sciences describing complex interactions involving trust within human populations. As whole, these models demonstrate the capabilities of PISKaS providing fertile scenarios where to explore the dynamics of complex systems., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Complex systems are governed by dynamic processes whose underlying causal rules are difficult to unravel. However, chemical reactions, molecular interactions, and many other complex systems can be usually represented as concentrations or quantities that vary over time, which provides a framework to study these dynamic relationships. An increasing number of tools use these quantifications to simulate dynamically complex systems to better understand their underlying processes. The application of such methods covers several research areas from biology and chemistry to ecology and even social sciences.In the following chapter, we introduce the concept of rule-based simulations based on the Stochastic Simulation Algorithm (SSA) as well as other mathematical methods such as Ordinary Differential Equations (ODE) models to describe agent-based systems. Besides, we describe the mathematical framework behind Kappa (κ), a rule-based language for the modeling of complex systems, and some extensions for spaßtial models implemented in PISKaS (Parallel Implementation of a Spatial Kappa Simulator). To facilitate the understanding of these methods, we include examples of how these models can be used to describe population dynamics in a simple predator-prey ecosystem or to simulate circadian rhythm changes.

Arsenic (As) is a global contaminant of terrestrial and aquatic environments posing concern for environmental and human health. The effects of subacute concentrations of arsenic trioxide (As III ) and dimethylarsinic acid (DMA V ) were examined using Crandell Rees feline kidney (CRFK), human hepatocellular carcinoma (PLC/PRF/5), and epithelioma papulosum cyprini (EPC). Whole monolayer with suffering cells (confluence 100%, pyknosis and refractive cells; value scale = 2) led to identification of subacute As concentrations for the three cell lines. The selected As III concentrations were 1.33 µM for CRFK and 33.37 µM for PLC/PRF/5 and EPC, at 48 hr time point. The selected DMA V concentrations were 0.67 mM for PLC/PRF/5, 1.33 mM for CRFK, and 2.67 mM for EPC for 48 hr. Unlike the As III test, the three cell lines did not exhibit marked susceptibility to DMA V -mediated toxicity. Several oxidative stress biomarker levels, directly or indirectly associated with reactive oxygen species (ROS) elimination including superoxide dismutase, catalase, glutathione peroxidases, glutathione reductase, glutathione S-transferase, glyoxalase I, glyoxalase II, and total glutathione, were determined in the three cell lines at 24 and 48 hr. Antioxidant responses in metal-treated cells were significantly altered compared to controls, suggesting a perturbation of redox state. The weakening of antioxidant pathway in either healthy or tumoral cells was greater using As III than DMA V . Differences in level of several oxidative stress biomarkers suggest that the oxidative stress mechanism induced by As III is distinctly different from DMA V . Multifaceted mechanisms of action underlying ROS generation in tumor and nontumor cells versus As III and DMA V exposure are thus involved. Since As-mediated toxicity is quite complex, more data regarding both oxidant-enhancement and oxidant-lowering strategies may be useful to improve knowledge regarding the influence of As on human and animal cells.

Deltamethrin is a pyrethroid insecticide that is considered extremely toxic to aquatic organisms. We evaluated the effect of subacute doses (0.033, 0.1, or 0.3 mg/kg) of deltamethrin on micronucleus frequency and oxidative stress markers in Rainbow Trout Oncorhynchus mykiss at 1, 2, 3, 4, and 8 d after intracoelomic injection. No genotoxic damage was recorded, as no specimen showed a micronucleus number above the physiological range. Deltamethrin exposure elicited a transient reduction in the levels of superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferase and a persistent decrease in glutathione reductase activity. Overall, the lower antioxidant enzyme activity in the deltamethrin-treated fish was mainly dose-dependent. Received May 27, 2016 accepted June 18, 2017.

Abandoned tailing dumps (ATDs) offer an opportunity to identify the main physicochemical filters that determine colonization of vegetation in solid mine wastes. The current study determined the soil physicochemical factors that explain the compositional variation of pioneer vegetal species on ATDs from surrounding areas in semiarid Mediterranean-climate type ecosystems of north-central Chile (Coquimbo Region). Geobotanical surveys-including physicochemical parameters of substrates (0-20 cm depth), plant richness, and coverage of plant species-were performed on 73 ATDs and surrounding areas. A total of 112 plant species were identified from which endemic/native species (67%) were more abundant than exotic species (33%) on ATDs. The distribution of sampling sites and plant species in canonical correspondence analysis (CCA) ordination diagrams indicated a gradual and progressive variation in species composition and abundance from surrounding areas to ATDs because of variations in total Cu concentration (1.3%) and the percentage of soil particles <2 μm (1.8%). According to the CCA, there were 10 plant species with greater abundance on sites with high total Cu concentrations and fine-textured substrates, which could be useful for developing plant-based stabilization programs of ATDs in semiarid Mediterranean-climate type ecosystems of north-central Chile.

Effects of selenium diets (Se, 0.3 and 1.2mgkg(-1)) on juvenile red swamp crayfish Procambarus clarkii were observed for eight weeks. Growth, condition factors and Se levels in exoskeleton and hepatopancreas for both sexes and diets were evaluated at three endpoints. The specific growth rate (SGR) showed a faster, but not statistically significant growth in Se exposed specimens. Se levels were higher in exoskeleton and hepatopancreas of both Se exposed males and females, when compared to controls. The abdomen-total weight relationship (Tw/B) showed no significant differences between Se exposed and control groups. A constant decline of HI values was recorded in both Se exposed sexes and the same trend was observed in control males. Se exposed females evidenced lower HI after 4 and 8 weeks when compared to controls. Therefore, evident reductions of the health indicator values HI suggested that selenium can deplete the hepatopancreas energy reserves, mainly in juvenile male crayfish., (Copyright © 2013 Elsevier B.V. All rights reserved.)