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Fedele, G., Edwards, M. D., Bhutani, S., Hares, J. M., Murbach, M., Green, E. W., et al. (2014). Genetic Analysis of Circadian Responses to Low Frequency Electromagnetic Fields in <italic>Drosophila melanogaster</italic>. PLoS Genet, 10(12), e1004804EP–.
Abstract: <title>Author Summary</title> <p>Low frequency electromagnetic fields (EMFs) are associated with electrical power lines and have been implicated in the development of childhood leukemias. However, the Earth also has a natural EMF that animals can detect and which they use in order to navigate and orient themselves, particularly during migrations. One way they might do this is by using specialised photoreceptors called cryptochromes, which when activated by light, generate changes within the molecule that are susceptible to EMFs. Cryptochromes are important components of animal circadian clocks, the 24 hour timers that determine daily behavioral and physiological cycles. We have studied the circadian behavior of the fruitfly and have observed some novel and robust effects of EMFs on the fly's sleep-wake cycle that are mediated by cryptochrome. By using cryptochrome mutants we find that our results do not support the classic model for how this molecule might respond to EMFs. We also show that mammalian cryptochromes can respond to EMF when placed into transgenic Drosophila, whereas in mammalian clock neurons, they cannot. Consequently, the EMF responsiveness of cryptochrome is determined by its intracellular environment, suggesting that other, unknown molecules that interact with cryptochrome are also very important.</p>
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Fedele, G., Green, E. W., Rosato, E., & Kyriacou, C. P. (2014). An electromagnetic field disrupts negative geotaxis in Drosophila via a CRY-dependent pathway. Nature communications, 5, 4391.
Abstract: Many higher animals have evolved the ability to use the Earth's magnetic field, particularly for orientation. Drosophila melanogaster also respond to electromagnetic fields (EMFs), although the reported effects are quite modest. Here we report that negative geotaxis in flies, scored as climbing, is disrupted by a static EMF, and this is mediated by cryptochrome (CRY), the blue-light circadian photoreceptor. CRYs may sense EMFs via formation of radical pairs of electrons requiring photoactivation of flavin adenine dinucleotide (FAD) bound near a triad of Trp residues, but mutation of the terminal Trp in the triad maintains EMF responsiveness in climbing. In contrast, deletion of the CRY C terminus disrupts EMF responses, indicating that it plays an important signalling role. CRY expression in a subset of clock neurons, or the photoreceptors, or the antennae, is sufficient to mediate negative geotaxis and EMF sensitivity. Climbing therefore provides a robust and reliable phenotype for studying EMF responses in Drosophila.
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Frilot, C. 2nd, Carrubba, S., & Marino, A. A. (2014). Sensory transduction of weak electromagnetic fields: role of glutamate neurotransmission mediated by NMDA receptors. Neuroscience, 258, 184–191.
Abstract: Subliminal electromagnetic fields (EMFs) triggered nonlinear evoked potentials in awake but not anesthetized animals, and increased glucose metabolism in the hindbrain. Field detection occurred somewhere in the head and possibly was an unrecognized function of sensory neurons in facial skin, which synapse in the trigeminal nucleus and project to the thalamus via glutamate-dependent pathways. If so, anesthetic agents that antagonize glutamate neurotransmission would be expected to degrade EMF-evoked potentials (EEPs) to a greater extent than agents having different pharmacological effects. We tested the hypothesis using ketamine which blocks N-methyl-d-aspartate (NMDA) receptors (NMDARs), and xylazine which is an alpha(2)-adrenoreceptor agonist. Electroencephalograms (EEGs) of rats were examined using recurrence analysis to observe EEPs in the presence and absence of ketamine and/or xylazine anesthesia. Auditory evoked potentials (AEPs) served as positive controls. The frequency of observation of evoked potentials in a given condition (wake or anesthesia) was compared with that due to chance using the Fisher's exact test. EEPs were observed in awake rats but not while they were under anesthesia produced using a cocktail of xylazine and ketamine. In another experiment each rat was measured while awake and while under anesthesia produced using either xylazine or ketamine. EEPs and AEPs were detected during wake and under xylazine (P<0.05 in each of the four measurements). In contrast, neither EEPs nor AEPs were observed when anesthesia was produced partly or wholly using ketamine. The duration and latency of the EEPs was unaltered by xylazine anesthesia. The afferent signal triggered by the transduction of weak EMFs was likely mediated by NMDAR-mediated glutamate neurotransmission.
Keywords: Acoustic Stimulation; Adrenergic alpha-2 Receptor Agonists/pharmacology; Anesthesia; Animals; Brain/drug effects/*physiology; Electroencephalography; *Electromagnetic Fields; Evoked Potentials/drug effects; Evoked Potentials, Auditory/drug effects; Excitatory Amino Acid Antagonists/pharmacology; Female; Ketamine/pharmacology; Perception/drug effects/*physiology; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-2/metabolism; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors/*metabolism; Wakefulness/drug effects/*physiology; Xylazine/pharmacology; %D; %R; Abr; AEPs; Coiflet; Daubechies; Db; EEGs; EEPs; EMF-evoked potentials; EMFs; N-methyl-d-aspartate; Nmda; NMDA receptor; Nmdar; Xk; amplitude threshold coefficients; analysis of brain recurrence; atc; auditory evoked potentials; cerebellum; coif; electroencephalograms; electromagnetic fields; evoked potentials; ketamine; nonlinear analysis; percent determinism; percent recurrence; xylazine; xylazine and ketamine
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Gawad, C., Koh, W., & Quake, S. R. (2014). Dissecting the clonal origins of childhood acute lymphoblastic leukemia by single-cell genomics. Proc Natl Acad Sci U S A, 111(50), 17947–17952.
Abstract: Many cancers have substantial genomic heterogeneity within a given tumor, and to fully understand that diversity requires the ability to perform single cell analysis. We performed targeted sequencing of a panel of single nucleotide variants (SNVs), deletions, and IgH sequences in 1,479 single tumor cells from six acute lymphoblastic leukemia (ALL) patients. By accurately segregating groups of cooccurring mutations into distinct clonal populations, we identified codominant clones in the majority of patients. Evaluation of intraclonal mutation patterns identified clone-specific punctuated cytosine mutagenesis events, showed that most structural variants are acquired before SNVs, determined that KRAS mutations occur late in disease development but are not sufficient for clonal dominance, and identified clones within the same patient that are arrested at varied stages in B-cell development. Taken together, these data order the sequence of genetic events that underlie childhood ALL and provide a framework for understanding the development of the disease at single-cell resolution.
Keywords: acute lymphoblastic leukemia; clonal evolution; cytosine mutagenesis; intratumor heterogeneity; single-cell genomics
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Giorgi, G., Lecciso, M., Capri, M., Lukas Yani, S., Virelli, A., Bersani, F., et al. (2014). An evaluation of genotoxicity in human neuronal-type cells subjected to oxidative stress under an extremely low frequency pulsed magnetic field. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 775-776, 31–37.
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