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

A Simple Iterative Model Accurately Captures Complex Trapline Formation by Bumblebees Across Spatial Scales and Flower Arrangements

PMCID: PMC3591286This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Infection-mediated priming of phagocytes protects against lethal secondary Aspergillus fumigatus challenge

Phagocytes restrict the germination of Aspergillus fumigatus conidia and prevent the establishment of invasive pulmonary aspergillosis in immunecompetent mice. Here we report that immunecompetent mice recovering from a primary A. fumigatus challenge are protected against a secondary lethal challenge. Using RAGγc knock-out mice we show that this protection is independent of T, B and NK cells. In protected mice, lung phagocytes are recruited more rapidly and are more efficient in conidial phagocytosis and killing. Protection was also associated with an enhanced expression of CXCR2 and Dectin-1 on bone marrow phagocytes. We also show that protective lung cytokine and chemokine responses are induced more rapidly and with enhanced dynamics in protected mice. Our findings support the hypothesis that following a first encounter with a non-lethal dose of A. fumigatus conidia, the innate immune system is primed and can mediate protection against a secondary lethal infection

The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence

Funding: This work was funded by the European Research Council [http://erc.europa.eu/], AJPB (STRIFE Advanced Grant; C-2009-AdG-249793). The work was also supported by: the Wellcome Trust [www.wellcome.ac.uk], AJPB (080088, 097377); the UK Biotechnology and Biological Research Council [www.bbsrc.ac.uk], AJPB (BB/F00513X/1, BB/K017365/1); the CNPq-Brazil [http://cnpq.br], GMA (Science without Borders fellowship 202976/2014-9); and the National Centre for the Replacement, Refinement and Reduction of Animals in Research [www.nc3rs.org.uk], DMM (NC/K000306/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments We thank Dr. Elizabeth Johnson (Mycology Reference Laboratory, Bristol) for providing strains, and the Aberdeen Proteomics facility for the biotyping of S. cerevisiae clinical isolates, and to Euroscarf for providing S. cerevisiae strains and plasmids. We are grateful to our Microscopy Facility in the Institute of Medical Sciences for their expert help with the electron microscopy, and to our friends in the Aberdeen Fungal Group for insightful discussions.Peer reviewedPublisher PD

Hawking temperature in the eternal BTZ black hole: an example of Holography in AdS spacetime

We review the relation between AdS spacetime in 1+2 dimensions and the BTZ black hole. Later we show that a ground state in AdS spacetime becomes a thermal state in the BTZ black hole. We show that this is true in the bulk and in the boundary of AdS spacetime. The existence of this thermal state is tantamount to say that the Unruh effect exists in AdS spacetime and becomes the Hawking effect for an eternal BTZ black hole. In order to make this we use the correspondence introduced in Algebraic Holography between algebras of quasi-local observables associated to wedges and doble cones regions in the bulk of AdS spacetime and its conformal boundary respectively. Also we give the real scalar quantum field as a concrete heuristic realization of this formalism.Comment: 29 page

Neuronal networks provide rapid neuroprotection against spreading toxicity

Acute secondary neuronal cell death, as seen in neurodegenerative disease, cerebral ischemia (stroke) and traumatic brain injury (TBI), drives spreading neurotoxicity into surrounding, undamaged, brain areas. This spreading toxicity occurs via two mechanisms, synaptic toxicity through hyperactivity, and excitotoxicity following the accumulation of extracellular glutamate. To date, there are no fast-acting therapeutic tools capable of terminating secondary spreading toxicity within a time frame relevant to the emergency treatment of stroke or TBI patients. Here, using hippocampal neurons (DIV 15-20) cultured in microfluidic devices in order to deliver a localized excitotoxic insult, we replicate secondary spreading toxicity and demonstrate that this process is driven by GluN2B receptors. In addition to the modeling of spreading toxicity, this approach has uncovered a previously unknown, fast acting, GluN2A-dependent neuroprotective signaling mechanism. This mechanism utilizes the innate capacity of surrounding neuronal networks to provide protection against both forms of spreading neuronal toxicity, synaptic hyperactivity and direct glutamate excitotoxicity. Importantly, network neuroprotection against spreading toxicity can be effectively stimulated after an excitotoxic insult has been delivered, and may identify a new therapeutic window to limit brain damage

Whisker Movements Reveal Spatial Attention: A Unified Computational Model of Active Sensing Control in the Rat

Spatial attention is most often investigated in the visual modality through measurement of eye movements, with primates, including humans, a widely-studied model. Its study in laboratory rodents, such as mice and rats, requires different techniques, owing to the lack of a visual fovea and the particular ethological relevance of orienting movements of the snout and the whiskers in these animals. In recent years, several reliable relationships have been observed between environmental and behavioural variables and movements of the whiskers, but the function of these responses, as well as how they integrate, remains unclear. Here, we propose a unifying abstract model of whisker movement control that has as its key variable the region of space that is the animal's current focus of attention, and demonstrate, using computer-simulated behavioral experiments, that the model is consistent with a broad range of experimental observations. A core hypothesis is that the rat explicitly decodes the location in space of whisker contacts and that this representation is used to regulate whisker drive signals. This proposition stands in contrast to earlier proposals that the modulation of whisker movement during exploration is mediated primarily by reflex loops. We go on to argue that the superior colliculus is a candidate neural substrate for the siting of a head-centred map guiding whisker movement, in analogy to current models of visual attention. The proposed model has the potential to offer a more complete understanding of whisker control as well as to highlight the potential of the rodent and its whiskers as a tool for the study of mammalian attention

A Practical Approach to the Secure Computation of the Moore-Penrose Pseudoinverse over the Rationals

Solving linear systems of equations is a universal problem. In the context of secure multiparty computation (MPC), a method to solve such systems, especially for the case in which the rank of the system is unknown and should remain private, is an important building block. We devise an efficient and data-oblivious algorithm (meaning that the algorithm\u27s execution time and branching behavior are independent of all secrets) for solving a bounded integral linear system of unknown rank over the rational numbers via the Moore-Penrose pseudoinverse, using finite-field arithmetic. I.e., we compute the Moore-Penrose inverse over a finite field of sufficiently large order, so that we can recover the rational solution from the solution over the finite field. While we have designed the algorithm with an MPC context in mind, it could be valuable also in other contexts where data-obliviousness is required, like secure enclaves in CPUs. Previous work by Cramer, Kiltz and Padró (CRYPTO 2007) proposes a constant-rounds protocol for computing the Moore-Penrose pseudoinverse over a finite field. The asymptotic complexity (counted as the number of secure multiplications) of their solution is $O(m^4 + n^2 m)$, where $m$ and $n$, $m\leq n$, are the dimensions of the linear system. To reduce the number of secure multiplications, we sacrifice the constant-rounds property and propose a protocol for computing the Moore-Penrose pseudoinverse over the rational numbers in a linear number of rounds, requiring only $O(m^2n)$ secure multiplications. To obtain the common denominator of the pseudoinverse, required for constructing an integer-representation of the pseudoinverse, we generalize a result by Ben-Israel for computing the squared volume of a matrix. Also, we show how to precondition a symmetric matrix to achieve generic rank profile while preserving symmetry and being able to remove the preconditioner after it has served its purpose. These results may be of independent interest