59 research outputs found
PGC-1alpha Down-Regulation Affects the Antioxidant Response in Friedreich's Ataxia
BACKGROUND: Cells from individuals with Friedreich's ataxia (FRDA) show reduced activities of antioxidant enzymes and cannot up-regulate their expression when exposed to oxidative stress. This blunted antioxidant response may play a central role in the pathogenesis. We previously reported that Peroxisome Proliferator Activated Receptor Gamma (PPARgamma) Coactivator 1-alpha (PGC-1alpha), a transcriptional master regulator of mitochondrial biogenesis and antioxidant responses, is down-regulated in most cell types from FRDA patients and animal models. METHODOLOGY/PRINCIPAL FINDINGS: We used primary fibroblasts from FRDA patients and the knock in-knock out animal model for the disease (KIKO mouse) to determine basal superoxide dismutase 2 (SOD2) levels and the response to oxidative stress induced by the addition of hydrogen peroxide. We measured the same parameters after pharmacological stimulation of PGC-1alpha. Compared to control cells, PGC-1alpha and SOD2 levels were decreased in FRDA cells and did not change after addition of hydrogen peroxide. PGC-1alpha direct silencing with siRNA in control fibroblasts led to a similar loss of SOD2 response to oxidative stress as observed in FRDA fibroblasts. PGC-1alpha activation with the PPARgamma agonist (Pioglitazone) or with a cAMP-dependent protein kinase (AMPK) agonist (AICAR) restored normal SOD2 induction. Treatment of the KIKO mice with Pioglitazone significantly up-regulates SOD2 in cerebellum and spinal cord. CONCLUSIONS/SIGNIFICANCE: PGC-1alpha down-regulation is likely to contribute to the blunted antioxidant response observed in cells from FRDA patients. This response can be restored by AMPK and PPARgamma agonists, suggesting a potential therapeutic approach for FRDA.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe
Safety and Effectiveness of SAF-R, a Novel Patient Positioning Device for Robot-Assisted Pelvic Surgery in Trendelenburg Position
Novel microsatellite markers for conservation of Australian native Samadera bidwillii
Ashwath, N ORCiD: 0000-0002-4032-4507; Naik, VM ORCiD: 0000-0002-6223-5484Microsatellite markers were developed for Samadera bidwillii, a nationally listed vulnerable shrub or small tree, to enable investigation of its genetic structure and diversity within and among populations from its known distribution throughout coastal areas mainly in fragmented and disturbed lands from Mackay to Gympie, Queensland, Australia. The loci were tested for cross-amplification in related Samadera species. Ten polymorphic microsatellite markers were isolated and characterised from an enriched library of S. bidwillii, which exhibited di- and trinucleotide repeats. The mean number of alleles per locus ranged from 1.3 to 2.5 and mean expected and observed heterozygosities ranged from 0.06 to 0.33 and from 0.03 to 0.26, respectively in five populations. All loci successfully amplified in six other closely associated Samadera species also reported from Australia. Developed loci can be used in genetic diversity, population structure and gene flow studies with an emphasis on the conservation of S. bidwillii and related species
Optogenetic investigation of the LGN koniocellular influence on V1 activity
The lateral geniculate nucleus (LGN) of the primate thalamus is organized into parallel parvo-, magno- and konio-cellular projection streams to primary visual cortex (V1). While magno and parvo cells label positive for Parvalbumin and project to layer-4 of V1, konio neurons project to the superficial layers of V1 and are positive for CamKII and Calbindin [1] [2]. Of the three systems, our understanding of the konio pathway and its contribution to vision is still very limited. Here we used optogenetics in anaesthetized macaque monkeys to investigate the influence of koniocellular LGN neurons on V1. To this end we injected the construct AAV5-CamKIIa-ChR2-eYFP into the LGN of two monkeys. Post-mortem histological and immunohistochemical analysis verified that ChR2 expression was predominantly present in the koniocellular system, which is characterized by its expression of CamKII and a focus on the LGN intercalated layers. In earlier experiments optogenetic stimulation that was applied to neurons in the LGN intercalated layers resulted in activation of the superficial layers in V1, but not layer 4, as determined from current-source-density measurements (CSD) from multi-contact laminar recordings in V1. Preliminary analysis of the cortical LFP also showed a power decrease in the beta frequency range (15-30Hz) for the superficial layers during optogenetic stimulation. In additional control experiments in one monkey, we found that electrical micro-stimulation in a parvocellular layer activated layer 4 of V1 similar to visual flicker stimulation. In contrast, electrical microstimulation in the intercalated LGN layers induced activity in superficial layers of V1 similarly to the optogenetic stimulation. In summary, we show for the first time the effective connectivity of the koniocellular LGN projection to V1 and its influence on the LFP. Methodologically, our results demonstrate that both circuit probing approaches, optogenetics and electrical microstimulation, render results with very similar specificity. Reference 1. Hendry, S.H. and T. Yoshioka, A neurochemically distinct third channel in the macaque dorsal lateral geniculate nucleus. Science, 1994. 264(5158): p. 575-577. 2. Casagrande, V.A., et al., The morphology of the koniocellular axon pathway in the macaque monkey. Cereb Cortex, 2007. 17(10): p. 2334-2345
Functional identification of primate lateral geniculate nucleus projections to visual cortex using optogenetics and electrical stimulation
Optogenetics and electrical stimulation are routinely used to assess neuronal connectivity. However cell-specific approaches, especially in primates, are still very limited. Here we compare the capacities of optogenetics and electrical stimulation to isolate the specific pathways from the lateral geniculate nucleus (LGN) to primary visual cortex (V1) in the macaque visual system. The organization of LGN into three anatomically separate and neurochemically distinct cell projection systems with virtually no cross-talk provides unique conditions to test for cell-specific targeting by electrical and optogenetic stimulation techniques. For the optogenetics experiments, we injected AAV5-CamKIIα-ChR2-eYFP into the LGN of four macaque monkeys. Histological analysis revealed primarily the predicted laminar expression pattern of the optogenetic construct in CamKIIα-rich LGN konio layers, but also showed some expression in parvalbumin positive magno- and parvo cells. We also observed a retrograde tracing mechanism of the AAV5 virus particles that labeled V1 layer 6 cortico-thalamic feedback neurons and retinal ganglion cells. That expression of the construct also allowed modulation of spiking activity in LGN was confirmed in prior electrophysiology experiments. Neurons expressing ChR2 could be identified reliably based on their short latency (<5ms) spiking responses to direct blue light (473nm) stimulation. Parallel laminar-resolved recordings of the V1 local field potential showed that selective activation of LGN konio layers with optogenetics caused selective electrical current inflow in the supra-granular layers of V1 in agreement with anatomical predictions about the koniocellular projection. Electrical stimulation of LGN konio layers revealed the same supra-granular V1 activation pattern. In contrast, electrical stimulation of LGN parvo layers activated also V1 granular layers in a way that closely resembled visual stimulus driven responses. These findings indicate comparable capacities of both stimulation methods to isolate and identify spatially segregated thalamo-cortical circuit mechanisms of the primate brain
Neuron
Electrical microstimulation and more recently optogenetics are widely used to map large-scale brain circuits. However, the neuronal specificity achieved with both methods is not well understood. Here we compare cell-targeted optogenetics and electrical microstimulation in the macaque monkey brain to functionally map the koniocellular lateral geniculate nucleus (LGN) projection to primary visual cortex (V1). Selective activation of the LGN konio neurons with CamK-specific optogenetics caused selective electrical current inflow in the supra-granular layers of V1. Electrical microstimulation targeted at LGN konio layers revealed the same supra-granular V1 activation pattern as the one elicited by optogenetics. Taken together, these findings establish a selective koniocellular LGN influence on V1 supra-granular layers, and they indicate comparable capacities of both stimulation methods to isolate thalamo-cortical circuits in the primate brain
Establishing user needs for a stability assessment tool to guide wheelchair prescription
Purpose: The WheelSense project aims to develop a system for assessing the stability and performance of wheelchairs through a user-centred design process. This study sought to capture user needs and define the specification for the system. Method: A mixed methods approach was adopted. An online survey was completed by 98 participants working in wheelchair provision. The results were built upon through 10 semi-structured interviews and one focus group (n = 5) with professionals working in wheelchair provision in three NHS Trusts in the UK. Results: The results provided a picture of the current UK practice in stability testing. Issues with the reliability and usefulness of the existing methods used to assess the stability and performance of wheelchairs were highlighted. Requirements for a new system were ascertained. These included improved accuracy of tipping angles, features to support record keeping, improved client/carer education support and ability to model or predict client-wheelchair system performance in different configurations. Conclusions: The paper concludes that there is a need for improved tools to determine the stability of the client-wheelchair system and support the prescription process, to ensure client safety and optimum equipment performance. A list of requirements has been produced to guide the future development of WheelSense.
Implications for Rehabilitation
The results of this survey and interview-based study present a picture of wheelchair stability testing practices in the UK, and highlight the need for new, more informative methods for guiding wheelchair prescription.
The requirements for the design of a new system, or further development of existing tools to support the stability testing and prescription of wheelchairs have been established
A novel system for wheelchair stability assessment : design and initial results
Wheelchairs should provide safe and reliable functioning in various road conditions and situations, ease of propulsion, and high maneuverability. Often, wheelchairs need further modification and installation of additional equipment (ventilators, oxygen cylinders, etc) which affect their stability. Wheelchair stability is also dependent on a user's body characteristics that can result in a shifting of the centre of mass e.g. limb amputations, and obesity, etc. Adaptation of the wheelchair requires additional assessment and wheelchair tuning by highly skilled rehabilitation engineers. In this paper, we discuss the design and initial testing of a novel wheelchair stability assessment system. The developed WheelSense system consists of a force platform that senses the weight distribution of the wheelchair, the centre of the contact points, and the distances between contact points of the wheels. The measurement platform is linked via WiFi connection to a portable tablet computer where the platform's sensor signals are processed and the wheelchair stability parameters are calculated. An intuitive touchscreen GUI is used for visualization of the stability results and navigation through separate measurement modes. The mechanical platform was designed to be foldable and light-weighted and thus, to be easily transportable which gives additional advantages when the system is used outside of a clinical engineering department. The initial design is being evaluated through four prototype systems installed for clinical testing in 3 large hospitals in the UK. The initial results indicate that the developed measurement system possesses high accuracy and ease of operatio
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