Despite heated debates over the safety of genetically modified (GM) food, GM crops have been expanding rapidly. Much research has focused on the expansion of GM crops. However, the spatiotemporal dynamics of non-genetically modified (non-GM) crops are not clear, although they may have significant environmental and agronomic impacts and important policy implications. To understand the dynamics of non-GM crops and to inform the debates among relevant stakeholders, we conducted spatiotemporal analyses of China’s major non-GM soybean production region, the Heilongjiang Province. Even though the total soybean planting area decreased from 2005 to 2010, surprisingly, there were hotspots of increase. The results also showed hotspots of loss as well as a large decline in the number and continuity of soybean plots. Since China is the largest non-GM soybean producer in the world, the decline of its major production region may signal the continual decline of global non-GM soybeans. Genetically modified (GM) crops continue to expand rapidly around the world, which has resulted in heated debates on a range of relevant issues such as health hazard and food safety1An excellent example is soybeans, which are an important crop for vegetable oil and protein, and one of the most important commodities in the global trade of food. Soybeans were originally domesticated in China approximately 3,100 years ago48Apparently, as the top two soybean producers in the world, the United States and Brazil are closely associated with China, their largest customer. In response to the increased domestic demand for soybean oil and soybean meal induced by a large population and economic growth, China further increased its soybean import. Chinese soybean imports exceeded exports in 1995 and have been growing since. The imports reached 55 million tons in 2010, accounting for 56% of the world’s total soybean exports85112, Heilongjiang  is a main agricultural production province, where soybeans, corn, and rice are three major crops. As the lead soybean-growing region, its production accounted for approximately one-quarter to one-third of the nation’s annual soybean production over the past decade914Throughout China, soybean lands are generally small and fragmented, and difficult to inventory either by fieldwork or remote sensing techniques. The exception is the traditional leading soybean production region – Heilongjiang Province in northeast China . CoverinInformation on the spatiotemporal dynamics of soybean production has important scientific value and far-reaching policy implications. For instance, because soybeans fix nitrogen and other crops cannot, the conversion from soybeans to other crops such as corn requires the application (and often overuse) of much more fertilizer. Thus, the conversion causes more severe environmental problems Because more than 80% of China’s soybean consumption now depends on soybean imports, spatiotemporal dynamics of soybean production in China can lead to changes in land cover and land use in soybean-exporting countries such as Brazil17To address the urgent need for understanding the spatiotemporal dynamics of non-GM soybeans in China, we used the major cropland data layers of 2005 and 2010 interpreted from satellite data to map the changes in soybean planting areas in Heilongjiang. We also measured the spatial patterns of the changes at multiple spatial scales.The dynamics of soybean planting areas are complex . AlthougThe profiles in In Unlike other land cover types such as forest, the dynamics of agricultural land are relatively fast and complex. In Heilongjiang, soybean loss was extensive, primarily due to the changes in land cover and land use. Specifically, the changes include the conversion from soybeans to corn, rice , or othe1524Many studies have designated a change in continuity as an important early warning signal of a critical transition in landscapes262728Because imported GM soybeans are less expensive, many farmers in China have already abandoned the cultivation of non-GM soybeans on their plots and, therefore, displaced domestic soybean production to the soybean-exporting countries of the world221731Results from this study confirm the important scientific value and policy implications of the information of the spatiotemporal patterns of non-GM soybean production, as highlighted in the Introduction. These results are important for a variety of policy makers, farmers, and other stakeholders across the world. Information about the spatiotemporal patterns of non-GM soybean production derived from this work could help government agencies  to target and manage areas converted from soybeans to corn. It can also encourage the development of new corn varieties with a short growing season, which helps increase the ability to cope with extreme weather events after soybean lands are converted to corn fields. At the same time, our work provides information for cultivation plans in soybean-exporting countries like Brazil. For example, the significant decline in Jiamusi prefecture 17353637Crop-specific analyses in China rely heavily on statistics data published in yearbooks, but the yearbooks do not display the detailed spatial distributions of crops. Cropland data interpreted from satellite data are needed to understand changes in crop cover over space. A comprehensive land-cover analysis needs to examine the spatial patterns of changed extents39The major cropland data layers of 2005 and 2010, including the locations of soybeans, corn, and rice in Heilongjiang, were created by the Chinese Academy of Agricultural Sciences 14. The dTo spatially map the changes in soybean planting area in Heilongjiang, a change detection analysis was first used to map soybean gain and loss at the pixel level between 2005 and 2010 42. Next,44How to cite this article: Sun, J. et al. Spatiotemporal patterns of non-genetically modified crops in the era of expansion of genetically modified food. Sci. Rep.5, 14180; doi: 10.1038/srep14180 (2015).


This review highlights the fundamental role of nutrition in the maintenance of health, the immune response, and disease prevention. Emerging global mechanistic insights in the field of nutritional immunology cannot be gained through reductionist methods alone or by analyzing a single nutrient at a time. We propose to investigate nutritional immunology as a massively interacting system of interconnected multistage and multiscale networks that encompass hidden mechanisms by which nutrition, microbiome, metabolism, genetic predisposition, and the immune system interact to delineate health and disease. The review sets an unconventional path to apply complex science methodologies to nutritional immunology research, discovery, and development through “use cases” centered around the impact of nutrition on the gut microbiome and immune responses. Our systems nutritional immunology analyses, which include modeling and informatics methodologies in combination with pre-clinical and clinical studies, have the potential to discover emerging systems-wide properties at the interface of the immune system, nutrition, microbiome, and metabolism. The knowledge that food affects health was first mentioned in the writings of ancient Egyptians and Indians –3. ArounThe proper nutritional supply during the period of gestation, neonatal maturation, and weaning contributes toward the development of balanced immune responses. With an increasing shift in our focus toward using dietary interventions to regulate the host defense, it is important to understand the effect of overall nutrition derived from these interventions. The nutritional quality of the wholesome diet modulates the interactions between the immune system, microbiome, and metabolism.It is estimated that demand of feeding a population will increase up to nine billion people needing food by 2050, which necessitates the need for devising methods that not only meet the demand but also ensure continuous wholesome food supply . TherefoMicrobes are important components of the human ecosystem, and they account for approximately 100 trillion, including both the ones residing outside as well as inside the human body , 12. TheFirmicutes Bacilli along the length of the gut, leading to increased adiposity. The effect was shown to be reversible, based on the combinations of recipient–donor diets. These studies , ameliorated the airway inflammation in germ-free adult offspring  bacteria, by modulating the components of host innate immune system. A dysregulation of homeostasis between host and gut microbes leads to dysbiosis, which can give rise to pathogenic states, such as inflammatory bowel disease (IBD) , 26 as sffspring . The stuffspring  showed t barrier . The pro barrier . Another barrier . The proOverall the changes in the composition of the gut microbiome can modulate the induction of regulatory versus effector immune responses. Probiotics have been shown to beneficially modulate the intestinal ecosystem. Another group of non-digestible food ingredients is the prebiotics that favors the growth of health-promoting bacteria, proving beneficial to the host , 22, 31.Parabacteroides  infections causes diarrhea-like symptoms in immune-compromised individuals and particularly in severe cases in children with malnutrition. A study by Philipson et al.  have been studied extensively over the past decade . CLA is a mixture of positional and geometric isomers of octadecadienoic acid. The use of CLA has been explored due to numerous anti-inflammatory and anti-oxidant properties that have been characterized in animal models –58. Dietin silico experimentation of the Phase III placebo-controlled, randomized clinical trial , a plant phytohormone, which when used as a dietary component elicits immunomodulatory properties. A benefit of dietary ABA-supplementation in mice includes anti-diabetic effects, anti-atherosclerotic, and an anti-hypersensitive effect that has been shown in various studies –66. The The research on the role of single nutrients in immune functions is extensive; however, this is not the case for multiple nutrients and the existing combinatorial effect of interactions between the various nutrients remains largely unknown. The interactions between multiple nutrients can negatively affect the immune system, for example, excess of calcium interferes with leukocyte function by displacing magnesium ions, causing reduction in cell adhesion processes . The nutomic levels  in response to nutrition. An effort toward post-genomics data, and multi-omic data integration by using modeling provides a deeper insight of the interaction between our genes, microbiome, and diet. Metabolomics is one of such -omics technology that involves the study of small molecules or metabolites present in the biological samples in order to study the effects on metabolic process under varying biological conditions 015-2020 , a mechaThe main challenges in systems biology frameworks are the complexity of systems and the output in terms of vast amount of data with scattered pieces of knowledge that needs to be connected together and be made sense of. The need for development of computational tools becomes imperative for the integration of the data . The advOver the past decade, a significant increase in computational power and availability of larger experimental datasets has allowed models to be more comprehensive and in some cases multi-scaled , 81–84. Computational tools and big data help revolutionize biological research in a way that is shifting the paradigm from top-down or bottom-up approaches to a middle-out approach. The latter is based on conceptualizing models and tools at the level that provides the richest data and connection that to higher or lower levels for comprehensive integrated systems. Building massively interacting multiscale models  anchored around unanswered immunological questions holds a promise for the advancement of the field of nutritional immunology into unprecedented scientific discoveries. A recent work by Ramsundar et al.  investigWith the continuous generation of massive amount of data, there is an urgent need to integrate big data, theory, procedural knowledge, and mechanistic information to synthesize and simulate recognizable behaviors of massively interacting systems. Mathematical modeling and simulation are the techniques that can be utilized for dynamic knowledge testing. Models have the power to discover new findings through effective computational technologies. The knowledge acquired from the computer simulations can form a formal basis of testing the finding in the lab, and validate the known findings . The twoin silico experimentation that was used to study the complex host–pathogen interactions as well as host–nutrient–microbiota actions  , 84, the actions . ENISI V actions  providesulations , 107–110109−1012 . While tin vivo and in vitro models have been consistently used in order to test hypothesis and perform quantitative studies. However, traditional reductionist experiments have led incremental knowledge generation due to the abundance of reductionist approaches. Over the past decade, new computational techniques, such as in silico methods  and its application as a treatment option for the in silico clinical trial. MIEP performed series of modeling studies that included computational-based drug design methods  can be examined. The output can provide valuable data for accelerating drug development pipelines with improved capability to predict the likely response to any treatment , 114.in silico experimentation and modeling have the capability to yield basic insights and translational applications in critical illnesses, many challenges still remain in this rapidly evolving field  determination of the role of H. pylori-infected mononuclear phagocytes on the modulation of mucosal immune responses to the bacterium; and (7) successful delivery of a summer school and symposium in Computational Immunology (Notable MIEP-based achievements include (1) development and enhancement of a suite of tools for ABM (ENISI)- and ODE (COPASI)-based modeling of immunological processes , 123; COr pylori , modulatby IL-21 ; (3) devnfection , 128 andnfection , 130;  and the effect of interaction of different nutrients on the massively interacting system can be predicted using advanced machine-learning methods. These predictions can be tested in lab and the deviations can be used to update the models. A key aspect of the nutritional systems immunology cycle is the validation step. That step is inherently reductionist. However, if performed in the broader context of systems nutritional immunology, then the validation studies are guided by the existing theory and data. Another way would include the use of multiscale models wherein the knowledge obtained from multi-omics studies, regarding the regulatory mechanism of nutrition, can be studied with high levels of details ranging from the cellular level to whole body, population, and policy level. The data obtained from the nutritional intervention studies integrated with -omics and targeted modeling-driven mechanistic studies will provide a comprehensive framework to simulate the physiological mechanisms and immunological changes in the body after the intake of nutrients.in silico experiments would lead to advancements in research for better treatment for disease mechanisms, assessment of disease risk, and prediction of optimal interventions for the immune-mediated diseases, with an ultimate future goal of expanding the outputs for application in precision medicine. In this review, we specifically highlight the pressing need for the development of predictive systems modeling that provide a comprehensive mechanistic understanding of the system. The conceptual modeling approaches and the computational techniques need to be integrated with advanced big data analytics methods, such as statistical and machine-learning algorithms. In summary, the use of an iterative systems biology cycle of experimental simulation, data collection, along with mathematical and computational model building, simulations, prediction, calibration, refinement, and validation have the potential to gain a systems-level mechanistic understanding in order to guide nutrition-based precision medicine, health, and wellness.A major goal in the advancement of systems nutritional immunology research and development is to build comprehensive, multiscale network models that will accurately predict global and local effects of nutrition-based interventions. The identification of the efficacy of these nutritional-based interventions on the immune system using Contributed to the design of the paper: JB-R, RH, and VA. Contributed to the writing and reviewing of the manuscript: MV, JB-R, VA, RH, AC, CP, AL, and NT-J. Contributed to the making of the figures: MV, AL, and NT-J.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.


Denmark has an extraordinarily large and well-preserved collection of archaeological skin garments found in peat bogs, dated to approximately 920 BC – AD 775. These objects provide not only the possibility to study prehistoric skin costume and technologies, but also to investigate the animal species used for the production of skin garments. Until recently, species identification of archaeological skin was primarily performed by light and scanning electron microscopy or the analysis of ancient DNA. However, the efficacy of these methods can be limited due to the harsh, mostly acidic environment of peat bogs leading to morphological and molecular degradation within the samples. We compared species assignment results of twelve archaeological skin samples from Danish bogs using Mass Spectrometry (MS)-based peptide sequencing, against results obtained using light and scanning electron microscopy. While it was difficult to obtain reliable results using microscopy, MS enabled the identification of several species-diagnostic peptides, mostly from collagen and keratins, allowing confident species discrimination even among taxonomically close organisms, such as sheep and goat. Unlike previous MS-based methods, mostly relying on peptide fingerprinting, the shotgun sequencing approach we describe aims to identify the complete extracted ancient proteome, without preselected specific targets. As an example, we report the identification, in one of the samples, of two peptides uniquely assigned to bovine foetal haemoglobin, indicating the production of skin from a calf slaughtered within the first months of its life. We conclude that MS-based peptide sequencing is a reliable method for species identification of samples from bogs. The mass spectrometry proteomics data were deposited in the ProteomeXchange Consortium with the dataset identifier PXD001029. Skin and leather artefacts are rarely found in archaeological contexts, as biogenic and non-biogenic factors rapidly cause their complete decomposition Danish peat bogs, in particular, have yielded one of the world’s finest collections of prehistoric textiles and skins, including more than 68 well-preserved prehistoric skin objects These exceptional finds provide a unique opportunity to not only investigate prehistoric skin costume technologies, but also understand which animal species were used in the process. This is crucial as species-specific morphological characteristics of skins, such as size, thickness, flexibility and function determine costume properties and the number of elements required to produce a skin object th century Attempts to identify the species origin of archaeological skin objects have been carried out since the 19Lutra lutra) and wolf (Canis lupus) skins were, however, also identified in one cape, and deerskin (Cervus) in another Species identification is also commonly performed utilizing hair through the evaluation of ‘diagnostic’ morphological traits, including: hair diameter, length of the fibre, shape and distance of the cuticles scales, appearance and dimension of the medulla and cortex In recent decades, new methods based on the analyses of ancient biomolecules have been applied for the species identification of hide and leather. An ancient DNA-based approach was successfully applied to ancient parchment, bookbinding and clothing of hide and leather More recently, an alternative molecular approach for species identification, adopting mass spectrometry (MS) to analyse collagen and keratin residues extracted from small archaeological bone fragments, as well as skin and fur, was presented We explored the potential of MS-based high throughput ancient peptide sequencing as a reliable approach for the species identification of archaeological skin objects from peat bogs. Unlike previous methods based on mass fingerprinting of peptides from selected collagen and keratin molecules, the shotgun sequencing approach aims to identify the total extracted ancient proteome, with no specific target selected in advance. In this study, we subjected samples from eleven archaeological skin objects to species identification employing three different approaches. Two of these rely on microscopy: the first combines macroscopic observation (MO) of the skin and inspection of the associated hairs by light microscopy (LM), while the second adopts light and scanning electron microscopy (SEM)-based observation of the hair morphology. The third approach is based on ancient peptide sequencing by MS. The conclusions reached by the three methods are compared, and the advantages and limitations of the various approaches discussed.Twelve samples from eleven skin garments (ten capes and a tunic) from seven peat bog localities in Denmark were selected for this study . All samThe archaeological samples 1–12,  were prohttp://proteomecentral.proteomexchange.org) via the PRIDE partner repository The mass spectrometry proteomics data were deposited in the ProteomeXchange Consortium  and high-resolution tandem mass spectrometry (MS/MS) are described in details as Supplementary Information , it was possible to identify at least one species-diagnostic peptide for all samples except two: 9 and 11. Peptides were considered diagnostic when, after BLAST search Bos taurus), water buffalo  and yak (Bos mutus) were considered diagnostic for cattle. For samples lacking at least one species-diagnostic peptide, i.e. sample 9 and 11, species identification was attempted based on a set of peptides The search strategy adopted enabled the determination of a set of species-specific peptides , and three as goat , while for one sample (sample 11), identified as ovine, it was not possible to detect any marker to discriminate between sheep and goatskin (Two skin samples were identified as bovine (sample 2 and 10), six as sheep  in sample 10 . This prThe lack of consensus among the results of the microscopy-based methods, for half of the analysed samples, illustrates that their use as a tool in species identification is not straightforward. Most likely, the challenges hampering the macroscopic and microscopic identification of archaeological skins and hair constitute part of the explanation for these discrepancies. However, the two microscopic methods applied hold different advantages for species identification. Light microscopy provides information on the colour or pigmentation of the hair and the structure of the medulla, while SEM allows enhanced observation of the scale patterns due to high magnification and a 3D view. The macroscopic observation of the size and thickness of skin elements immediately excludes several species from further consideration. For instance, sample 1 was previously identified as deer The result of “LM+SEM” suggested that the skin in question was horse skin . However, distinguishing between horse and goatskin with light microscopy and SEM is difficult as illustrated in Table S1 and Fig. S4 in O. aries) and goat (C. hircus) in public databases. This clearly demonstrates the rapid progress in this field. An example of the immediate implications of these contributions is that, until recently, the MS-based discrimination of the hairless skin and bone remains of sheep and goats was solely based on a single, relatively long, collagen peptide In addition, the availability of the cattle reference proteome and the recent public release of extended lists of sheep and goat proteins allowed for an exhaustive peptide and protein identification without limiting the search to a subset of the most abundant collagens and keratins MartesApart from improving species identification, the availability of a reference proteome, or an extended protein list, for the most common domestic animals further enables the identification of proteins solely expressed in a specific tissue, developmental phase, or biological process Despite the novel, reliable results providing secure species assignment, the identification of archaeological skin garments based on MS-based ancient peptide sequencing also comes with certain limitations. In particular, reference protein databases are still incomplete, as exhaustive protein lists are at the moment only available for a limited number of species. This shortcoming, however, will eventually become less of an issue in the near future, as the rapid progress of genome-sequencing projects will soon make reference proteomes available for an increasing number of species, enabling even more secure species identification and higher taxonomical resolution. MS-analysis remains a  destructive approach, requiring sophisticated equipment and laboratory facilities. Consequently, it cannot be immediately available for all archaeological skin samples, and its diagnostic value is limited to the analysed skin element, which is only one among the many elements used to assemble a skin garment.Although PMF-based approaches allow relatively rapid and inexpensive characterisation, thus making this approach ideal for large-scale applications and commercial quality control analyses, the maximisation of molecular recovery and data interpretation is crucial when applying even minimally destructive analyses to irreplaceable material of high cultural heritage value. Despite the necessity to sacrifice small parts of archaeological objects in the process, the collection and public sharing of the richest possible set of molecular information compatible with the technology and knowledge available at the time of analysis is of infinite value for the understanding of our distant past.The aim of this study was to compare established, morphology-based methods for species identification of archaeological skin objects from bogs with MS-based ancient peptide sequencing. The three methods adopted, in some cases, gave inconsistent results. Microscopy was challenged by general problems caused by degraded and partial fibres of archaeological material, while MS yielded secure peptide signals indicating that this method is suitable for application in the archaeological context examined. It thus represents a promising approach for future archaeological skin garment species identification. Although public databases of protein sequences are not yet complete, they already enable the determination of the most common domesticated species. Microscopy, on the other hand, holds the advantage of being relatively inexpensive, non-destructive, and easily applicable to a large number of samples, and sometimes, the sole option when dealing with mineralised samples. MS-based peptide sequencing could also be used to improve microscopy-based identification through the creation of reference collections of archaeological skin samples securely identified by peptide sequencing validation.Based on the results presented here, it may be concluded that morphology-based species identification methods represent valid preliminary screening tools; however, for de-haired samples, or samples assigned by microscopy to species other than sheep, mass spectrometry-based peptide sequencing is highly recommended for achieving secure species identification.File S1Supporting Information file containing supporting text, figures and tables.(PDF)Click here for additional data file.


However, the distinct odor of soybeans has limited the acceptance of such foods, particularly in Western countries. In Japan, while tofu and soy milk have long been habitually consumed, the development of novel, palatable food products has not been easy. The unpleasant odor of soy milk and the absorption efficiency for isoflavones can be improved using a recently developed fermented soy milk beverage. Cancer has been the leading cause of death, and breast cancer is the most common malignancy among women. The most common type of breast cancer is estrogen-dependent, and the anti-estrogenic effects of isoflavones are known. The present review focuses on the characteristics of soy milk fermented using probiotics, an epidemiological study examining the incidence of breast cancer and soy isoflavone consumption, and a non-clinical study examining breast cancer prevention using fermented soy milk beverage.The various beneficial effects of soybeans, which are rich in phytochemicals, have received much attention because of increasing health awareness. Soy milk that has been fermented using lactic acid bacteria has been used to prepare cheese-like products,  A double-blinded trial was also conducted in 138 patients with superficial transitional cell carcinoma of the bladder following a transurethral resection to evaluate the prophylaxis of recurrence. As a result, the oral administration of an LcS preparation was found to be safe and effective for preventing the recurrence of superficial bladder cancer [In addition to the results of an epidemiological study examining breast cancer prevention, the results of clinical studies have also shown that LcS can exert a cancer preventive effect. Some strains of probiotics have exhibited a cancer preventive efficacy in animal models, but to our knowledge, LcS is the only strain that has been shown to be effective in human studies. A prospective cohort study in patients with previously treated colorectal cancer compared the incidence of the reappearance of colorectal neoplasms during the study period between patients with and those without the intake of LcS . The resr cancer . The resetc., have shown that soybean intake may reduce the risk of breast cancer in Japanese women and have excluded the involvement of isoflavones in the promotion of breast cancer [etc. [Analyses of cohort studies, t cancer ,53. In tt cancer . A longit cancer . In Westt cancer . On the er [etc. ,58,59,60


Exposure to stress increases vulnerability to drug abuse, as well as relapse liability in addicted individuals. Chronic drug use alters stress response in a manner that increases drug seeking behaviors and relapse. Drug exposure and withdrawal have been shown to alter stress responses, and corticosteroid mediators of stress have been shown to impact addiction-related brain function and drug-seeking behavior. Despite the documented interplay between stress and substance abuse, the mechanisms by which stress exposure and drug seeking interact remain largely unknown. Recent studies indicate that microRNAs (miRNA) play a significant role in stress modulation as well as addiction-related processes including neurogenesis, synapse development, plasticity, drug acquisition, withdrawal and relapse. MiRNAs are short non-coding RNAs that function as bidirectional epigenetic modulators of gene expression through imperfect sequence targeted degradation and/or translational repression of mRNAs. They serve as dynamic regulators of CNS physiology and pathophysiology, and facilitate rapid and long-lasting changes to complex systems and behaviors. MiRNAs function in glucocorticoid signaling and the mesolimbic dopamine reward system, as well as mood disorders related to drug withdrawal. The literature suggests miRNAs play a pivotal role in the interaction between exposures to stress, addiction-related processes, and negative affective states resulting from extended drug withdrawal. This manuscript reviews recent evidence for the role of miRNAs in the modulation of stress and cocaine responses, and discusses potential mediation of the interaction of these systems by miRNAs. Uncovering the mechanism behind the association of stress and drug taking has the potential to impact the treatment of drug abuse and prevention of relapse. Further comprehension of these complex interactions may provide promising new targets for the treatment of drug addiction. Considerable evidence supports the overlap between the stress and reward systems of the brain and that alterations in stress systems may contribute to increased liability to abuse drugs including cocaine  play significant roles in the modulation of both the stress and reward systems of the brain. The literature has long documented that both the reward and stress systems function in responding to the acute effects of drugs of abuse, as well as withdrawal/abstinence from chronic drug exposure. Chronic exposure to cocaine results in dysregulation of brain reward circuitry and recruitment of the brain stress systems leading to long-term cocaine dependence. Long lasting changes in both reward and stress systems lead to increased vulnerability to relapse during periods of abstinence. Several miRNAs have been identified which are co-regulated by chronic cocaine exposure and various models of rodent stress responding. These include, but are not limited to miR-134, 135a, 375, and the miR-212/132 family. Further, these miRNAs function in signaling pathways long known to regulate reward and stress response such as dopamine and CRF signaling, and glutamate transmission. It is well-established that CREB, CRF, and BDNF, among other molecules, play key roles in both stress and drug seeking/abuse. These molecules are therefore widely theorized to mediate the interaction between stress and drug seeking/abuse. Further, many of the miRNAs shown to regulate these molecules also function in immune and inflammatory responses, mechanisms known to play vital roles in the etiology of addiction. For instance, miR-132 and miR-212, shown to play a critical role in cocaine self-administration, also play important roles in TLR2 ligand-mediated TNF-α secretion (Nahid et al., This review posits that miRNAs serve as master regulators of both the stress and reward systems through coordinated regulation of a large number key molecules and facilitate cross-talk between stress, reward, synaptic plasticity, and immune/inflammatory responses. Through integration of these signaling pathways, miRNAs serve as master regulators of downstream behavioral and cellular responses to drugs of abuse. In turn, miRNA expression is itself regulated by external stimuli including stress and drug exposure. MicroRNAs are highly conserved between species, however, species specific differences do exist. Within species, there are tissue and cell type differences in expression regulated by post-transcriptional modification of more ubiquitously expressed pre-miRNAs. This is likely necessary due to the ability of a single miRNA to regulate numerous target genes. While the complexity of miRNA regulation of gene expression poses a daunting challenge, it is an area of study that holds immense promise for future advancement of drug abuse research and the biomedical sciences as a whole. We argue that miRNAs co-regulated by stress and chronic cocaine represent prime targets for study in order to further elucidate the etiology of the transition from casual drug use to drug dependence. Further, this population of miRNAs represents promising targets for identification of novel treatments for drug abuse.MBD and EMU wrote the manuscript.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.


Sulfur is an essential nutrient, necessary for synthesis of many metabolites. The uptake of sulfate, primary and secondary assimilation, the biosynthesis, storage, and final utilization of sulfur (S) containing compounds requires a lot of movement between organs, cells, and organelles. Efficient transport systems of S-containing compounds across the internal barriers or the plasma membrane and organellar membranes are therefore required. Here, we review a current state of knowledge of the transport of a range of S-containing metabolites within and between the cells as well as of their long distance transport. An improved understanding of mechanisms and regulation of transport will facilitate successful engineering of the respective pathways, to improve the plant yield, biotic interaction and nutritional properties of crops. Sulfur (S) is as an essential macronutrient for plant growth, development, and response to environmental changes. It is required for the biosynthesis of proteins, co-enzymes, prosthetic groups, vitamins, amino acids like Cys and Met, GSH, and secondary metabolites such as GSL and sulfoflavonoids. Understanding S metabolism in plants is essential for human nutrition as Met is an essential amino acid and as many S containing secondary metabolites and specialized peptides  are important for biotic and abiotic interactions of crop plants and their yield. Sulfur uptake and distribution is tightly controlled in response to developmentally or environmentally induced changes in nutrient demand . AlthougTaken up from the soil, sulfate is incorporated into adenosine-5′-phosphosulfate followed by reduction into sulfite and then sulfide and Cys biosynthesis. In parallel, adenosine-5′-phosphosulfate can be further phosphorylated to 3′-phosphoadenosine-5′-phosphosulfate, which is used for sulfation reactions . Cys is Arabidopsis and about 140 more sulfur metabolites that have not been assigned to the databases to date have been reported recently (2S), and secondary metabolites . Given the large number of metabolites within S-assimilation pathway, and the localization of enzymes and pathways in different compartments, a wide spectrum of plant metabolite transporters has to be expected. Plants have evolved a network of transporters to maintain homeostasis of sulfur and S-derived compounds. Specific intra-and inter-cellular transporters are needed to store the sulfur or to channel it in biochemical processes allowing biosynthesis of important S-containing metabolites.About 300 different metabolites are predicted to incorporate sulfur in recently . These mDespite their importance for sulfur homeostasis, our knowledge of intracellular and intercellular transporters in S assimilation is still limited. In recent years, significant progress has been made in elucidating the functions of some carriers important in S-metabolism in plants. Still, many transport proteins remain unidentified. This review provides an overview of known transport proteins in sulfur metabolism within the cell and plant as a whole and aims understanding of their role in the maintenance of sulfur levels in plants.Stylosanthes hamate, a tropical forage legume. These cDNAs encoded two of high affinity transporters and one a low affinity transporter /sulfate symporters, and sulfate/anion  antiporters . Plants lacking both these transporters are unable to take up sulfate in low concentrations and are strongly affected in growth  and yet to be identified SULTRs localized in various membranes within the plant cell.The SULTR family is best characterized in n growth . The tran growth . On the  mutants . In addi mutants , but mor mutants . The two mutants . Group 4 mutants . The fir mutants . The oth mutants . Interess leaves . Figure Brassica oleracea, poplar, wheat, and Medicago truncatula . Investigations of Cys transport across mitochondrial membrane revealed presence of multiple transport systems with different kinetic properties . This conclusion has been confirmed by showing that cytosolic expression of GSH synthase rescues the seedling lethal gsh2 mutant . In addition, GSH is one of the forms of reduced sulfur subjected to long-distance transport . While the presence of such GSH transporters was long recognized, the molecular nature of such carriers is still far from being determined. The identification of high affinity GSH transporter in yeast . They facilitate transport of GSH and γ-EC, probably as export from the plastids . In addition, traditionally it was thought that Met synthesis in plants requires transport of homocysteine from plastids to the cytoplasm, as the activity of the last enzyme of the biosynthetic pathway, MS, was found in this compartment only . This transporter, similar to yeast mitochondrial SAM carrier, was shown to be additionally localized in mitochondria, and to contains five transmembrane helices . Plant SMM transporters are not known, but expression of a yeast SMM transporter in pea resulted in improved sulfur and nitrogen content of the seeds . The MTOB-transporter was identified as BAT5 or BASS5 following its activation in trans by R2R3 MYB factors regulating GSL biosynthesis . However, the identity of this transporter, which is involved in the export of amino acid, is unknown. It was also not possible to analyze whether keto-acids or amino acids are preferentially exported from the chloroplasts. Theoretically, the export of both types substrates is possible from chloroplasts as the transamination  of keto acids could be catalyzed by both chloroplastidic BCAT3 . The existence of this transporter has been postulated , which is essential for the sulfation of GSLs, flavonols, peptides, and other sulfated compounds in the cytoplasm has been recently identified . Golgi in plants is known to contain the TPST. TPST catalyzes the post-translational Tyr-sulfation of peptides by the transfer of sulfate from PAPS to the phenolic group of tyrosine  phenotype. Several Golgi-localized transporters of PAPS have been described in different organisms like Drosophila , stored there or further metabolized and/or transported . Vacuolar localization of secondary metabolites has been suggested long time ago but it was experimentally demonstrated using water-free environment gradient centrifugation of Arabidopsis leaf tissue only recently  and we consider them below.After completion of biosynthesis, secondary metabolites like GSLs and flavonoids, which are present at high concentrations in the cell, need to be imported into the vacuole , which is maintained by Hnnotated . For comnnotated . In strinnotated . ABC trannotated .S-conjugate pump) in the transport of glutathionylated anthocyanins has been originally reported in maize and petunia  where they can export yet-unidentified but highly toxic compounds to the site of invasion of non-host pathogens of Arabidopsis (Arabidopsis against non-host pathogen (induced defense of Arabidopsis against the grass powdery mildew Blumeria graminis hordei) is a phytochelatin synthase, suggesting possible PEN4-mediated glutathionylation of products to be transported by PDR8/PEN3. Another member of the ABC family in wheat known as LR34, controls durable disease resistance against some of the most devastating fungal pathogens such as leaf rust and stripe rust, potentially by exporting other antifungal metabolites although the mechanism is currently not understood . It could be further demonstrated that anthocyanins are transported to the cell wall or the vacuole by at least two distinct vesicle trafficking pathways  from the production site in ER-associated cytoplasm to the tonoplast  in onoplast . Previou MtMATE2  and it wBrassica napus were shown to move through the phloem to seeds, where the radioactivity was detected . Using Xenopus oocytes as an expression system it could be shown that GTR1 and GTR2 are high affinity plasma membrane-localized GSL-specific proton symporters . The ability of the GTRs to transport GSL may have arisen through neo-functionalization of NRT/PTR family members. The retained ability of both GTR1 and GTR2 to transport nitrate corroborates such a de novo functional specification. Notably, there are more examples of NRT/PTR proteins transporting different types of substrates. Thus, the NRT1.1 which was mainly known as nitrate transporter . A first indication that intercellular or long distance transport may play an important role in the compartmentation of different flavonoids has been obtained in cotyledons and flower buds of Catharanthus roseus -flavonoid conjugates it could be shown that flavonoids can be selectively and unidirectionally transported to specific cell/tissue types and from one organ to another (Flavonoids are produced at high levels in photosynthetically active organs as the expression of key biosynthetic gene encoding for CHS is dependent on light. These secondary metabolites were also found in heterotrophic root tissue where they contribute to many important functions like lateral development, gravitropic response, legume nodulation, the induction of the hyphal branching of arbuscular mycorrhizal fungi, as well as the response to phosphate starvation and the inhibition of polar auxin transport . Althougs roseus . Furtherolecules . Moreove another . It has  another .34S labeling, exploitation of natural variation, and mathematical modeling will be necessary to obtain the comprehensive list of S-metabolite transporters and to understand the role they play in controlling sulfur metabolism and homeostasis in plants. The increased use of these approaches in sulfur research makes hope for a rapid progress in dissection of the network of transporters in sulfur metabolism.Although sulfur-metabolites represent only a small portion of plant metabolites, the pathways of their synthesis are complex and their function and homeostasis require a large number of intra- and intercellular transport steps. Many of these transporters have been characterized, with some of the main gaps having been filled very recently. Thus, the plastidic SULTR has been identified, the GSL transporter found, as well the plastidic PAPS transporter. However, many other transporters still await discovery, above all the transporter responsible for a major flux of sulfate in the cells, the import into vacuole. With better understanding of secondary sulfur metabolism, the need for specific transporters is being recognized, such as the Golgi PAPS transporter, tonoplast GSL, and sulfoflavonoid transporter, and transporters responsible for cellular movement of minor sulfated compounds. Apart from the gene discovery, other questions have to be addressed: the regulation of the transporters of S metabolites, their contribution to the control fluxes of sulfur throughout the plant, both on cellular and whole plant levels, and the role of these transporters in the interactions of plants with other organisms. New tools and approaches, e.g., 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.


Perinatal complications in both term- and preterm-born infants are a leading cause of neonatal morbidities and mortality. Infants face different challenges in the neonatal intensive care unit with long-term morbidities such as perinatal brain injury and bronchopulmonary dysplasia being particularly devastating. While advances in perinatal medicine have improved our understanding of the pathogenesis, effective therapies to prevent and/or reduce the severity of these disorders are still lacking. The potential of mesenchymal stem/stromal cell (MSC) therapy has emerged during the last two decades, and an increasing effort is conducted to address brain- and lung-related morbidities in neonates at risk. Various studies support the notion that MSCs have protective effects. MSCs are an easy source and may be readily available after birth in a clinical setting. MSCs’ mechanisms of action are diverse, including migration and homing, release of growth factors and immunomodulation, and the potential to replace injured cells. Here, we review the pathophysiology of perinatally acquired brain and lung injuries and focus on MSCs as potential candidates for therapeutic strategies summarizing preclinical and clinical evidence. Despite advances in obstetrics and neonatology, both preterm- and term-born infants continue to face serious risks during pregnancy, parturition, and adaptation after birth. Perinatal medicine is therefore a major public health issue around the world. The clinical presentation after perinatal complications or preterm birth in an individual child is complex. This complexity results from multiple potential causal pathways, signs, and symptoms of injury. Typical pathologies in these newborns include perinatal brain injury and bronchopulmonary dysplasia (BPD), among others. New avenues to treat these morbidities have emerged among which stem cells being particularly promising. The body of knowledge of stem cell biology and their function in tissue regeneration and protection has broadened exponentially in the last two decades. This review will discuss mesenchymal stem/stromal cells (MSCs) as a therapeutic approach for both brain and lung diseases in infants at risk. Furthermore, we will highlight the preclinical and clinical data that have emerged on the role of MSCs in perinatal medicine.Perinatally acquired organ injury affects both term and preterm infants. Depending on the timing of injury and/or delivery, infants need to cope with different challenges. In the developing brain of a preterm infant, the spectrum of injury suggests that the underlying pathophysiology is not due to a single lesion but consists of white and gray matter disturbances . Thus, aTogether, therapeutic approaches to counteract the consequences of perinatally acquired injury are sparse, and new measures are desperately needed especially for preterm infants , 15–17.Experimental studies identified different phases of perinatally induced neuronal death. Primary neuronal death is related to depletion of tissue energy reserves with primary energy failure. The secondary and tertiary phases are related to excitotoxicity, mitochondrial dysfunction, and free radical accumulation leading to cell necrosis or apoptosis with impaired myelination and/or axonal function . The secThe regulation of the inflammatory responses in the newborn appears to be a link that may explain some of the common features of organ injury in preterm infants. Many studies identified characteristic inflammatory changes and altered growth factor signaling in BPD such as initial influx of neutrophils into the lung followed by increased numbers of macrophages . The relTaken together, perinatal inflammation is a strong modulator of both physiologic and pathophysiologic development of the neonatal organs. The fetal inflammatory response to certain cues such as lipopolysaccharides (LPS)  can be dStem cells are broadly defined as cells with self-renewing and differentiation capacity. Although stem cells derived from embryonic tissue were identified first, the clinical use is limited due to ethical concerns and tumorigenic potential , 38. CliMSC-based therapies are an attractive strategy since the pathophysiology of perinatally acquired injury is heterogeneous and MSCs have the capacity to adapt to the microenvironment of injured organs. The strategy may be either or both replacement/restoration of lost tissue and/or protection/salvage of injured cells. In term infants at risk for hypoxic-ischemic injury or neonatal ischemic stroke, MSCs could exert a neuroprotective effect starting at the acute phase of injury. The timing and presentation of the injury are usually well defined. MSCs could provide trophic support and/or amelioration of the inflammatory responses, leading to repair or reduced cell death. However, the different cell types, transplantation routes, and the timing need to be accounted for. Given the gold standard therapy of hypothermia for this kind of injury, MSCs have to proof additive/synergistic effects in order to be considered . In contThe approach of MSCs as a therapy for perinatal injury is based on several crucial properties of MSCs, including delivery of the cells “homing” to the site of injury. Migration and homing to the tissue of injury is influenced by multiple factors including age, passage, and number of cells; culture conditions; and delivery method . The appWhile MSCs have a proven restorative capacity in response to injury cues, the question of potential protective mechanisms remains unclear. Most of the available data comes from adult neurodegenerative and lung diseases or in vitro studies. Studies identified the induction of cytokines, interleukins, and trophic factors predominately involved in neurogenesis, angiogenesis, hematopoiesis, and cardiovascular regeneration being crucial for the mostly paracrine effects , 72. ForMSCs’ multipotency and self-renewal properties make them valid candidates for providing both lung and brain cell regeneration/replacement. Although, this strategy for repair carries risks such as tumorigenic potential , 38, MSCThe translation from bench to bedside requires the most efficacious and safest approach. Thus, the question of cell-based versus cell-free therapy needs to be addressed. Given that the MSCs’ therapeutic potential has been shown to be largely triggered via paracrine effects and not differentiation, recent studies focus on extracellular vehicles (EV) . These aAs a result of the remarkable regenerative potential of MSCs, MSCs are ideal candidates for clinical cell therapy. MSCs are easily available, have a good safety profile and homing capacity, and importantly are relatively immunoprivileged, allowing allogeneic transplantation. Not surprisingly, MSCs have been tested in clinical trials in several neurodegenerative diseases such as stroke –118, amyFirst, what are the appropriate age, passage, and dosage of the transplanted MSCs? Freshly isolated MSCs may be beneficial compared to cultured cells, but is this practicable in a clinical setting especially in the context of preterm infants ?What is the best source and application route of MSCs? Banking of UCB and placental tissue offer an easily accessible and ethically responsible source of MSCs, and minimally invasive routes are currently tested , 134–136Finally, how does the transplantation of MSCs impact the standard care in the neonatal intensive care unit? The lack of effective interventions for many morbidities related to prematurity unlocks the potential of cell-based personalized treatments. Safe and effective clinical interventions are future perspectives bearing hope to improve the lifelong outcomes of the infants in our care. This has to be proven in long-term follow-up studies.Given the array of potential regenerative mechanisms of MSCs to protect neonatal brain and lungs, therapeutic applications can be envisioned in the near future. The mechanisms span anti-apoptotic/pro-mitotic capacities leading to neovascularization by the stimulation of angiogenesis and anti-inflammatory responses. Further, stimulation of neuro- and gliogenesis, synaptogenesis, neurite outgrowth, and also immunomodulation are crucial. Available data clearly demonstrate that MSC and secreted factors are beneficial to treat a variety of neurodegenerative and lung disorders. Although the data are very promising, critical questions need to be answered:


Aristotle (384 BC-322BC), the Greek philosopher formulated the concept of the Four Causes , which in his view could explain how everything came about in the universe but its beginnings, called by him as the First Cause or the Uncaused Cause. Presently, modern Physics have a more elaborated view of the same principle considering that four discrete forces govern the interactions of matter in the known universe: gravity, electromagnetism, weak and strong nuclear force. As for the origins of the universe, we haven't made much conceptual progress since the Stageirian's work centuries ago.in silico descriptors of a given activity , solid-phase peptide synthesis, mass spectrometry and NMR structural analysis, in vitro and in vivo assays [Inspired by the Aristotelian Causality perceptiveness, its applications to chemical and biological systems, a novel screening strategy was conceived to find new biologically active molecules encrypted inside "parent macromolecules". The method  relays oo assays .


Computational biology can marry disciplines to help solve some of the most pressing problems in medical research. When built on fundamental evolutionary, biological, and/or physics principles and provided with large quantities of diverse experimental data, computing power, and rigorous statistics tools, efficient and effective computational strategies can help unlock the secrets of the genome to cure disease. Computational biology has undertaken this challenge, spearheading efforts to decode the genetic blueprints encrypted in the human germline and in somatic variations to decipher complex phenotypic consequences. It devises new and creative approaches to sift through the immense—and rapidly growing—assembled human genetic material, its products, the proteome and the metabolome, and their possible clinical ramifications.The cell is the basic unit of life; the nucleus houses the genetic material that is believed to have provided a distinct advantage to the evolving cell. The organization of the genome varies; it depends on cell type, stage of development, differentiation, disease status, and more. The higher-order spatial and temporal organization of genomes—which itself is a function of conditions and environment—is a driver of biological function in differentiation, development, and disease. Studies of genomics, epigenetics, big data analysis, imaging, and clinical cell and molecular biology all benefit from rigorous computational biology analyses and modeling. They profit from the testable hypotheses that computational biology provides. These link the genetic material to the physiological cell state; however, in-depth understanding of—and predicting—the phenotypic relationship to genome landscapes also requires effective algorithms to unravel the outcomes of small- and large-scale alterations on DNA, RNA, and protein molecules.Diseases can be viewed as perturbed states of molecular systems. They can be of different types, including single-gene (monogenic) diseases and multifactorial diseases, such as cancers, immune system diseases, neurodegenerative diseases, cardiovascular diseases, and metabolic diseases. They may involve genetic alterations or be more complex. They can also be infectious diseases where interacting molecular networks of both pathogens and humans are involved, with the pathogen protein subverting the cell’s machinery.The rapid development of next-generation methods for whole-genome, whole-exome, and targeted sequencing, complemented by earlier microarray technologies, including comparative genomic hybridization and single nucleotide polymorphism (SNP) genotyping arrays, has generated an unprecedented amount of data for analysis. The unraveling of the more-frequent-than-expected scope of submicroscopic copy-number variations (CNVs) and their link to structural variation and disease has yielded discoveries of novel phenotype associations. It is now well known that CNVs, as well as SNPs, are responsible for human evolution, genetic diversity, and susceptibility to genomic disorders. Some genomic disorders result from structural changes of the human genome that convey traits or susceptibility to traits. Such rearrangements are believed to occur because of architectural features of the genome that abet genome instability. Genome-wide association studies have revealed common variation, and targeted sequencing has provided fine mapping of the genomic regions surrounding common variants. New methods have been developed to detect and assess rare variant associations, enhancing the understanding of the genetic architecture of disease.The most common form of germline intra-species variation is the single nucleotide variant (SNV). Recent sequencing of whole human genomes has identified the number of SNVs in each individual to be in the range of 3–5 million. Although most SNVs are likely to be benign, some SNVs have a pathogenic effect and thus directly contribute to disease susceptibilities and drug sensitivities. Discovering these pathogenic SNVs is one of the main goals of modern genetics and genomics studies. Large-scale sequencing of cancer genomes has further uncovered thousands of somatic DNA alterations present in the tumor cells but not in the germline DNA of sequenced individuals. The implications of these alterations, which include SNVs, copy number changes, and structural rearrangements, on patient diagnosis, prognosis, and treatment regimens have become one of the central issues in 21st century cancer biology and medicine.The number of genomic alterations discovered by next-generation sequencing methods is too large to be directly assessed by wet bench methods, such as cell culture experiments and animal models, or by statistical associations in case-control or family-based study designs. Computational biology is increasingly playing a role in prioritizing genomic alterations most likely to be pathogenic or of clinical relevance in cancer because computer algorithms can perform high-throughput analysis of large datasets. Computer models can also integrate genomic data with information about gene expression, methylation, regulatory and protein interaction networks, as well as clinical and imaging data.There is continuous increase in the scale of genomic datasets as well as in the difficulty of identifying functionally and clinically relevant genetic variation. Among the many challenges posed to computational biology is to push the boundaries of what we might be able to learn from the genome alone while considering its cell/tissue environment, physiological state, and occurrence in disease. If significant strides are made and specific associations and linkages are identified, progress will be made toward sufficiently robust predictions with rewarding prognostic medical implications.PLOS Computational Biology has assembled a Focus Feature on the genome landscapes of disease: strategies to predict the phenotypic consequences of human germline and somatic variation. International efforts to sequence large patient cohorts and healthy control populations are generating exponentially increasing amounts of genomic data. Without the ability to interpret the phenotypic consequences of germline and somatic variation, this data collection will have limited value. We hope that this Focus Feature will inform the readership of PLOS Computational Biology about current state-of-the-art of computational methods to predict these consequences, provide perspective on key successes and limitations in this area to date, and point to areas where progress is urgently needed.Focus Feature includes three papers. In the first, Yoo-Ah Kim, Dong-Yeon Cho, and Teresa Przytycka point to genotype-phenotype effects in cancer, which can be revealed via network approaches. The authors argue that cancer is a complex and heterogeneous disease and no two cancer cases are identical. Capturing the similarities as well as the differences is essential for a better understanding of the disease and its treatment. The authors review network-based approaches to cancer data analysis, focusing on their roles in modeling inter-tumor heterogeneity.The Jonas Reeb, Maximilian Hecht, Yannick Mahlich, Yana Bromberg, and Burkhard Rost describe predictions of molecular effects of sequence variants to bridge the gap from the micro level of molecular function to the systems/macro level of disease. David Masica and Rachel Karchin emphasize the importance of increasing the clinical relevance of in silico methods to predict pathogenic missense variants. They highlight the rapid accumulation of variants of unknown clinical significance, most of which cause amino acid substitutions (cSNVs). To interpret these variants, there is an urgent need to develop better in silico bioinformatic methods. They critically review the current state of the field, pointing to the progress and shortcomings in the development of bioinformatics missense variant classifiers. In particular, they advocate the increased use of endophenotypes, which are quantitative measurements that are correlated with phenotypes via shared genetic causes.Computational biology can tackle cancer through analysis of massive quantities of data. These analyses may allow correlating the data with phenotypic outcomes. Voluminous compilations permit reaping robust statistical trends, which can be exploited for predictions. Computation can also contribute to cancer research by unraveling the mechanisms through which particular genetic or acquired aberrations actually work. Molecular structures can contribute greatly to understanding of disease mechanisms and the design and computational screening of drugs. By combining data from genomics and molecular structure, computational biology can enable interpretation of genetic and epigenetic data to tailor disease treatments to individual patients. Together with experiments, the physical sciences, genetics, statistical “big data,” and clinical analysis, computational biology can help to lay the foundation for new paradigms in the translational sciences. We look forward to the time when these tools can elucidate the basis of cancer and provide predictive blueprints and combinatorial drug therapies. However, the challenge facing us is daunting.


Transposable elements (TEs) are abundant in mammalian genomes and appear to have contributed to the evolution of their hosts by providing novel regulatory or coding sequences. We analyzed different regions of long intergenic non-coding RNA (lincRNA) genes in human and mouse genomes to systematically assess the potential contribution of TEs to the evolution of the structure and regulation of expression of lincRNA genes. Introns of lincRNA genes contain the highest percentage of TE-derived sequences (TES), followed by exons and then promoter regions although the density of TEs is not significantly different between exons and promoters. Higher frequencies of ancient TEs in promoters and exons compared to introns implies that many lincRNA genes emerged before the split of primates and rodents. The content of TES in lincRNA genes is substantially higher than that in protein-coding genes, especially in exons and promoter regions. A significant positive correlation was detected between the content of TEs and evolutionary rate of lincRNAs indicating that inserted TEs are preferentially fixed in fast-evolving lincRNA genes. These results are consistent with the repeat insertion domains of LncRNAs hypothesis under which TEs have substantially contributed to the origin, evolution, and, in particular, fast functional diversification, of lincRNA genes. Traditionally, genomes have been perceived mostly as repositories of protein-coding genes. Although this might be largely true in the case of viruses, prokaryotes, and unicellular eukaryotes, numerous recent studies on the genomes of multicellular eukaryotes, particularly animals, have revealed a vast non-coding RNome, i.e., numerous genes encoding various classes of non-coding RNAs (ncRNAs)  is scarce because very few of the lincRNAs have been experimentally characterized. Nevertheless, the functional range of this class of ncRNA is believed to be broad on the basis of indirect evidence  into the Lnx3 gene, which gave rise to simple tandem repeats  higher than in the respective regions of protein-coding genes  comprise at least half of the mammalian genomes, and in particular, are found in most lincRNAs. We identified TES in 69% of the human lincRNAs and 51% of the mouse lincRNAs. These values are somewhat lower than the previously reported 83% of TES in human lincRNAs  .The avoidance of TES in lincRNAs is consistent with purifying selection, which is an important feature of lincRNA evolution  Figure . We also) Figure , and a s) Figure . ConsistAnalysis of different classes of TEs indicates that the fractions of each class are similar for introns of lincRNA and protein-coding genes and whole genomes Figures  and 4. IP < 10−5 according to the Fisher exact test) was detected in exons and especially in promoter regions compared to introns , conceivably, because the smaller SINEs that encode no proteins are more suitable for exaptation than the larger, protein-coding LINEs. The prodigious exaptation of TE could account, at least in part, for the functionality of many lincRNAs despite their rapid evolution.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.http://www.frontiersin.org/article/10.3389/fbioe.2015.00071/abstractThe Supplementary Material for this article can be found online at Click here for additional data file.