6,897 research outputs found
The relationship of alpha-synuclein to mitochondrial dynamics and quality control
No full textMaintenance of mitochondrial health is essential for neuronal survival and relies upon dynamic changes in the mitochondrial network and effective mitochondrial quality control mechanisms including the mitochondrial-derived vesicle pathway and mitophagy. Mitochondrial dysfunction has been implicated in driving the pathology of several neurodegenerative diseases, including Parkinson’s disease (PD) where dopaminergic neurons in the substantia nigra are selectively degenerated. In addition, many genes with PD-associated mutations have defined functions in organelle quality control, indicating that dysregulation in mitochondrial quality control may represent a key element of pathology. The most well-characterized aspect of PD pathology relates to alpha-synuclein; an aggregation-prone protein that forms intracellular Lewy-body inclusions. Details of how alpha-synuclein exerts its toxicity in PD is not completely known, however, dysfunctional mitochondria have been observed in both PD patients and models of alpha-synuclein pathology. Accordingly, an association between alpha-synuclein and mitochondrial function has been established. This relates to alpha-synuclein’s role in mitochondrial transport, dynamics, and quality control. Despite these relationships, there is limited research defining the direct mechanisms linking alpha-synuclein to mitochondrial dynamics and quality control. In this review, we will discuss the current literature addressing this association and provide insight into the proposed mechanisms promoting these functional relationships. We will also consider some of the alternative mechanisms linking alpha-synuclein with mitochondrial dynamics and speculate what the relationship between alpha-synuclein and mitochondria might mean both physiologically and in relation to PD
Investigating the relationship between alpha-synuclein and mitochondrial quality control
No full textMitochondrial quality control (mito-QC) co-ordinates dynamics changes in the mitochondrial network to maintain cellular health. Dysregulation in mito-QC has been associated with numerous pathologies, including Parkinson’s disease (PD) which is characterised by degeneration of dopaminergic neurons in the substantia nigra. The mechanism for neuronal death in PD is still not known, but it has been linked to aggregation of alpha-synuclein; a protein which pathologically forms Lewy-body inclusions. A relationship between alpha-synuclein and mito-QC has been established based on the presence of dysfunctional mitochondria in both PD patients and models of alpha-synuclein pathology. Since alpha-synuclein associates with and remodels phospholipid membranes, has a mitochondrial targeting sequence and can enter mitochondria through the TOM complex, it may have a close relationship with mitochondria in both a physiological and pathological context. Recent research has shown that monomeric alpha-synuclein may use mitochondrial membranes to seed aggregation of toxic oligomeric species, potentiating disease pathogenesis. Despite this, research often uses pre-formed fibrillar alpha-synuclein to assess pathogenic phenotypes, short-cutting the important oligomerisation process that has been hypothesised to cause more damage than the resultant fibrils. As such, we applied CRISPR/Cas9 technology to create two stable alpha-synuclein overexpression cell lines in SH-SY5Y, providing an environment that permits de-novo oligomer formation. We evaluated whether gain-of-function influenced mito-QC through analysing responses to mitochondrial damage in cells overexpressing either wild-type or A53T alpha-synuclein, the latter being a PD-associated mutant with an increased aggregation propensity. This included investigating mitochondrial-derived vesicle formation, PINK1/Parkin mitophagy and alterations in the mitochondrial network alongside probing for direct associations between alpha-synuclein and mitochondria. Our results provide a thorough assessment of the relationship between alpha-synuclein, mitochondria and the endolysosomal system in a pathological context. We hypothesise that alpha-synuclein is able to negatively influence protective mito-QC mechanisms in a pathological context
Implications of the Improvement of Teaching Quality for Professional Development (PD) of Academics at the Colleges of Applied Sciences (CASs) in the Sultanate of Oman
No full textThe Oman Accreditation Council (OAC), which is called later the Oman Academic Accreditation Authority (OAAA), designed a higher education institution (HEI) Quality Assurance (QA) framework for Omani public and private Higher Education Institutions (HEIs), starting with a quality audit process in 2008. The Colleges of Applied Sciences (CASs), as a public HEI, are required to ensure the quality of all services and activities to meet particular national standards (specified in the framework) in order to gain a HEI and programme certificate. In line with a quality audit scope, the quality of the fields of PD and related teaching quality should be ensured and enhanced by the promotion and contribution of the former field to the maintenance and improvement of the latter one.
The chief purpose of this study was to identify the uptake and implications of the growing requirement to improve teaching quality and the PD of academics at the CASs in the Sultanate of Oman especially in the context of the application of the QA framework. The study focused on examining the academics’ participation in professional development programmes (PDPs) and current perceptions of PD with respect to the improvement of teaching quality improvement at these colleges. The current study also dealt with a reorganization and prioritization of academics’ PD needs, barriers to effective PD, and factors to enhance PD of academics regarding teaching quality improvement in the colleges.
Based on the purpose and research objectives, the current study adopted both positivist (quantitative) and interpretive (qualitative) research paradigms. Because the study perused quantitative and qualitative data regarding certain variables, it chose a mixed-research design. The researcher designed survey questionnaire to collect quantitative data and a semi-structured interview and a focus group discussion to probe and interpret quantitative findings. After fulfillment of the validity and reliability measurements, a self-completion questionnaire was distributed to a stratified random sample of academics (170) over the six CASs. A total of 150 questionnaires (out of 170) were completed and returned and the response-rate reached 88.2%. The quantitative data was analyzed by appropriate analysis using the Statistical Package for Social sciences (SPSS), while the qualitative data was analyzed by appropriate qualitative analysis.
The findings of the study showed that the level of academics’ participation in PDPs to improve teaching quality in the last two years in the CASs seems to be unsatisfactorily low. The current perceptions of the PD situations in the colleges, relating to teaching quality improvement, signified a shortage in the number of available PDPs and/or a discouragement of academics’ participation in these programmes in the last two years. The study also revealed all the 22 PD needs of academics regarding the improvement of teaching quality are significantly demanded by participants; the higher rated needs focused on a development of ‘student centred’ skills, such as critical thinking and problem-solving skills.
Furthermore, the study illustrated that the highest significant perceived barriers to effective PD in the CASs, as related to teaching quality improvement, focus on a lack of a clear institutional PD policy and a lack of appropriately systematic PD plans. The study also revealed all 10 perceived factors to enhance PD regarding teaching quality improvement are very important. The most significant factors represented and stressed particular problematic issues (the high rated barriers) and a reduction of a heavy workload to enhance academics’ participation in PD regarding the improvement of teaching quality.
Conclusions drawn from the discussion of the findings of study include a lack of a clear PD policy at national and institutional levels and absence of a particular authority/unit concerning PD issues in Omani HEIs. The two problematic issues resulted in a lack of systematic and realistic PD plans in the CASs, involving a lack of academics’ involvement in PD plans, a misconnection of academics’ PD needs to PD, inappropriate facilities and resources allocation, and inappropriate evaluation processes of PD. In addition, the conclusions also include that PD of academics regarding the improvement of teaching quality in the colleges requires more attention and focus to manage particular significant issues perceived by participants as both barriers and potential facilitators relating to PD of academics.
Based on identified conclusions, particular implications for policy and practice to enhance PD to improve teaching quality were set at three levels: governmental, institutional, and individual. Moreover, achievements of the current study according to the research questions were identified and contributions of the study to the fields of PD, teaching quality, and the context of QA and quality audit in HE were addressed. Based on the findings and conclusions, particular directions and recommended issues were suggested to be studied by further research to benefit the enhancement of PD and related teaching quality improvement
Investigating the impact of alterations in alpha-synuclein on mitochondrial health, mitochondrial quality control and neuronal differentiation
No full textMitochondrial quality control (mito-QC) co-ordinates dynamic changes in the mitochondrial network that maintain optimal function and cell health. Dysregulated mito-QC has been associated with numerous pathologies, including Parkinson’s disease (PD) which is characterised by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The mechanisms of neuronal death in PD are still unknown, but have been linked to the aggregation of a-synuclein; a protein which pathologically forms intracellular inclusions, known as Lewy bodies, in PD brains. A relationship between a-synuclein and mito-QC has been established based on the presence of dysfunctional mitochondria in both PD patients and models of a-synuclein pathology. However, exactly how a-synuclein may impact mito-QC mechanisms is not well understood. Recent research has shown that a-synuclein can use mitochondrial membranes to seed aggregation of toxic oligomeric species, resulting in mitochondrial dysfunction and potentiating disease pathogenesis. Though the majority of research has focused on the hypothesis that pathological a-synuclein may exhibit a toxic gain-of-function that disrupts mito-QC, it is also possible that this could occur through a-synuclein loss-of-function. Since a-synuclein associates with and remodels phospholipid membranes, has been suggested to contain a mitochondrial targeting sequence and can be mitochondrially imported, it may have a physiological role in mito-QC that is lost under pathological circumstances.In an a-synuclein loss-of-function model, I observe that physiological a-synuclein is not required for mitochondrial energy production or co-ordination of mito-QC. I do not find evidence of a direct functional association between endogenous a-synuclein and mitochondria, however I suggest that a-synuclein may modulate autophagy flux and lysosomal morphology through its action as a cytosolic molecular chaperone. This provides novel insight into a-synuclein’s physiological function in the context of mito-QC. I also investigated the impact of pathological a-synuclein on mito-QC, where I found that a-synuclein overexpression did not disrupt mitochondrial function or damage-induced whole mitochondrial clearance, but did influence autophagosome number and lysosomal size. Since alterations in these phenotypes were also seen in my loss-of-function model, I consider that physiological a-synuclein may have a role in modulating autophagy that is disrupted in pathological circumstances such as PD.Overexpression of ³-synuclein also increased mitochondrial fragmentation and mitochondrial-derivedvesicles (MDVs) at steady state, suggesting that excess ³-synuclein increases the baseline mito-QC response. I suggest that upregulation of these responses may occur due to an a-synuclein-induced increase in oxidative stress. Together, these data indicate that pathological a-synuclein, rather than a lack of physiological a-synuclein, is primarily responsible for dysregulated mitochondrial function in PD.Since a-synuclein’s pathological impact primarily occurs in dopaminergic neurons of the SNpc, it would be important to further investigate interactions between a-synuclein and mito-QC in a model that better recapitulates this neuronal environment. Accordingly, I generated a neuronal model through differentiation of SH-SY5Y cells that can be used for future work. In this study, I characterised how perturbations in a-synuclein expression impacted neuronal phenotype in differentiated cells, finding that overexpression of a-synuclein A53T, but not wild-type, reduced neuronal morphology and expression of neuronal markers. Interestingly, a-synuclein knockout cells showed a similar but less exaggerated phenotype, suggesting that defects in neuronal differentiation in both cell lines may be explained by loss of physiological a-synuclein activity. This provides insight into a-synuclein’s role in neuronal development
Fullerene-like WS<sub>2</sub> supported Pd catalyst for hydrogen evolution reaction
No full textHydrogen is the most desirable green energy carrier and electrocatalytic hydrogen evolution reaction (HER) from water is a promising route for hydrogen production. The search for efficient, low-cost HER catalysts is a challenging and attracting topic. In this work, we report that inorganic fullerene-like WS2 supported Pd nanoparticles (Pd/WS2), with Pd loading of 0.76 wt%, are active for electrocatalytic HER conducted in 0.5 M H2SO4 solution, with overpotential at 10 mA cm−2 current density of ~130 mV and Tafel slope of 82.4 mV dec−1, which is comparable to that of Pt/WS2 (0.88 wt% Pt loading) with higher costs. Characteristic results indicate that WO3 impurities were in-situ produced on the WS2 surface and the Pd NPs are primarily located inside the WS2 nanocages. Contrasting experiments suggest that the WO3 impurities play a crucial role in generating Hads intermediate and the Pd NPs are active sites of H2 production, and a reaction mechanism is proposed. The Pd/WS2 catalyst also shows good long-term stability owing to the location of Pd NPs inside the WS2 cages. The high HER activity, low costs and good stability make the Pd catalyst a potential alternative to Pt catalyst for HER.Green Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Micro and Nano Engineerin
Enhanced T-Cell Immunity to Osteosarcoma Through Antibody Blockade of PD-1/PD-L1 Interactions
No full textabstract: Osteosarcoma is the most common bone cancer in children and adolescents. Although 70% of patients with localized disease are cured with chemotherapy and surgical resection, patients with metastatic osteosarcoma are typically refractory to treatment. Numerous lines of evidence suggest that cytotoxic T lymphocytes (CTLs) limit the development of metastatic osteosarcoma. We have investigated the role of PD-1, an inhibitory TNFR family protein expressed on CTLs, in limiting the efficacy of immune-mediated control of metastatic osteosarcoma. We show that human metastatic, but not primary, osteosarcoma tumors express a ligand for PD-1 (PD-L1) and that tumor-infiltrating CTLs express PD-1, suggesting this pathway may limit CTLs control of metastatic osteosarcoma in patients. PD-L1 is also expressed on the K7M2 osteosarcoma tumor cell line that establishes metastases in mice, and PD-1 is expressed on tumor-infiltrating CTLs during disease progression. Blockade of PD-1/PD-L1 interactions dramatically improves the function of osteosarcoma-reactive CTLs in vitro and in vivo, and results in decreased tumor burden and increased survival in the K7M2 mouse model of metastatic osteosarcoma. Our results suggest that blockade of PD-1/PD-L1 interactions in patients with metastatic osteosarcoma should be pursued as a therapeutic strategy.This is a non-final version of an article published in final form as Lussier, Danielle M., O'Neill, Lauren, Nieves, Lizbeth M., McAfee, Megan S., Holechek, Susan A., Collins, Andrea W., Dickman, Paul, Jacobsen, Jeffrey, Hingorani, Pooja, & Blattman, Joseph N. (2015). Enhanced T-Cell Immunity to Osteosarcoma Through Antibody Blockade of PD-1/PD-L1 Interactions. JOURNAL OF IMMUNOTHERAPY, 38(3), 96-106. http://dx.doi.org/10.1097/CJI.000000000000006
Restoration of lowland raised bogs damaged by peat extraction - with particular emphasis on Sphagnum regeneration.
No full text1. Revegetation trends in abandoned peat workings indicate that peat cuttings are
generally too dry for spontaneous re-establishment of raised bog vegetation. The latter
was restricted to small flooded peat pits which had recolonised 'hydroserally' to
support floating rafts of bog vegetation.
2. The water storage capacity of cut-over bog surfaces is low compared with
undisturbed bog and blocking drains in a peat field at Thorne Moors, S. Yorks, was
insufficient to prevent water-table instability. Experiments suggest this may severely
inhibit Sphagnum growth. Lagoons may increase water storage on a bog surface and
facilitate development of raised bog vegetation as floating rafts. This 'hydroseral'
approach may be necessary to restore raised bog vegetation to some areas.
3. Hydrochemical conditions of cut-over sites may differ significantly from
undisturbed bogs with implications for Sphagnum growth. Water samples from a peat
field at Thorne Moors were comparatively acidic and contained comparatively high
concentrations of most major ions (particularly NH4 and SO4), except phosphorus.
Moderate nutrient enrichment is unlikely to adversely affect Sphagnum and additions
of phosphorus to flooded peat pits significantly increased its growth. In solution
culture, low pH (3.0-3.5) was sub-optimal for Sphagnum growth, but the use of
CaCO3 to reduce acidity in the field had a toxic effect.
4. Sphagnum recolonisation may be limited by availability of propagules in cut-over
areas. Experiments indicate that deliberate re-introduction encourages Sphagnum raft
development, which is pioneered by aquatic species that regenerate more prolifically
from fragments than intact gametophytes. Sphagnum rafts are encouraged in shallow
water (< 5 0cm) and pools of small area. Numerous management options exist
physically and chemically assisting raft development
Modeling of Surface Segregation for Binary Alloys in Vacuum and Gas Environments: Applied to Pd-alloys
No full textComputational modeling offers the possibility to design alloys in a cheaper and faster way. A model for surface segregation for binary alloys in vacuum and by adsorption and absorption of gases was developed and applied. The proposed model was used in conjunction with the Miedema semi-empirical model for the calculation of enthalpies of solution and formation of binary alloys and with the cluster variation method (CVM) for the calculation of the ? and ? phase boundaries in the ternary Pd-M-H systems. The models for segregation were applied in a temperature range from 298K to 600K, considering the surface plane (111) of the FCC crystal structure. The model for segregation in vacuum was applied to Pd-Au, Pd-Ag, Pd-Cu, Pd-Ni and Pd-Pt. For this case Pd is segregated for the Pd-Pt alloys only. By increasing the temperature from 298K to 600K, the surface concentrations of Pd decreased for all of the alloys. By varying the plane from (111) to (100) few changes were observed. The calculated results compared to experiments were found to be in good agreement for Pd-Au and Pd-Ag. For the model of surface segregation by adsorption and chemisorption, H2, CO and O2 gases on Pd-Ag, Pd-Cu, Pd-Ni and Pd-Pt were considered. In the presence of adsorbed or chemisorbed hydrogen, segregation of Pd was found for Pd-Ag, Pd-Cu and Pd-Pt alloys. For adsorbed O2 and CO on Pd-Ag and Pd-Cu alloys gases, segregation of Pd was enhanced. The model for segregation by absorption of hydrogen was applied for Pd-Ag, Pd-Cu, Pd-Ni and Pd-Pt alloys, using a hydrogen (bulk) concentration of 0.50 H/M. No Pd segregation was found for Pd-Ag alloys. For Pd-Pt alloys, Pd segregation was observed. For Pd-Cu alloys with large concentrations of Pd, a surface enrichment of Pd was calculated, while for alloys with low concentration of Pd a slight Cu surface enrichment was observed. Enhanced segregation of Ni was found for Pd-Ni alloys. The H/M fractions at the boundaries of the ? and ? phase obtained with the CVM for the Pd85Ag15H system were used as input values to calculate the surface concentration of Ag. As the hydrogen concentration was increased, the surface segregation of Pd also increased. For the surface segregation by adsorption and absorption combined, segregation of Pd was observed for Pd-Ag, Pd-Cu and Pd-Pt alloys. Surface enrichment of Ni was found for Pd-Ni alloys. The proposed model enables to predict surface segregation under various conditions and the results show that it is affected by many parameters.Master Materials Science and EngineeringDepartment of Materials Science and EngineeringMechanical, Maritime and Materials Engineerin
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Novel fuzzy logic controllers with self-tuning capability
No full textTwo controllers which extend the PD+I fuzzy logic controller to deal with the plant having time varying nonlinear dynamics are proposed. The adaptation ability of the first self tuning PD+I fuzzy logic controller (STPD+I_31) is achieved by adjusting the output scaling factor automatically thereby contributing to significant improvement in performance. Second controller (STPD+I_9) is the simplified version of STPD+I_31 which is designed under the imposed constraint that allows only minimum number of rules in the rule bases. The proposed controllers are compared with two classical nonlinear controllers: the pole placement self tuning PID controller and sliding mode controller. All the controllers are applied to the two-links revolute robot for the tracking control. The tracking performance of STPD+I_31 and STPD+I_9 are much better than the pole placement self tuning PID controller during high speed motions while the performance are comparable at low and medium speed. In addition, STPD+I_31 and STPD+I_9 outperform sliding mode controller using same method of comparison study
Metrological Qualification of PD Analysers for Insulation Diagnosis of HVDC and HVAC Grids
No full textOn-site partial discharge (PD) measurements have turned out to be a very efficient technique for determining the insulation condition in high-voltage electrical grids (AIS, cable systems, GIS, HVDC converters, etc.); however, there is not any standardised procedure for determining the performances of PD measuring systems. In on-line and on-site PD measurements, high-frequency current transformers (HFCTs) are commonly used as sensors as they allow for monitoring over long distances in high-voltage installations. To ensure the required performances, a metrological qualification of the PD analysers by applying an evaluation procedure is necessary. A novel evaluation procedure was established to specify the quantities to be measured (electrical charge and PD repetition rate) and to describe the evaluation tests considering the measured influence parameters: noise, charge amplitude, pulse width and time interval between consecutive pulses. This procedure was applied to different types of PD analysers used for off-line measurements, sporadic on-line measurements and continuous PD monitoring. The procedure was validated in a round-robin test involving two metrological institutes (RISE from Sweden and FFII from Spain) and three universities (TUDelft from the Netherlands, TAU from Finland and UPM from Spain). With this round-robin test, the effectiveness of the proposed qualification procedure for discriminating between efficient and inappropriate PD analysers was demonstrated. Furthermore, it was shown that the PD charge quantity can be properly determined for on-line measurements and continuous monitoring by integrating the pulse signals acquired with HFCT sensors. In this case, these sensors must have a flat frequency spectrum in the range between several tens of kHz and at least two tens of MHz, where the frequency pulse content is more significant. The proposed qualification procedure can be useful for improving the future versions of the technical specification TS IEC 62478 and the standard IEC 60270.High Voltage Technology Grou
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