Effective therapies for peripheral nerve repair are still lacking despite active research in this field over the past years.The limited knowledge of biomolecules that equally promote axon regeneration and glial cell d...Effective therapies for peripheral nerve repair are still lacking despite active research in this field over the past years.The limited knowledge of biomolecules that equally promote axon regeneration and glial cell dynamics,which are critical for nerve regeneration,poses a major challenge in developing effective therapies.Here,we showed that the neurotrophic factor mesencephalic astrocyte-derived neurotrophic factor(MANF)equally promotes axon regeneration and glial cell dynamics favorable for nerve regeneration.Using adult rodent models,we showed that the endogenous expression of MANF is restricted to non-peptidergic sensory neurons.However,supplementation of exogenous MANF promoted the growth of all subtypes of adult sensory neurons.We also demonstrated that exogenous MANF promotes the proliferation and migration of adult primary Schwann Cells(SCs).Furthermore,we showed that local and repeated administration of MANF to injured nerves promotes axon regeneration in mice models.Finally,we devised a therapeutic approach by programming nerve-resident SCs to locally and continuously deliver MANF to injured nerves and showed that this approach improves axon regeneration.Overall,this work developed a therapeutic approach by harnessing the power of SCs as a local delivery system for MANF for nerve repair.展开更多
Radio Frequency Interferences (RFI), such as strong Continuous Wave Interferences (CWI), can influence the Quality of Service (QoS) of communications, increasing the Bit Error Rate (BER) and decreasing the Signal-to-N...Radio Frequency Interferences (RFI), such as strong Continuous Wave Interferences (CWI), can influence the Quality of Service (QoS) of communications, increasing the Bit Error Rate (BER) and decreasing the Signal-to-Noise Ratio (SNR) in any wireless transmission, including in a Digital Video Broadcasting (DVB-S2) receiver. Therefore, this paper presents an algorithm for detecting and mitigating a Multi-tone Continuous Wave Interference (MCWI) using a Multiple Adaptive Notch Filter (MANF), based on the lattice form structure. The Adaptive Notch Filter (ANF) is constructed using the second-order IIR NF. The approach consists in developing a robust low-complexity algorithm for removing unknown MCWI. The MANF model is a multistage model, with each stage consisting of two ANFs: the adaptive IIR notch filter <i>H</i><i><sub>l</sub></i>(<i>z</i>) and the adaptive IIR notch filter <i>H</i><i><sub>N</sub></i>(<i>z</i>), which can detect and mitigate CWI. In this model, the ANF is used for estimating the Jamming-to-Signal Ratio (JSR) and the frequency of the interference (<i>w(0)</i>) by using an LMS-based algorithm. The depth of the notch is then adjusted based on the estimation of the JSR. In contrast, the ANF <i>H</i><i><sub>N</sub></i>(<i>z</i>) is used to mitigate the CW interference. Simulation results show that the proposed ANF is an effective method for eliminating/reducing the effects of MCWI, and yields better system performance than full suppression (<i>k<sub>N</sub></i>=1) for low JSR values, and mostly the same performance for high JSR values. Moreover, the proposed can detect low and high JSR and track hopping frequency interference and provides better Bit error ratio (BER) performance compared to the case without an IIR notch filter.展开更多
Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) are involved in neuroprotection and mitigating endoplasmic reticulum (ER) stress in the brain and peripheral ...Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) are involved in neuroprotection and mitigating endoplasmic reticulum (ER) stress in the brain and peripheral organs. In earlier work, an increase in histone acetylation, following treatment with an epigenetic modulator, valproic acid, was associated with induction of CDNF and MANF in cultured cells and rat brain. These findings prompted an investigation of the effects of DNA methyltransferase (DNMT) inhibitors, which can alter epigenetic function, on the expression of CDNF and MANF. Rat C6 glioma cells were treated with a micromolar range of DNMT inhibitors: 5-aza-2’-deoxycytidine (DAC or decitabine), 5-azacytidine (AZA) or zebularine (ZEB) for 24 h. Subsequently, qPCR analysis was used to examine the mRNA expression of DNMT1, ten-eleven translocation methylcytosine dioxygenase 2 (TET-2), CDNF and MANF. A significant dose-dependent decrease in DNMT1 mRNA levels, together with a significant increase in TET-2 expression, was observed following treatment with AZA or DAC. Importantly, DAC, AZA and ZEB caused a significant dose-dependent increase in CDNF mRNA levels. In contrast, MANF mRNA expression decreased following treatment with AZA, with no significant effects observed with DAC or ZEB. Western analysis revealed no significant changes in CDNF protein levels following treatment with DAC for 24 h. The significant increase in CDNF expression, following treatment with DNMT1 inhibitors, suggests that DNA methylation is involved in the regulation of this neurotrophic factor. Clarification of the epigenetic or other mechanisms underlying the regulation of CDNF may provide novel therapeutic approaches in neurodegenerative and ER stress-related disorders.展开更多
基金supported by the College of Medicine Research Award from the College of Medicine at the University of Saskatchewan to AK(Krishnan)supported by the Natural Sciences and Engineering Research Council(NSERC)of Canada Discovery Launch Supplement(DGECR-2020-00049)to AKthe CoMGRAD fellowship from the College of Medicine to BS.
文摘Effective therapies for peripheral nerve repair are still lacking despite active research in this field over the past years.The limited knowledge of biomolecules that equally promote axon regeneration and glial cell dynamics,which are critical for nerve regeneration,poses a major challenge in developing effective therapies.Here,we showed that the neurotrophic factor mesencephalic astrocyte-derived neurotrophic factor(MANF)equally promotes axon regeneration and glial cell dynamics favorable for nerve regeneration.Using adult rodent models,we showed that the endogenous expression of MANF is restricted to non-peptidergic sensory neurons.However,supplementation of exogenous MANF promoted the growth of all subtypes of adult sensory neurons.We also demonstrated that exogenous MANF promotes the proliferation and migration of adult primary Schwann Cells(SCs).Furthermore,we showed that local and repeated administration of MANF to injured nerves promotes axon regeneration in mice models.Finally,we devised a therapeutic approach by programming nerve-resident SCs to locally and continuously deliver MANF to injured nerves and showed that this approach improves axon regeneration.Overall,this work developed a therapeutic approach by harnessing the power of SCs as a local delivery system for MANF for nerve repair.
文摘Radio Frequency Interferences (RFI), such as strong Continuous Wave Interferences (CWI), can influence the Quality of Service (QoS) of communications, increasing the Bit Error Rate (BER) and decreasing the Signal-to-Noise Ratio (SNR) in any wireless transmission, including in a Digital Video Broadcasting (DVB-S2) receiver. Therefore, this paper presents an algorithm for detecting and mitigating a Multi-tone Continuous Wave Interference (MCWI) using a Multiple Adaptive Notch Filter (MANF), based on the lattice form structure. The Adaptive Notch Filter (ANF) is constructed using the second-order IIR NF. The approach consists in developing a robust low-complexity algorithm for removing unknown MCWI. The MANF model is a multistage model, with each stage consisting of two ANFs: the adaptive IIR notch filter <i>H</i><i><sub>l</sub></i>(<i>z</i>) and the adaptive IIR notch filter <i>H</i><i><sub>N</sub></i>(<i>z</i>), which can detect and mitigate CWI. In this model, the ANF is used for estimating the Jamming-to-Signal Ratio (JSR) and the frequency of the interference (<i>w(0)</i>) by using an LMS-based algorithm. The depth of the notch is then adjusted based on the estimation of the JSR. In contrast, the ANF <i>H</i><i><sub>N</sub></i>(<i>z</i>) is used to mitigate the CW interference. Simulation results show that the proposed ANF is an effective method for eliminating/reducing the effects of MCWI, and yields better system performance than full suppression (<i>k<sub>N</sub></i>=1) for low JSR values, and mostly the same performance for high JSR values. Moreover, the proposed can detect low and high JSR and track hopping frequency interference and provides better Bit error ratio (BER) performance compared to the case without an IIR notch filter.
文摘Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) are involved in neuroprotection and mitigating endoplasmic reticulum (ER) stress in the brain and peripheral organs. In earlier work, an increase in histone acetylation, following treatment with an epigenetic modulator, valproic acid, was associated with induction of CDNF and MANF in cultured cells and rat brain. These findings prompted an investigation of the effects of DNA methyltransferase (DNMT) inhibitors, which can alter epigenetic function, on the expression of CDNF and MANF. Rat C6 glioma cells were treated with a micromolar range of DNMT inhibitors: 5-aza-2’-deoxycytidine (DAC or decitabine), 5-azacytidine (AZA) or zebularine (ZEB) for 24 h. Subsequently, qPCR analysis was used to examine the mRNA expression of DNMT1, ten-eleven translocation methylcytosine dioxygenase 2 (TET-2), CDNF and MANF. A significant dose-dependent decrease in DNMT1 mRNA levels, together with a significant increase in TET-2 expression, was observed following treatment with AZA or DAC. Importantly, DAC, AZA and ZEB caused a significant dose-dependent increase in CDNF mRNA levels. In contrast, MANF mRNA expression decreased following treatment with AZA, with no significant effects observed with DAC or ZEB. Western analysis revealed no significant changes in CDNF protein levels following treatment with DAC for 24 h. The significant increase in CDNF expression, following treatment with DNMT1 inhibitors, suggests that DNA methylation is involved in the regulation of this neurotrophic factor. Clarification of the epigenetic or other mechanisms underlying the regulation of CDNF may provide novel therapeutic approaches in neurodegenerative and ER stress-related disorders.
