Functional response of microbial communities in lab-controlled oil-contaminated marine sediment.

Crude oil contamination is one of the biggest problems in modern society. As oil enters into contact with the environment, especially if the point of contact is a body of water, it begins a weathering process by mixing and spreading. This is dangerous to local living organisms' communities and can impact diversity. However, despite unfavorable conditions, some microorganisms in these environments can survive using hydrocarbons as a nutrient source. Thus, understanding the local community dynamics of contaminated areas is essential. In this work, we analyzed the 16S rRNA amplicon sequencing and metatranscriptomic data of uncontaminated versus contaminated shallow marine sediment from publicly available datasets. We investigated the local population's taxonomic composition, species diversity, and fluctuations over time. Co-expression analysis coupled with functional enrichment showed us a prevalence of hydrocarbon-degrading functionality while keeping a distinct transcriptional profile between the late stages of oil contamination and the uncontaminated control. Processes related to the degradation of aromatic compounds and the metabolism of propanoate and butanoate were coupled with evidence of enhanced activity such as flagellar assembly and two-component system. Many enzymes of the anaerobic toluene degradation pathways were also enriched in our results. Furthermore, our diversity and taxonomical analyses showed a prevalence of the class Desulfobacteria, indicating interesting targets for bioremediation applications on marine sediment.

Potential role of exitron-containing homeobox genes in cancer.

Homeobox genes are protagonists in developmental and cancer biology, making comprehending their regulation pivotal in multiple molecular pathways. Exitrons, also known as intronic exons, are new players in the transcriptional organization, providing additional splicing variants whose functions are still vastly unknown. Exitron splicing sites were identified in eight homeobox genes, which has not been yet debated in the scientific literature. Due to the intimate connection between homeobox genes and tumorigenesis, it is worth investing more time in understanding how these less explored exitron-containing transcriptional isoforms could play a role in modulating the homeobox gene's biological functions. The perspectives devised in this article are meant to instigate fresh debates on how the transcriptional variants retaining exitrons identified in the human homeobox genes HOXA1, HOXA9, HOXD8, NKX3.1, and DLX6 can be examined in the context of tumorigenesis. This article is categorized under: Cancer > Genetics/Genomics/Epigenetics.

Transcriptomic Analysis of Long Non-Coding RNA during Candida albicans Infection.

Candida albicans is one of the most commonly found species in fungal infections. Due to its clinical importance, molecular aspects of the host immune defense against the fungus are of interest to biomedical sciences. Long non-coding RNAs (lncRNAs) have been investigated in different pathologies and gained widespread attention regarding their role as gene regulators. However, the biological processes in which most lncRNAs perform their function are still unclear. This study investigates the association between lncRNAs with host response to C. albicans using a public RNA-Seq dataset from lung samples of female C57BL/6J wild-type Mus musculus with induced C. albicans infection. The animals were exposed to the fungus for 24 h before sample collection. We selected lncRNAs and protein-coding genes related to the host immune response by combining the results from different computational approaches used for gene selection: differential expression gene analysis, co-expression genes network analysis, and machine learning-based gene selection. Using a guilt by association strategy, we inferred connections between 41 lncRNAs and 25 biological processes. Our results indicated that nine up-regulated lncRNAs were associated with biological processes derived from the response to wounding: 1200007C13Rik, 4833418N02Rik, Gm12840, Gm15832, Gm20186, Gm38037, Gm45774, Gm4610, Mir22hg, and Mirt1. Additionally, 29 lncRNAs were related to genes involved in immune response, while 22 lncRNAs were associated with processes related to reactive species production. These results support the participation of lncRNAs during C. albicans infection, and may contribute to new studies investigating lncRNA functions in the immune response.

Cystic Fibrosis: Systems Biology Analysis from Homozygous p.Phe508del Variant Patients' Samples Reveals Perturbations in Tissue-Specific Pathways.

Cystic fibrosis (CF) is an autosomal recessive disorder, caused by diverse genetic variants for the CF transmembrane conductance regulator (CFTR) protein. Among these, p.Phe508del is the most prevalent variant. The effects of this variant on the physiology of each tissue remains unknown. This study is aimed at predicting cell signaling pathways present in different tissues of fibrocystic patients, homozygous for p.Phe508del. The study involved analysis of two microarray datasets, E-GEOD-15568 and E-MTAB-360 corresponding to the rectal and bronchial epithelium, respectively, obtained from the ArrayExpress repository. Particularly, differentially expressed genes (DEGs) were predicted, protein-protein interaction (PPI) networks were designed, and centrality and functional interaction networks were analyzed. The study reported that p.Phe508del-mutated CFTR-allele in homozygous state influenced the whole gene expression in each tissue differently. Interestingly, gene ontology (GO) term enrichment analysis revealed that only "neutrophil activation" was shared between both tissues; however, nonshared DEGs were grouped into the same GO term. For further verification, functional interaction networks were generated, wherein no shared nodes were reported between these tissues. These results suggested that the p.Phe508del-mutated CFTR-allele in homozygous state promoted tissue-specific pathways in fibrocystic patients. The generated data might further assist in prediction diagnosis to define biomarkers or devising therapeutic strategies.

Influence of transcriptional variants on metastasis.

Cancer metastasis is defined as the dissemination of malignant cells from the primary tumor site, leading to colonization of distant organs and the establishment of a secondary tumor. Metastasis is frequently associated with chemoresistance and is the major cause of cancer-related mortality. Metastatic cells need to acquire the ability to resist to stresses provided by different environments, such as reactive oxygen species, shear stress, hemodynamic forces, stromal composition, and immune responses, to colonize other tissues. Hence, only a small population of cells has a metastasis-initiating potential. Several studies have revealed the misregulation of transcriptional variants during cancer progression, and many splice events can be used to distinguish between normal and tumoral tissue. These variants, which are abnormally expressed in malignant cells, contribute to an adaptive response of tumor cells and the success of the metastatic cascade, promoting an anomalous cell cycle, cellular adhesion, resistance to death, cell survival, migration and invasion. Understanding the different aspects of splicing regulation and the influence of transcriptional variants that control metastatic cells is critical for the development of therapeutic strategies. In this review, we describe how transcriptional variants contribute to metastatic competence and discuss how targeting specific isoforms may be a promising therapeutic strategy.

A network flow approach to predict protein targets and flavonoid backbones to treat respiratory syncytial virus infection.

BACKGROUND: Respiratory syncytial virus (RSV) infection is the major cause of respiratory disease in lower respiratory tract in infants and young children. Attempts to develop effective vaccines or pharmacological treatments to inhibit RSV infection without undesired effects on human health have been unsuccessful. However, RSV infection has been reported to be affected by flavonoids. The mechanisms underlying viral inhibition induced by these compounds are largely unknown, making the development of new drugs difficult. METHODS: To understand the mechanisms induced by flavonoids to inhibit RSV infection, a systems pharmacology-based study was performed using microarray data from primary culture of human bronchial cells infected by RSV, together with compound-proteomic interaction data available for Homo sapiens. RESULTS: After an initial evaluation of 26 flavonoids, 5 compounds (resveratrol, quercetin, myricetin, apigenin, and tricetin) were identified through topological analysis of a major chemical-protein (CP) and protein-protein interacting (PPI) network. In a nonclustered form, these flavonoids regulate directly the activity of two protein bottlenecks involved in inflammation and apoptosis. CONCLUSIONS: Our findings may potentially help uncovering mechanisms of action of early RSV infection and provide chemical backbones and their protein targets in the difficult quest to develop new effective drugs.

Systems Chemo-Biology and Transcriptomic Meta-Analysis Reveal the Molecular Roles of Bioactive Lipids in Cardiomyocyte Differentiation.

Lipids, which are essential constituents of biological membranes, play structural and functional roles in the cell. In recent years, certain lipids have been identified as regulatory signaling molecules and have been termed "bioactive lipids". Subsequently, the importance of bioactive lipids in stem cell differentiation and cardiogenesis has gained increasing recognition. Therefore, the aim of this study was to identify the biological processes underlying murine cardiac differentiation and the mechanisms by which bioactive lipids affect these processes. For this purpose, a transcriptomic meta-analysis of microarray and RNA-seq data from murine stem cells undergoing cardiogenic differentiation was performed. The differentially expressed genes identified via this meta-analysis, as well as bioactive lipids, were evaluated using systems chemo-biology tools. These data indicated that bioactive lipids are associated with the regulation of cell motility, cell adhesion, cytoskeletal rearrangement, and gene expression. Moreover, bioactive lipids integrate the signaling pathways involved in cell migration, the secretion and remodeling of extracellular matrix components, and the establishment of the cardiac phenotype. In conclusion, this study provides new insights into the contribution of bioactive lipids to the induction of cellular responses to various stimuli, which may originate from the extracellular environment and morphogens, and the manner in which this contribution directly affects murine heart morphogenesis.

Development and aging: two opposite but complementary phenomena.

Aging is a consequence of an organism's evolution, where specific traits that lead to the organism's development eventually promote aged phenotypes or could lead to age-related diseases. In this sense, one theory that broadly explored development and its association to aging is the developmental aging theory (DevAge), which also encompasses most known age-associated theories. Thus, we employed different systems biology tools to prospect developmental and aging-associated networks for human and murine models for evolutionary comparison. The gathered data suggest a model where proteins related to inflammation, development, epigenetic mechanisms and oxygen homeostasis coordinate the interplay between development and aging. Moreover, the mechanism also appears to be evolutionary conserved in both mammalian models, further corroborating the DevAge molecular model.

Fetal alcohol syndrome, chemo-biology and OMICS: ethanol effects on vitamin metabolism during neurodevelopment as measured by systems biology analysis.

Fetal alcohol syndrome (FAS) is a prenatal disease characterized by fetal morphological and neurological abnormalities originating from exposure to alcohol. Although FAS is a well-described pathology, the molecular mechanisms underlying its progression are virtually unknown. Moreover, alcohol abuse can affect vitamin metabolism and absorption, although how alcohol impairs such biochemical pathways remains to be elucidated. We employed a variety of systems chemo-biology tools to understand the interplay between ethanol metabolism and vitamins during mouse neurodevelopment. For this purpose, we designed interactomes and employed transcriptomic data analysis approaches to study the neural tissue of Mus musculus exposed to ethanol prenatally and postnatally, simulating conditions that could lead to FAS development at different life stages. Our results showed that FAS can promote early changes in neurotransmitter release and glutamate equilibrium, as well as an abnormal calcium influx that can lead to neuroinflammation and impaired neurodifferentiation, both extensively connected with vitamin action and metabolism. Genes related to retinoic acid, niacin, vitamin D, and folate metabolism were underexpressed during neurodevelopment and appear to contribute to neuroinflammation progression and impaired synapsis. Our results also indicate that genes coding for tubulin, tubulin-associated proteins, synapse plasticity proteins, and proteins related to neurodifferentiation are extensively affected by ethanol exposure. Finally, we developed a molecular model of how ethanol can affect vitamin metabolism and impair neurodevelopment.

The importance of sphingolipids and reactive oxygen species in cardiovascular development.

The heart is the first organ in the embryo to form. Its structural and functional complexity is the result of a thorough developmental program, where sphingolipids play an important role in cardiogenesis, heart maturation, angiogenesis, the regulation of vascular tone and vessel permeability. Sphingolipids are necessary for signal transduction and membrane microdomain formation. In addition, recent evidence suggests that sphingolipid metabolism is directly interconnected to the modulation of oxidative stress. However, cardiovascular development is highly sensitive to excessive reactive species production, and disturbances in sphingolipid metabolism can lead to abnormal development and cardiac disease. Therefore, in this review, we address the molecular link between sphingolipids and oxidative stress, connecting these pathways to cardiovascular development and cardiovascular disease.

Toxicological effects of the different substances in tobacco smoke on human embryonic development by a systems chemo-biology approach.

The physiological and molecular effects of tobacco smoke in adult humans and the development of cancer have been well described. In contrast, how tobacco smoke affects embryonic development remains poorly understood. Morphological studies of the fetuses of smoking pregnant women have shown various physical deformities induced by constant fetal exposure to tobacco components, especially nicotine. In addition, nicotine exposure decreases fetal body weight and bone/cartilage growth in addition to decreasing cranial diameter and tibia length. Unfortunately, the molecular pathways leading to these morphological anomalies are not completely understood. In this study, we applied interactome data mining tools and small compound interaction networks to elucidate possible molecular pathways associated with the effects of tobacco smoke components during embryonic development in pregnant female smokers. Our analysis showed a relationship between nicotine and 50 additional harmful substances involved in a variety of biological process that can cause abnormal proliferation, impaired cell differentiation, and increased oxidative stress. We also describe how nicotine can negatively affect retinoic acid signaling and cell differentiation through inhibition of retinoic acid receptors. In addition, nicotine causes a stress reaction and/or a pro-inflammatory response that inhibits the agonistic action of retinoic acid. Moreover, we show that the effect of cigarette smoke on the developing fetus could represent systemic and aggressive impacts in the short term, causing malformations during certain stages of development. Our work provides the first approach describing how different tobacco constituents affect a broad range of biological process in human embryonic development.

Melatonin as a central molecule connecting neural development and calcium signaling.

Melatonin (MEL) is a neuroendocrine hormone secreted by the pineal gland in association with the suprachiasmatic nucleus and peripheral tissues. MEL has been observed to play a critical role in the reproductive process and in the fetomaternal interface. Extrapineal synthesis has been reported in mammalian models during pregnancy, especially by the placenta tissue. MEL can regulate intracellular processes (e.g., G-proteins) and the activity of second messengers (e.g., cAMP, IP(3,) Ca(2+)). During neurodevelopment, these activities regulated by melatonin have an important role as an intracellular signaling for gene expression regulation. To review the role of MEL in neurodevelopment, we built interactome networks of different proteins that act in these processes using systems biology tools. The analyses of interactome networks revealed that MEL could modulate neurodevelopment through the regulation of Ca(2+) intracellular levels and influencing BMP/SMAD signaling, thus affecting neural gene responses and neuronal differentiation.

The developmental aging and origins of health and disease hypotheses explained by different protein networks.

One theory that attempts to explain how and why an organism ages is the developmental hypothesis of aging (DevAge), which describes how developmental programming leads to aging in adults. Interestingly, the developmental origins of health and disease hypothesis (DOHaD) asserts that some aging-associated diseases that occur in adults are closely related to development and to conditions in the intrauterine environment. Thus, both aging and aging-associated diseases can be viewed, at least in part, as the result of a developmental program that is activated early in embryogenesis and persists throughout the lifespan of the organism. We would expect this developmental program to be regulated by a set of interacting protein networks that connect environmental and molecular signals. However, the connection between aging and development is not clear. Thus, a systems biology approach that incorporates different "omic" databases for two mammalian models, Homo sapiens and Mus musculus, was used to evaluate how development and aging are interconnected. Interestingly, three major, evolutionarily conserved processes, namely the immune system, epigenetics, and aerobic metabolism, appear to regulate aging and development in both H. sapiens and M. musculus. Considering that these three processes are essential to embryogenesis, the protein networks within these processes are subjected to strong selective pressure to eliminate gross developmental abnormalities in early embryogenesis. This selective pressure becomes more relaxed in the adult organism, permitting the onset of aging-associated diseases and inflammation-related aging; this concept echoes the antagonistic pleiotropy hypothesis of aging.