Benefits and risks of the hormetic effects of dietary isothiocyanates on cancer prevention

The isothiocyanate (ITC) sulforaphane (SFN) was shown at low levels (1-5 µM) to promote cell proliferation to 120-143% of the controls in a number of human cell lines, whilst at high levels (10-40 µM) it inhibited such cell proliferation. Similar dose responses were observed for cell migration, i.e. SFN at 2.5 µM increased cell migration in bladder cancer T24 cells to 128% whilst high levels inhibited cell migration. This hormetic action was also found in an angiogenesis assay where SFN at 2.5 µM promoted endothelial tube formation (118% of the control), whereas at 10-20 µM it caused significant inhibition. The precise mechanism by which SFN influences promotion of cell growth and migration is not known, but probably involves activation of autophagy since an autophagy inhibitor, 3-methyladenine, abolished the effect of SFN on cell migration. Moreover, low doses of SFN offered a protective effect against free-radical mediated cell death, an effect that was enhanced by co-treatment with selenium. These results suggest that SFN may either prevent or promote tumour cell growth depending on the dose and the nature of the target cells. In normal cells, the promotion of cell growth may be of benefit, but in transformed or cancer cells it may be an undesirable risk factor. In summary, ITCs have a biphasic effect on cell growth and migration. The benefits and risks of ITCs are not only determined by the doses, but are affected by interactions with Se and the measured endpoint

Meditation Awareness Training for individuals with fibromyalgia syndrome: an interpretative phenomenological analysis of participants' experiences

Fibromyalgia syndrome (FMS) is a complex and poorly understood psychosomatic pain disorder. The illness has been the subject of controversy, both in terms of the alleged lack of interest and capability of the medical community to understand and support patients with FMS, and the burden that such individuals place upon economic and healthcare re- sources. Due to the lack of convincing data for the effectiveness of extant pharmacological and non-pharmacological FMS treatments, a recent direction in FMS research has been the empirical investigation of mindfulness and other meditation-based approaches. The present qualitative study explored whether following participation in a mindfulness-based intervention, patients with FMS report experiencing changes in (i) how they experience and relate to their illness and (ii) their attitudes towards societal participation, work and unemployment. Ten individuals with FMS were randomly selected from the intervention arm of a randomised controlled trial (RCT) evaluating the effectiveness of a mindfulness-based intervention known as Meditation Awareness Training (MAT) for the treatment of FMS. Transcripts of semi-structured interviews were analysed using Interpretative Phenomenological Analysis, a robust and rigorous qualitative methodology for analysing sub jective experiences. Five super-ordinate themes emerged from the dataset: (i) reservations about participating,(ii) improvements in psychosomatic well-being,(iii) spiritual growth,(iv) awareness of impermanence and (v) increased sense of citizenship. MAT was experienced as both an acceptable and accessible intervention by individuals with FMS, and participants reported experiencing improvements in psychosocial functioning as well as an increased sense of societal responsibility. MAT appears to have utility for treating FMS and for changing the attitudes of some individuals with FMS towards community engagement and societal contribution

A mathematical and computational review of Hartree-Fock SCF methods in Quantum Chemistry

We present here a review of the fundamental topics of Hartree-Fock theory in Quantum Chemistry. From the molecular Hamiltonian, using and discussing the Born-Oppenheimer approximation, we arrive to the Hartree and Hartree-Fock equations for the electronic problem. Special emphasis is placed in the most relevant mathematical aspects of the theoretical derivation of the final equations, as well as in the results regarding the existence and uniqueness of their solutions. All Hartree-Fock versions with different spin restrictions are systematically extracted from the general case, thus providing a unifying framework. Then, the discretization of the one-electron orbitals space is reviewed and the Roothaan-Hall formalism introduced. This leads to a exposition of the basic underlying concepts related to the construction and selection of Gaussian basis sets, focusing in algorithmic efficiency issues. Finally, we close the review with a section in which the most relevant modern developments (specially those related to the design of linear-scaling methods) are commented and linked to the issues discussed. The whole work is intentionally introductory and rather self-contained, so that it may be useful for non experts that aim to use quantum chemical methods in interdisciplinary applications. Moreover, much material that is found scattered in the literature has been put together here to facilitate comprehension and to serve as a handy reference.Comment: 64 pages, 3 figures, tMPH2e.cls style file, doublesp, mathbbol and subeqn package

Towards a science of climate and energy choices

The linked problems of energy sustainability and climate change are among the most complex and daunting facing humanity at the start of the twenty-first century. This joint Nature Energy and Nature Climate Change Collection illustrates how understanding and addressing these problems will require an integrated science of coupled human and natural systems; including technological systems, but also extending well beyond the domain of engineering or even economics. It demonstrates the value of replacing the stylized assumptions about human behaviour that are common in policy analysis, with ones based on data-driven science. We draw from and engage articles in the Collection to identify key contributions to understanding non-technological factors connecting economic activity and greenhouse gas emissions, describe a multi-dimensional space of human action on climate and energy issues, and illustrate key themes, dimensions and contributions towards fundamental understanding and informed decision making

A theoretical foundation for multi-scale regular vegetation patterns

Self-organized regular vegetation patterns are widespread and thought to mediate ecosystem functions such as productivity and robustness, but the mechanisms underlying their origin and maintenance remain disputed. Particularly controversial are landscapes of overdispersed (evenly spaced) elements, such as North American Mima mounds, Brazilian murundus, South African heuweltjies, and, famously, Namibian fairy circles. Two competing hypotheses are currently debated. On the one hand, models of scale-dependent feedbacks, whereby plants facilitate neighbours while competing with distant individuals, can reproduce various regular patterns identified in satellite imagery. Owing to deep theoretical roots and apparent generality, scale-dependent feedbacks are widely viewed as a unifying and near-universal principle of regular-pattern formation despite scant empirical evidence. On the other hand, many overdispersed vegetation patterns worldwide have been attributed to subterranean ecosystem engineers such as termites, ants, and rodents. Although potentially consistent with territorial competition, this interpretation has been challenged theoretically and empirically and (unlike scale-dependent feedbacks) lacks a unifying dynamical theory, fuelling scepticism about its plausibility and generality. Here we provide a general theoretical foundation for self-organization of social-insect colonies, validated using data from four continents, which demonstrates that intraspecific competition between territorial animals can generate the large-scale hexagonal regularity of these patterns. However, this mechanism is not mutually exclusive with scale-dependent feedbacks. Using Namib Desert fairy circles as a case study, we present field data showing that these landscapes exhibit multi-scale patterning-previously undocumented in this system-that cannot be explained by either mechanism in isolation. These multi-scale patterns and other emergent properties, such as enhanced resistance to and recovery from drought, instead arise from dynamic interactions in our theoretical framework, which couples both mechanisms. The potentially global extent of animal-induced regularity in vegetation-which can modulate other patterning processes in functionally important ways-emphasizes the need to integrate multiple mechanisms of ecological self-organization

Long-Term Effects of the Periconception Period on Embryo Epigenetic Profile and Phenotype: The Role of Stress and How This Effect Is Mediated

Stress represents an unavoidable aspect of human life, and pathologies associated with dysregulation of stress mechanisms - particularly psychiatric disorders - represent a significant global health problem. While it has long been observed that levels of stress experienced in the periconception period may greatly affect the offspring's risk of psychiatric disorders, the mechanisms underlying these associations are not yet comprehensively understood. In order to address this question, this chapter will take a 'top-down' approach, by first defining stress and associated concepts, before exploring the mechanistic basis of the stress response in the form of the hypothalamic-pituitary-adrenal (HPA) axis, and how dysregulation of the HPA axis can impede our mental and physical health, primarily via imbalances in glucocorticoids (GCs) and their corresponding receptors (GRs) in the brain. The current extent of knowledge pertaining to the impact of stress on developmental programming and epigenetic inheritance is then extensively discussed, including the role of chromatin remodelling associated with specific HPA axis-related genes and the possible role of regulatory RNAs as messengers of environmental stress both in the intrauterine environment and across the germ line. Furthering our understanding of the role of stress on embryonic development is crucial if we are to increase our predictive power of disease risk and devise-effective treatments and intervention strategies

The 12p13.33/RAD52 locus and genetic susceptibility to squamous cell cancers of upper aerodigestive tract

Acknowledgments: The authors thank all of the participants who took part in this research and the funders and support and technical staff who made this study possible. We also acknowledge and thank The Cancer Genome Atlas initiative whose data contributed heavily to this study. Funding: Funding for study coordination, genotyping of replication studies and statistical analysis was provided by the US National Institutes of Health (R01 CA092039 05/05S1) and the National Institute of Dental and Craniofacial Research (1R03DE020116). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Mycobacteria counteract a TLR-mediated nitrosative defense mechanism in a zebrafish infection model.

Pulmonary tuberculosis (TB), caused by the intracellular bacterial pathogen Mycobacterium tuberculosis (Mtb), is a major world health problem. The production of reactive nitrogen species (RNS) is a potent cytostatic and cytotoxic defense mechanism against intracellular pathogens. Nevertheless, the protective role of RNS during Mtb infection remains controversial. Here we use an anti-nitrotyrosine antibody as a readout to study nitration output by the zebrafish host during early mycobacterial pathogenesis. We found that recognition of Mycobacterium marinum, a close relative of Mtb, was sufficient to induce a nitrosative defense mechanism in a manner dependent on MyD88, the central adaptor protein in Toll like receptor (TLR) mediated pathogen recognition. However, this host response was attenuated by mycobacteria via a virulence mechanism independent of the well-characterized RD1 virulence locus. Our results indicate a mechanism of pathogenic mycobacteria to circumvent host defense in vivo. Shifting the balance of host-pathogen interactions in favor of the host by targeting this virulence mechanism may help to alleviate the problem of infection with Mtb strains that are resistant to multiple drug treatments

Self domestication and the evolution of language

We set out an account of how self-domestication plays a crucial role in the evolution of language. In doing so, we focus on the growing body of work that treats language structure as emerging from the process ofcultural transmission. We argue that a full recognition of the importance of cultural transmission fundamentally changes the kind ofquestionswe should be asking regarding the biological basis of language structure. If we think of language structure as reflecting an accumulated set of changes in our genome, then we might ask something like, "What are the genetic bases of language structure and why were they selected?" However, if cultural evolution can account for language structure, then this question no longer applies. Instead, we face the task of accounting for the origin of the traits that enabled that process of structure-creating cultural evolution to get started in the first place. In light of work on cultural evolution, then, the new question for biological evolution becomes, "How did those precursor traits evolve?" We identify two key precursor traits: (1) the transmission of the communication system throughlearning; and (2) the ability to infer thecommunicative intentassociated with a signal or action. We then describe two comparative case studies-the Bengalese finch and the domestic dog-in which parallel traits can be seen emerging followingdomestication. Finally, we turn to the role of domestication in human evolution. We argue that the cultural evolution of language structure has its origin in an earlier process of self-domestication.</p

Mechanisms of hypoxic up-regulation of versican gene expression in macrophages

Hypoxia is a hallmark of many pathological tissues. Macrophages accumulate in hypoxic sites and up-regulate a range of hypoxia-inducible genes. The matrix proteoglycan versican has been identified as one such gene, but the mechanisms responsible for hypoxic induction are not fully characterised. Here we investigate the up-regulation of versican by hypoxia in primary human monocyte-derived macrophages (HMDM), and, intriguingly, show that versican mRNA is up-regulated much more highly (&gt;600 fold) by long term hypoxia (5 days) than by 1 day of hypoxia (48 fold). We report that versican mRNA decay rates are not affected by hypoxia, demonstrating that hypoxic induction of versican mRNA is mediated by increased transcription. Deletion analysis of the promoter identified two regions required for high level promoter activity of luciferase reporter constructs in human macrophages. The hypoxia-inducible transcription factor HIF-1 has previously been implicated as a key potential regulator of versican expression in hypoxia, however our data suggest that HIF-1 up-regulation is unlikely to be principally responsible for the high levels of induction observed in HMDM. Treatment of HMDM with two distinct specific inhibitors of Phosphoinositide 3-kinase (PI3K), LY290042 and wortmannin, significantly reduced induction of versican mRNA by hypoxia and provides evidence of a role for PI3K in hypoxic up-regulation of versican expression