Elitt, Christopher M; Malin, Sacha A; Koerber, H Richard; Davis, Brian M; Albers, Kathryn M
Artemin, a member of the glial cell line-derived neurotrophic factor (GDNF) family, supports a subpopulation of trigeminal sensory neurons through activation of the Ret/GFRalpha3 receptor tyrosine kinase complex. In a previous study we showed that artemin is increased in inflamed skin of wildtype mice and that transgenic overexpression of artemin in skin increases TRPV1 and TRPA1 expression in dorsal root ganglia neurons. In this study we examined how transgenic overexpression of artemin in tongue epithelium affects the anatomy, gene expression and calcium handling properties of trigeminal sensory afferents. At the RNA level, trigeminal ganglia of artemin overexpresser mice (ART-OEs) had an 81% increase in GFRalpha3, a 190% increase in TRPV1 and a 403% increase in TRPA1 compared to wildtype (WT) controls. Myelinated and unmyelinated fibers of the lingual nerve were increased in diameter, as was the density of GFRalpha3 and TRPV1-positive innervation to the dorsal anterior tongue and fungiform papilla. Retrograde labeling of trigeminal afferents by WGA injection into the tip of the tongue showed an increased percentage of GFRalpha3, TRPV1 and isolectin B4 afferents in ART-OE mice. ART-OE afferents had larger calcium transients in response to ligands of TRPV1 (capsaicin) and TRPA1 (mustard oil). Behavioral sensitivity was also exhibited by ART-OE mice to capsaicin and mustard oil, measured using a two-choice drinking test. These results suggest a potential role for artemin-responsive GFRalpha3/TRPV1/TRPA1 sensory afferents in mediating sensitivity associated with tissue injury, chemical sensitivity or disease states such as burning mouth syndrome.
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Background Artemin (Artn), a member of the glial cell line-derived growth factor (GDNF) family, supports the development and function of a subpopulation of peptidergic, TRPV1-positive sensory neurons. Artn (enovin, neublastin) is elevated in inflamed tissue and its injection in skin causes transient thermal hyperalgesia. A genome wide expression analysis of trigeminal ganglia of mice that overexpress Artn in the skin (ART-OE mice) showed elevation in nicotinic acetylcholine receptor (nAChR) subunits, suggesting these ion channels contribute to Artn-induced sensitivity. Here we have used gene expression, immunolabeling, patch clamp electrophysiology and behavioral testing assays to investigate the link between Artn, nicotinic subunit expression and thermal hypersensitivity. Results Reverse transcriptase-PCR validation showed increased levels of mRNAs encoding the nAChR subunits α3 (13.3-fold), β3 (4-fold) and β4 (7.7-fold) in trigeminal ganglia and α3 (4-fold) and β4 (2.8-fold) in dorsal root ganglia (DRG) of ART-OE mice. Sensory ganglia of ART-OE mice had increased immunoreactivity for nAChRα3 and exhibited increased overlap in labeling with GFRα3-positive neurons. Patch clamp analysis of back-labeled cutaneous afferents showed that while the majority of nicotine-evoked currents in DRG neurons had biophysical and pharmacological properties of α7-subunit containing nAChRs, the Artn-induced increase in α3 and β4 subunits resulted in functional channels. Behavioral analysis of ART-OE and wildtype mice showed that Artn-induced thermal hyperalgesia can be blocked by mecamylamine or hexamethonium. Complete Freund’s adjuvant (CFA) inflammation of paw skin, which causes an increase in Artn in the skin, also increased the level of nAChR mRNAs in DRG. Finally, the increase in nAChRs transcription was not dependent on the Artn-induced increase in TRPV1 or TRPA1 in ART-OE mice since nAChRs were elevated in ganglia of TRPV1/TRPA1 double knockout mice. Conclusions
Elitt, Christopher M; McIlwrath, Sabrina L; Lawson, Jeffery J; Malin, Sacha A; Molliver, Derek C; Cornuet, Pamela K; Koerber, H Richard; Davis, Brian M; Albers, Kathryn M
Artemin, a neuronal survival factor in the glial cell line-derived neurotrophic factor family, binds the glycosylphosphatidylinositol-anchored protein GFRalpha3 and the receptor tyrosine kinase Ret. Expression of the GFRalpha3 receptor is primarily restricted to the peripheral nervous system and is found in a subpopulation of nociceptive sensory neurons of the dorsal root ganglia (DRGs) that coexpress the Ret and TrkA receptor tyrosine kinases and the thermosensitive channel TRPV1. To determine how artemin affects sensory neuron properties, transgenic mice that overexpress artemin in skin keratinocytes (ART-OE mice) were analyzed. Expression of artemin caused a 20.5% increase in DRG neuron number and increased the level of mRNA encoding GFRalpha3, TrkA, TRPV1, and the putative noxious cold-detecting channel TRPA1. Nearly all GFRalpha3-positive neurons expressed TRPV1 immunoreactivity, and most of these neurons were also positive for TRPA1. Interestingly, acid-sensing ion channel (ASIC) 1, 2a, 2b, and 3 mRNAs were decreased in the DRG, and this reduction was strongest in females. Analysis of sensory neuron physiological properties using an ex vivo preparation showed that cutaneous C-fiber nociceptors of ART-OE mice had reduced heat thresholds and increased firing rates in response to a heat ramp. No change in mechanical threshold was detected. Behavioral testing of ART-OE mice showed that they had increased sensitivity to both heat and noxious cold. These results indicate that the level of artemin in the skin modulates gene expression and response properties of afferents that project to the skin and that these changes lead to behavioral sensitivity to both hot and cold stimuli.
Shu-Ying, Wang; Elitt, Christopher M.; Malin, Sacha A.; Albers, Kathryn M.
Artemin is a neuronal survival and differentiation factor in the glial cell line-derived neurotrophic factor family. Its receptor GFRα3 is expressed by a subpopulation of nociceptor type sensory neurons in the dorsal root and trigeminal ganglia (DRG and TG). These neurons co-express the heat, capsaicin and proton-sensitive channel TRPV1 and the cold and chemical-sensitive channel TRPA1. To further investigate the effects of artemin on sensory neurons, we isolated transgenic mice (ART-OE mice) that overexpress artemin in keratinocytes of the skin and tongue. Enhanced levels of artemin led to a 20% increase in the total number of DRG neurons and increases in the level of mRNA encoding TRPV1 and TRPA1. Calcium imaging showed that isolated sensory neurons from ART-OE mice were hypersensitive to the TRPV1 agonist capsaicin and the TRPA1 agonist mustard oil. Behavioral testing of ART-OE mice also showed an increased sensitivity to heat, cold, capsaicin and mustard oil stimuli applied either to the skin or in the drinking water. Sensory neurons from wildtype mice also exhibited potentiated capsaicin responses following artemin addition to the media. In addition, injection of artemin into hindpaw skin produced transient thermal hyperalgesia. These findings indicate that artemin can modulate sensory function and that this regulation may occur through changes in channel gene expression. Because artemin mRNA expression is up-regulated in inflamed tissue and following nerve injury, it may have a significant role in cellular changes that underlie pain associated with pathological conditions. Manipulation of artemin expression may therefore offer a new pain treatment strategy. PMID:18958361
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Kennedy, W.J. Jr.; Turley, R.E.
A model is presented for use in comparing the energy consumption of various building construction types under two different work schedules. The model is general enough that it can be adapted to many different kinds of building construction; the input parameters are adaptable to the evaluation of many kinds of scheduling and many different possible combinations of unoccupied temperature settings. For the purposes of this analysis a manufacturing facility was selected which was patterned after a case study entitled Artos Company Manufacture of a Folding Step Stool. The analytical model used was the standard ASHRAE methodology for heating and cooling load calculations, combined with a procedure for computing solar heat loads.
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Huang, An-Cheng; Lien, Jin-Cherng; Lin, Meng-Wei; Yang, Jai-Sing; Wu, Ping-Ping; Chang, Shu-Jen; Lai, Tung-Yuan
Numerous studies have demonstrated that autophagy is associated with cancer development. Thus, agents to induce autophagy could be employed in some cases for the treatment of cancer. Our results showed that tetrandrine significantly decreased the viability of SAS cells in a concentration- and time-dependent manner. Tetrandrine induced nuclear condensation, demonstrated by DAPI staining. The early events in apoptosis analysed by Annexin V/PI staining indicated that the percentage of cells staining positive for Annexin V was slightly increased in SAS cells with tetrandrine treatment but was much lower following bafilomycin A1 pre-treatment. Tetrandrine caused AVO and MDC induction in SAS cells in a concentration-dependent manner by fluorescence microscopy. Tetrandrine also caused LC-3 expression in SAS cells in a time-dependent manner. Our results show that tetrandrine treatment induced the levels of cleaved caspase-3 in a concentration- and time-dependent manner. Tetrandrine treatment induced the levels of LC-3 II, Atg-5, beclin-1, p-S6, p-ULK, p-mTOR, p-Akt (S473) and raptor. Tetrandrine decreased cell viability, but bafilomycin A1, 3-MA, chloroquine and NAC protected tetrandrine-treated SAS cells against decrease of cell viability. Atg-5, beclin-1 siRNA decreased tetrandrine-induced cleaved caspase-3 and cleaved PARP in SAS cells and protected tetrandrine-treated SAS cells against decrease in cell viability. Chloroquine, NAC and bafilomycin A1 also decreased tetrandrine-induced cleaved caspase-3 and cleaved PARP in SAS cells. Our results indicate the tetrandrine induces apoptosis and autophagy of SAS human cancer cells via caspase-dependent and LC3-I and LC3-II‑dependent pathways.
Li, Ruiwen; Zhou, Peijiang; Guo, Yongyong; Lee, Jae-Seong; Zhou, Bingsheng
Tris (1, 3-dichloro-2-propyl) phosphate (TDCIPP), an extensively used organophosphorus flame retardant, is frequently detected in the environment and biota. Recent studies have shown that TDCIPP has neurotoxic effects. We hypothesized that the neurotoxicity might occur via the induction of the apoptosis and autophagy pathways. In the present study, we investigated TDCIPP-induced apoptotic death and autophagy in SH-SY5Y cells. Treatment with TDCIPP induced increased reactive oxygen species (ROS) generation and cell apoptosis, as well as autophagy. The autophagy inhibitor 3-methyladenine (3-MA) markedly decreased the expression of the autophagy marker beclin-1, microtubule-associated protein light chain 3-II (LC3II), p62/sequestosome 1 (SQSTM1) degradation, and promoted apoptosis. Conversely, the autophagy inducer rapamycin (Rapa) alleviated TDCIPP-induced apoptosis and markedly increased the expression of the autophagy markers. Pretreatment with N-acetyl cysteine (NAC) eliminated the increased ROS generation, resulting in increased cell viability. For further examination of the signaling pathways involved in TDCIPP-induced autophagy, compound C, a pharmacological inhibitor of adenosine monophosphate activated protein kinase (AMPK) was used. Western blotting showed that compound C markedly reduced the expression of phospho-AMPK (p-AMPK) and phospho-Unc-51-like kinase 1 (p-ULK1), increased phospho-mammalian target of rapamycin (p-mTOR) expression, and decreased beclin-1 and LC3II expression. These results suggested that the AMPK/mTOR/ULK1 signaling pathway was involved in TDCIPP-induced autophagy. The antioxidant NAC antagonized TDCIPP-induced activation of AMPK and autophagy. Taken together, our findings provide the first evidence that TDCIPP promotes apoptosis and autophagy simultaneously and that this process involves the ROS-mediated AMPK/mTOR/ULK1 pathways. Lastly, the induction of autophagy is a protective mechanism against TDCIPP-induced apoptosis.
Vodniza, A. Q.; Rojas, M.; Reyes, K.
The first amateur observation of an exoplanet was made from the Nyrola Observatory in September 16, 2000. (Marko Moilanen, Jalo Ojanperä, Jouni Sorvari, Aki Id and Arto Oksanen). The jovian-type planet orbits a star that is 153 light years far away, and was called HD209458b in Pegasus . The equipment used by this Observatory was a 16 inches MEADE LX200, a ST7E CCD SBIG camera with a V photometric filter and an f/6.3 focal distance reducer. At the University of Nariño Observatory we have a similar equipment. The equipment we employed is: 14"LX200 GPS MEADE telescope and STL-1001 SBIG. The camera we used in our search is much more sensible than the one used by the Nyrola Observatory . From the Astronomical Observatory at the University of Nariño-COLOMBIA, we begun a systematic search for exoplanets. We have already confirmed the transit of the exoplanet TrES-3. This exoplanet was discovered by O'Donovan and other investigators, and turns around the GSC 03089- 00929, with an orbital period of 1.30619 days (31.34856 hours) and inclination of 82.15 deg . The TrES-3 is quite interesting because it has one of the smallest periods found on exoplanets. Jessie L. Christiansen, et.al. observed seven transits and they found that the duration of transit is 81.9+/-1.1 minutes and inclination of 81.99+/-0.30 deg , . We have captured a lot of data to elaborate the lightcurves so we can estimate the physical parameters of the exoplanet.
Waagen, Elizabeth O.
V834 CAR = Nova Car 2012 = TCP J10502000-6406480 was discovered by John Seach, Chatsworth Island, NSW, Australia, at magnitude 10.2 on 3 images with digital SLR, 50 mm f/1.0 lens on 2012 February 26.543 UT. The discovery was confirmed by Arto Oksanen, Muurame, Finland, and Caisey Harlingten at V=10.4 from CCD images taken 2012 March 1.1552 UT with a 0.50-m telescope in San Pedro de Atacama, Chile. Coordinates (from Oksanen and Harlingten): RA 10 50 19.66 Dec. -64 06 46.7 (J2000.0). Red spectra by F. M. Walter, Stony Brook University, and M. Hernandez, Cerro Tololo Interamerican Observatory, taken Mar. 7.01 UT with the SMARTS 1.5-m telescope (+ RC spectrograph) indicate the object appears to be a classical Fe II nova near maximum. N. N. Samus, on behalf of the GCVS team, reports that the name V834 Car has been assigned to this nova. The object was listed on Central Bueau for Astronomical Telegrams Transient Objects Confirmation Page (TOCP) as TCP J10502000-6406480. The discovery was initially announced in AAVSO Special Notice #266 (Waagen); additional information was published in IAU CBET 3040 (Daniel W. E. Green, ed.) and IAU Circular 9251 (Green, ed.). Finder charts and over 3,200 visual and photometric observations of V834 Car are available from the AAVSO (http://www.aavso.org). AAVSO International Database observations show that from its discovery at magnitude 10.4 on 2012 Mar. 1-2 UT, the nova has declined to magnitude 12.2 as of 2012 Mar. 15-16 UT.