The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding pla...The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding plays a role in ALS pathogenesis in two ways: non-ATG translation of the repeat can lead to aggregates of the known C9orf72 specific dipeptide polymer, whereas the repeat also can form neurotoxic RNA inclusions that dose-responsively kill motor neurons. We report the presence of a homology in the 5’untranslated region (UTR) of the messenger RNA encoding C9orf72 with the iron responsive elements (IRE) that control expression of iron-associated transcripts and predict that this RNA structure may iron-dependently regulate C9orf72 translation. We previously report altered serum ferritin levels track with severity of ALS in patients. Here, we conduct bioinformatics analyses to determine the secondary structure of the 5’UTR in C9orf72 mRNA and find it aligned with IREs in the human mitochondrial cis-aconitase and L and H-ferritin transcripts. Comparison of the role of RNA repeats in Friedriech’s ataxia and fragile X mental retardation suggests the utility of RNA based therapies for treatment of ALS. Antisense oligonucleotides (ASO) have been reported to therapeutically target these GGGGCC repeats. At the same time, because the function of C9orf72 is unknown, knockdown strategies carry some risk of inducing or compounding haploinsufficiency. We propose, for consideration, an approach that may enhance its therapeutic dynamic range by increasing the 5’UTR driven translation of C9orf72 protein to compensate for any potential ALS-specific or ASO-induced haploinsufficieny.展开更多
Metal nano layer coating for increasing the sensitivity of spectroscopic measurements is proposed and experimentally demonstrated in this paper. The metal nano layer will attract the micro-poisons from any measured aq...Metal nano layer coating for increasing the sensitivity of spectroscopic measurements is proposed and experimentally demonstrated in this paper. The metal nano layer will attract the micro-poisons from any measured aqueous sample increasing the concentration of the micro-poison in the vicinity of the surface and significantly improves the sensitivity of the spectroscopic measurement. The demonstration was carried out using Fourier Transform Infra-Red (FTIR) operating in the MIR 400 cm-1 - 4000 cm-1 and 5 nm Gold layer which was grown on silicon oxide substrate. In the experimental demonstration Malathion organophosphate pesticide was used as micro-poison. The spectroscopic measurement proves that Malathion was attracted to the metal nano layer. Furthermore, the absorption lines of Malathion were detected and recognized. This proof of principle can be applied to any Internal Reflection Elements (IRE) and it can be used to purify any aqueous solutions and atmosphere from micro-poisons which will be attracted to the metal Nano layer.展开更多
Objective:To examine whether exposure of mouse neuronal cells to radiofrequency fields used in mobile communication devices can induce stress in endoplasmic reticulum(ER)and activate unfolded protein response(UPR).Met...Objective:To examine whether exposure of mouse neuronal cells to radiofrequency fields used in mobile communication devices can induce stress in endoplasmic reticulum(ER)and activate unfolded protein response(UPR).Methods:HT22 mouse hippocampus neuronal cells were exposed to continuous wave 900 MHz radiofrequency fields(RF)at 120μW/cm2 power intensity for 4 h/d for 5 consecutive days.The positive control cells were irradiated with 4 Gy of 60Coγ-rays at a dose rate of 0.5 Gy/min(GR).Twenty-four hours after the last exposure,cells were collected,and the expressions of sensor transmembrane proteins were detected using Western blot analysis.Results:The expression levels of Ire1,PERK,p-IRE1 and p-PERK,GRP78 and CHOP proteins were detected.There were no statistically significant differences in the expression levels of IRE1 and PERK proteins in control(CT),sham(SH)-,RF-and GR-exposed cells(P<0.05).The phosphorylated protein levels of p-IRE1 and p-PERK were significantly increased in cells exposed to RF and GR(P<0.05).The expression levels of GRP78 and CHOP were significantly increased in RF-and GR-exposed cells compared to CT and SH-exposed cells(P<0.05).Cells treated with 1μg/ml TM for 24 h showed significantly increased expression levels of GRP78 and CHOP proteins compared to controls(P<0.05).In the presence of 2 mmol/L PBA,TM-induced increased levels of GRP78 and CHOP proteins were reduced(P<0.05).Conclusions:The exposure of non-ionizing 900 MHz RF was able to cause stress in HT22 mouse neuronal cells and activated UPR in ER.Since UPR plays an important role in both cell survival(when UPR is mitigated)and apoptosis/death(under unresolvable stress conditions),further studies are required to determine the fate of the cells exposed to RF.展开更多
文摘The hexanucleotide repeat mutation in the intron-1 of the chromosome 9 open reading frame (C9orf72) is a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Altered RNA folding plays a role in ALS pathogenesis in two ways: non-ATG translation of the repeat can lead to aggregates of the known C9orf72 specific dipeptide polymer, whereas the repeat also can form neurotoxic RNA inclusions that dose-responsively kill motor neurons. We report the presence of a homology in the 5’untranslated region (UTR) of the messenger RNA encoding C9orf72 with the iron responsive elements (IRE) that control expression of iron-associated transcripts and predict that this RNA structure may iron-dependently regulate C9orf72 translation. We previously report altered serum ferritin levels track with severity of ALS in patients. Here, we conduct bioinformatics analyses to determine the secondary structure of the 5’UTR in C9orf72 mRNA and find it aligned with IREs in the human mitochondrial cis-aconitase and L and H-ferritin transcripts. Comparison of the role of RNA repeats in Friedriech’s ataxia and fragile X mental retardation suggests the utility of RNA based therapies for treatment of ALS. Antisense oligonucleotides (ASO) have been reported to therapeutically target these GGGGCC repeats. At the same time, because the function of C9orf72 is unknown, knockdown strategies carry some risk of inducing or compounding haploinsufficiency. We propose, for consideration, an approach that may enhance its therapeutic dynamic range by increasing the 5’UTR driven translation of C9orf72 protein to compensate for any potential ALS-specific or ASO-induced haploinsufficieny.
文摘Metal nano layer coating for increasing the sensitivity of spectroscopic measurements is proposed and experimentally demonstrated in this paper. The metal nano layer will attract the micro-poisons from any measured aqueous sample increasing the concentration of the micro-poison in the vicinity of the surface and significantly improves the sensitivity of the spectroscopic measurement. The demonstration was carried out using Fourier Transform Infra-Red (FTIR) operating in the MIR 400 cm-1 - 4000 cm-1 and 5 nm Gold layer which was grown on silicon oxide substrate. In the experimental demonstration Malathion organophosphate pesticide was used as micro-poison. The spectroscopic measurement proves that Malathion was attracted to the metal nano layer. Furthermore, the absorption lines of Malathion were detected and recognized. This proof of principle can be applied to any Internal Reflection Elements (IRE) and it can be used to purify any aqueous solutions and atmosphere from micro-poisons which will be attracted to the metal Nano layer.
基金This research is supported by funding from the National Natural Science Foundation of China(Grant No.81373025).
文摘Objective:To examine whether exposure of mouse neuronal cells to radiofrequency fields used in mobile communication devices can induce stress in endoplasmic reticulum(ER)and activate unfolded protein response(UPR).Methods:HT22 mouse hippocampus neuronal cells were exposed to continuous wave 900 MHz radiofrequency fields(RF)at 120μW/cm2 power intensity for 4 h/d for 5 consecutive days.The positive control cells were irradiated with 4 Gy of 60Coγ-rays at a dose rate of 0.5 Gy/min(GR).Twenty-four hours after the last exposure,cells were collected,and the expressions of sensor transmembrane proteins were detected using Western blot analysis.Results:The expression levels of Ire1,PERK,p-IRE1 and p-PERK,GRP78 and CHOP proteins were detected.There were no statistically significant differences in the expression levels of IRE1 and PERK proteins in control(CT),sham(SH)-,RF-and GR-exposed cells(P<0.05).The phosphorylated protein levels of p-IRE1 and p-PERK were significantly increased in cells exposed to RF and GR(P<0.05).The expression levels of GRP78 and CHOP were significantly increased in RF-and GR-exposed cells compared to CT and SH-exposed cells(P<0.05).Cells treated with 1μg/ml TM for 24 h showed significantly increased expression levels of GRP78 and CHOP proteins compared to controls(P<0.05).In the presence of 2 mmol/L PBA,TM-induced increased levels of GRP78 and CHOP proteins were reduced(P<0.05).Conclusions:The exposure of non-ionizing 900 MHz RF was able to cause stress in HT22 mouse neuronal cells and activated UPR in ER.Since UPR plays an important role in both cell survival(when UPR is mitigated)and apoptosis/death(under unresolvable stress conditions),further studies are required to determine the fate of the cells exposed to RF.
