213 research outputs found
A comprehensive view of the epigenetic landscape part I : DNA methylation, passive and active DNA demethylation pathways and histone variants
In multicellular organisms, all the cells are genetically identical but turn genes on or off at the right time to promote differentiation into specific cell types. The regulation of higher-order chromatin structure is essential for genome-wide reprogramming and for tissue-specific patterns of gene expression. The complexity of the genome is regulated by epigenetic mechanisms, which act at the level of DNA, histones, and nucleosomes. Epigenetic machinery is involved in many biological processes, including genomic imprinting, X-chromosome inactivation, heterochromatin formation, and transcriptional regulation, as well as DNA damage repair. In this review, we summarize the recent understanding of DNA methylation, cytosine derivatives, active and passive demethylation pathways as well as histone variants. DNA methylation is one of the well-characterized epigenetic signaling tools. Cytosine methylation of promoter regions usually represses transcription but methylation in the gene body may have a positive correlation with gene expression. The attachment of a methyl group to cytosine residue in the DNA sequence is catalyzed by enzymes of the DNA methyltransferase family. Recent studies have shown that the Ten-Eleven translocation family enzymes are involved in stepwise oxidation of 5-methylcytosine, creating new cytosine derivatives including 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine. Additionally, histone variants into nucleosomes create another strategy to regulate the structure and function of chromatin. The replacement of canonical histones with specialized histone variants regulates accessibility of DNA, and thus may affect multiple biological processes, such as replication, transcription, DNA repair, and play a role in various disorders such as cancer
A Comprehensive View of the Epigenetic Landscape Part I: DNA Methylation, Passive and Active DNA Demethylation Pathways and Histone Variants
In multicellular organisms, all the cells are genetically identical but turn genes on or off at the right time to promote differentiation into specific cell types. The regulation of higher-order chromatin structure is essential for genome-wide reprogramming and for tissue-specific patterns of gene expression. The complexity of the genome is regulated by epigenetic mechanisms, which act at the level of DNA, histones, and nucleosomes. Epigenetic machinery is involved in many biological processes, including genomic imprinting, X-chromosome inactivation, heterochromatin formation, and transcriptional regulation, as well as DNA damage repair. In this review, we summarize the recent understanding of DNA methylation, cytosine derivatives, active and passive demethylation pathways as well as histone variants. DNA methylation is one of the well-characterized epigenetic signaling tools. Cytosine methylation of promoter regions usually represses transcription but methylation in the gene body may have a positive correlation with gene expression. The attachment of a methyl group to cytosine residue in the DNA sequence is catalyzed by enzymes of the DNA methyltransferase family. Recent studies have shown that the Ten-Eleven translocation family enzymes are involved in stepwise oxidation of 5-methylcytosine, creating new cytosine derivatives including 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine. Additionally, histone variants into nucleosomes create another strategy to regulate the structure and function of chromatin. The replacement of canonical histones with specialized histone variants regulates accessibility of DNA, and thus may affect multiple biological processes, such as replication, transcription, DNA repair, and play a role in various disorders such as cancer
Perinatal Manganese Exposure and Hydroxyl Radical Formation in Rat Brain
The present study was designed to investigate the role of pre- and postnatal manganese (Mn) exposure on hydroxyl radical (HOâą) formation in the brains of dopamine (DA) partially denervated rats (Parkinsonian rats). Wistar rats were given tap water containing 10,000 ppm manganese chloride during the duration of pregnancy and until the time of weaning. Control rat dams consumed tap water without added Mn. Three days after birth, rats of both groups were treated with 6-hydroxydopamine at one of three doses (15, 30, or 67 ”g, intraventricular on each side), or saline vehicle. We found that Mn content in the brain, kidney, liver, and bone was significantly elevated in dams exposed to Mn during pregnancy. In neonates, the major organs that accumulated Mn were the femoral bone and liver. However, Mn was not elevated in tissues in adulthood. To determine the possible effect on generation of the reactive species, HOâą in Mn-induced neurotoxicity, we analyzed the contents of 2.3- and 2.5-dihydroxybenzoic acid (spin trap products of salicylate; HOâą being an index of in vivo HOâą generation), as well as antioxidant enzyme activities of superoxide dismutase (SOD) isoenzymes and glutathione S-transferase (GST). 6-OHDA-depletion of DA produced enhanced HOâą formation in the brain tissue of newborn and adulthood rats that had been exposed to Mn, and the latter effect did not depend on the extent of DA denervation. Additionally, the extraneuronal, microdialysate, content of HOâą in neostriatum was likewise elevated in 6-OHDA-lesioned rats. Interestingly, there was no difference in extraneuronal HOâą formation in the neostriatum of Mn-exposed versus control rats. In summary, findings in this study indicate that Mn crosses the placenta but in contrast to other heavy metals, Mn is not deposited long term in tissues. Also, damage to the dopaminergic system acts as a âtrigger mechanism,â initiating a cascade of adverse events leading to a protracted increase in HOâą generation, and the effects of Mn and 6-OHDA are compounded. Moreover, HOâą generation parallels the suppression of SOD isoenzymes and GST in the brains of rats lesioned with 6-OHDA and/or intoxicated with Mnâthe most prominent impairments being in frontal cortex, striatum, and brain stem. In conclusion, ontogenetic Mn exposure, resulting in reactive oxygen species, HOâą formation, represents a risk factor for dopaminergic neurotoxicity and development of neurodegenerative disorders
Elevated Gene Expression of Glutamate Receptors in Noradrenergic Neurons From the Locus Coeruleus in Major Depression
Glutamate receptors are promising drug targets for the treatment of urgent suicide ideation and chronic major depressive disorder (MDD) that may lead to suicide completion. Antagonists of glutamatergic NMDA receptors reduce depressive symptoms faster than traditional antidepressants, with beneficial effects occurring within hours. Glutamate is the prominent excitatory input to the noradrenergic locus coeruleus (LC). The LC is activated by stress in part through this glutamatergic input. Evidence has accrued demonstrating that the LC may be overactive in MDD, while treatment with traditional antidepressants reduces LC activity. Pathological alterations of both glutamatergic and noradrenergic systems have been observed in depressive disorders, raising the prospect that disrupted glutamate-norepinephrine interactions may be a central component to depression and suicide pathobiology. This study examined the gene expression levels of glutamate receptors in post-mortem noradrenergic LC neurons from subjects with MDD (most died by suicide) and matched psychiatrically normal controls. Gene expression levels of glutamate receptors or receptor subunits were measured in LC neurons collected by laser capture microdissection. MDD subjects exhibited significantly higher expression levels of the NMDA receptor subunit genes, GRIN2B and GRIN2C, and the metabotropic receptor genes, GRM4 and GRM5, in LC neurons. Gene expression levels of these receptors in pyramidal neurons from prefrontal cortex (BA10) did not reveal abnormalities in MDD. These findings implicate disrupted glutamatergic-noradrenergic interactions at the level of the stress-sensitive LC in MDD and suicide, and provide a theoretical mechanism by which glutamate antagonists may exert rapid antidepressant effects
Current address: National Institutes of Health, Bldg. 8, Rm. 111, Be-thesda, MD 20892
ABSTRACT To investigate the influence of dopamine (DA) nerves on haloperidol (HAL)-induced oral dyskinesias, rats were first injected at 3 days after birth with 6-hydroxydopamine HBr (200 g i.c.v., salt form; 6-OHDA) or vehicle, after desipramine HCl (20 mg/kg i.p., 1 hr) pretreatment. Two months later HAL (1.5 mg/kg/day, 2 days a week for 4 weeks, then daily for 10 months) was added to the drinking water of half the rats. Numbers of vacuous chewing movements, recorded in 1-min increments every 10 min for 1 hr, increased from Ϝ5 to about 17 oral movements per session in intact rats, 14 weeks after instituting HAL (P Ϝ .01 vs. intact rats drinking tap water). In HAL-treated 6-OHDA-lesioned rats, oral activity increased to ϟ30 oral movements per session (P Ϝ .01 vs. HAL-treated intact rats). These levels of oral activity persisted in intact and 6-OHDA-lesioned rats as long as HAL was administered. After 11 months of HAL treatment, but 8 or 9 days after HAL withdrawal, DA was found to be reduced 97%, whereas serotonin was increased 29% in the striatum of 6-OHDA-lesioned rats. In HAL-treated intact and lesioned rats the B max for DA D 2 binding sites was elevated about 70%. With reverse transcription polymerase chain reaction, the mRNA level for DA D 2L but not D 2S receptors was also found to be elevated about 70%. In a fraction of 6-OHDA-lesioned rats that were observed for 8 months after HAL withdrawal, oral activity persisted without decrement and was not accompanied by a change in the B max or mRNA level for DA D 2 receptors. These findings demonstrate that in rats largely DA-denervated as neonates, long-term HAL treatment produces an unusually high number of oral movements that persists for 8 months after HAL withdrawal and is not accompanied by an increase in DA D 2 receptor expression. Tardive dyskinesia, an extrapyramidal syndrome caused by neuroleptics in the treatment of psychiatric disorders, is a disorder for which there is no satisfactory treatment. The prevalence of TD has increased steadily by about 1% per year during the past two decades Cholinergic systems are also known to have a prominent regulatory action on oral activity. Acute systemic treatments with pilocarpine, a muscarinic agonist, or physostigmine, a cholinesterase inhibitor, produce oral activity in rats. The same effect is produced when pilocarpine is injected directly into the ventrolateral striatum. Long-term treatment with physostigmine similarly increases oral activity. These many actions are attenuated by the muscarinic receptor antagonist, scopolamine Bilateral microinfusion of the GABA receptor antagonist bicuculline and GABA-depleting agent isoniazid into the sub
Sensor Calibration Systems and Methods for Infrared Cameras
Systems and methods directed to calibration techniques for infrared cameras are disclosed for some embodiments. For example, a method of determining infrared sensor calibration information, in accordance with an embodiment, includes performing a calibration operation on an infrared sensor to obtain calibration information, wherein the infrared sensor is not within an infrared camera core, and storing the calibration information
Multi-messenger observations of a binary neutron star merger
On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transientâs position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta