ORCID Profile
0000-0002-9618-753X
Current Organisations
Flinders University
,
University of South Australia
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Publisher: Springer Science and Business Media LLC
Date: 04-06-2018
DOI: 10.1038/S41380-018-0071-Z
Abstract: Tau pathology is characterized as a form of frontotemporal lobar degeneration (FTLD) known as FTLD-tau. The underlying pathogenic mechanisms are not known and no therapeutic interventions are currently available. Here, we report that the neurotrophin receptor p75NTR plays a critical role in the pathogenesis of FTLD-tau. The expression of p75NTR and the precursor of nerve growth factor (proNGF) were increased in the brains of FTLD-tau patients and mice (P301L transgenic). ProNGF-induced tau phosphorylation via p75NTR in vitro, which was associated with the AKT/glycogen synthase kinase (GSK)3β pathway. Genetic reduction of p75NTR in P301L mice rescued the memory deficits, alleviated tau hyperphosphorylation and restored the activity of the AKT/GSK3β pathway. Treatment of the P301L mice with the soluble p75NTR extracellular domain (p75ECD-Fc), which can antagonize neurotoxic ligands of p75NTR, effectively improved memory behavior and suppressed tau pathology. This suggests that p75NTR plays a crucial role in tau paGSKthology and represents a potential druggable target for FTLD-tau and related tauopathies.
Publisher: CSIRO Publishing
Date: 24-02-2023
DOI: 10.1071/AN22345
Abstract: Context In some regions of Australia, the Australian sheep blowfly (Lucilia cuprina) is resistant to some of the pesticides used to control flystrike in sheep. Few pesticide groups are available, so it is important to delay or prevent any increase in resistance. Aims This study examined some of the assumptions in a previously developed model of pesticide resistance and tested the use of pesticide rotations as a means of limiting blowfly resistance to pesticides. Methods A model of sheep blowfly pesticide resistance was added to a previous model of sheep blowfly strike, to allow simulation of a range of pesticide management options for control of flystrike in sheep that might avoid increasing pesticide resistance. Key results The model requires some assumptions of settings that are uncertain, but the effects are not sensitive to a wide range of values for these settings. Resistance may not be obvious for some years after a new product is introduced, but once it has been detected, the frequency of resistance genes will increase rapidly if use of the same pesticide continues. The use of different pesticide groups each year is preferable to continuous use of the same product, but this risks losing efficacy of multiple products rather than one product at a time. However, rotations do provide a longer period of good protection from flystrike before all products used in the rotation fail. The number of years of successful protection against flystrike is extended if there is a fitness disadvantage for resistance to the products used. Conclusions The model may be useful for examining interactions between genes for resistance to different pesticides and the effect of non-chemical methods of control of flystrike, to extend the useful life of the current range of pesticides. Implications By the time resistance is detected on a farm, the level of resistance is high and will increase rapidly if the same pesticides continue to be used. Other non-pesticide methods such as breeding sheep for resistance to flystrike may be long-term solutions where resistance has reduced pesticide protection.
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.BBALIP.2012.11.002
Abstract: ATP-binding cassette protein A1 (ABCA1) plays a key role in generating high-density lipoprotein (HDL). However, the detailed mechanism of HDL formation remains unclear in order to reveal it, chemicals that specifically block each step of HDL formation would be useful. Cyclosporine A inhibits ABCA1-mediated cholesterol efflux, but it is not clear whether this is mediated via inhibition of calcineurin. We analyzed the effects of cyclosporine A and related compounds on ABCA1 function in BHK/ABCA1 cells. Cyclosporine A, FK506, and pimecrolimus inhibited ABCA1-mediated cholesterol efflux in a concentration-dependent manner, with IC(50) of 7.6, 13.6, and 7.0μM, respectively. An mTOR inhibitor, rapamycin also inhibited ABCA1, with IC(50) of 18.8μM. The primary targets for these drugs were inhibited at much lower concentrations in BHK/ABCA1 cells, suggesting that they were not involved. Binding of [(3)H] cyclosporine A to purified ABCA1 could be clearly detected. Furthermore, a non-immunosuppressive cyclosporine, PSC833, inhibited ABCA1-mediated cholesterol efflux with IC(50) of 1.9μM, and efficiently competed with [(3)H] cyclosporine A binding to ABCA1. These results indicate that cyclosporine A and PSC833 inhibit ABCA1 via direct binding, and that the ABCA1 inhibitor PSC833 is an excellent candidate for further investigations of the detailed mechanisms underlying formation of HDL.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2014
DOI: 10.1007/S12035-014-8694-9
Abstract: Amyloid-beta (Aβ) is suggested to play a causal role in the pathogenesis of Alzheimer's disease (AD). Immunotherapies are among the most promising Aβ-targeting therapeutic strategies for AD. But, to date, all clinical trials of this modality have not been successful including Aβ vaccination (AN1792), anti-Aβ antibodies (bapineuzumab, solanezumab and ponezumab), and intravenous immunoglobulin (IVIG). We propose that one reason for the failures of these clinical trials may be the adverse effects of targeting the central clearance of amyloid plaques. The potential adverse effects include enhanced neurotoxicity related to Aβ oligomerization from plaques, neuroinflammation related to opsonized Aβ phagocytosis, autoimmunity related to cross-binding of antibodies to amyloid precursor protein (APP) on the neuron membrane, and antibody-mediated vascular and neuroskeletal damage. Overall, the majority of the adverse effects seen in clinical trials were associated with the entry of antibodies into the brain. Finally, we propose that peripheral Aβ clearance would be effective and safe for future Aβ-targeting therapies.
Publisher: Wiley
Date: 27-09-2018
DOI: 10.1111/JNC.14206
Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deposition of amyloid beta (Aβ) and dysregulation of neurotrophic signaling, causing synaptic dysfunction, loss of memory, and cell death. The expression of p75 neurotrophin receptor is elevated in the brain of AD patients, suggesting its involvement in this disease. However, the exact mechanism of its action is not yet clear. Here, we show that p75 interacts with beta-site amyloid precursor protein cleaving enzyme-1 (BACE1), and this interaction is enhanced in the presence of Aβ. Our results suggest that the colocalization of BACE1 and amyloid precursor protein (APP) is increased in the presence of both Aβ and p75 in cortical neurons. In addition, the localization of APP and BACE1 in early endosomes is increased in the presence of Aβ and p75. An increased phosphorylation of APP-Thr668 and BACE1-Ser498 by c-Jun N-terminal kinase (JNK) in the presence of Aβ and p75 could be responsible for this localization. In conclusion, our study proposes a potential involvement in amyloidogenesis for p75, which may represent a future therapeutic target for AD. Cover Image for this Issue: doi. 10.1111/jnc.14163.
Publisher: Springer Science and Business Media LLC
Date: 24-05-2018
DOI: 10.1007/S12035-018-1106-9
Abstract: The accumulation of excess intracellular or extracellular amyloid beta (Aβ) is one of the key pathological events in Alzheimer's disease (AD). Aβ is generated from the cleavage of amyloid precursor protein (APP) by beta secretase-1 (BACE1) and gamma secretase (γ-secretase) within the cells. The endocytic trafficking of APP facilitates amyloidogenesis while at the cell surface, APP is predominantly processed in a non-amyloidogenic manner. Several adaptor proteins bind to both APP and BACE1, regulating their trafficking and recycling along the secretory and endocytic pathways. The phosphorylation of APP at Thr668 and BACE1 at Ser498, also influence their trafficking. Neurotrophins and proneurotrophins also influence APP trafficking through their receptors. In this review, we describe the molecular trafficking pathways of APP and BACE1 that lead to Aβ generation, the involvement of different signaling molecules or adaptor proteins regulating APP and BACE1 subcellular localization. We have also discussed how neurotrophins could modulate amyloidogenesis through their receptors.
Publisher: CSIRO Publishing
Date: 2015
DOI: 10.1071/AN13265
Abstract: A model of the sheep breeding industry with nucleus flocks, multiplier flocks and commercial sheep flocks was used to examine the value of genomic selection. The model reflected a dual-purpose Merino breeding objective, with genomic information improving selection accuracy by 39% for rams at 6 months of age and by 17% at 18 months. The current level of net dollar benefit to the sheep industry from selection, but without genomic testing, can be improved by 10–14% for a closed three-tiered breeding structure with rams used at 18 months. If the rams are first used at 6–7 months then the dollar gains can be improved by 15–17%, since genomic information can provide proportionately greater gains for young animals that have limited phenotypic information. In a two-tiered breeding system, with nucleus flocks selling rams direct to commercial producers, rather than through multiplier flocks, the dollar gains to industry from genomic testing increased to ~12–13% for rams bred at 18 months, and 20–22% if nucleus rams are used at 6–7 months. The optimal structure requires two-stage selection, with an initial selection based on information available without genomic testing, to limit the cost of testing to only the superior rams. However, the optimum proportion of rams tested depends on the system and the cost of testing. In order to recover the cost of genomic testing, the nucleus flocks must recover up to 5% of the extra genetic gain as extra profit from sale of rams to commercial sheep producers.
Publisher: Springer Science and Business Media LLC
Date: 05-02-2020
Publisher: Impact Journals, LLC
Date: 03-09-2019
Publisher: CSIRO Publishing
Date: 2015
DOI: 10.1071/AN13412
Abstract: A deterministic model for predicting the prevalence of lice in sheep flocks was compared with a stochastic model. The stochastic model was based on data from 100 000 simulated farms and encompassed: a range of lice detection levels at shearing, whether or not treatment was applied where no lice were detected, the efficacy of treatments used, and the adequacy of quarantine measures against entering sheep. The deterministic model generated more extreme estimates of the effects of lice management changes, and was judged unsatisfactory for long-term decision making. Predictions based on the stochastic model were consistent with reported survey values, suggesting the stochastic model could be used to predict benefits and costs associated with changes in louse-control methods. According to the stochastic model, the two factors that could provide the greatest reduction in dollar costs were improvement of quarantine by limiting the incidence of lice entering the flock, and improvement of eradication methods. The deterministic model suggested that there would be large benefits from improvement in detection, but the stochastic model only found small dollar benefits with improved detection in the absence of changes such as more effective treatments. Changing the proportion of flocks that were treated when no lice were detected had little effect on the predicted incidence of lousy flocks.
Publisher: CSIRO Publishing
Date: 2015
DOI: 10.1071/AN14474
Abstract: A model of sheep lice management incorporating different assumed levels of lice prevalence in different regions of Australia was used to determine the conditions under which it would be cost-effective to treat sheep for lice at shearing when no lice had been detected. The probability that a flock might be infested was calculated from the probability that the previous treatment had failed to eradicate lice, purchased sheep may have introduced lice, or lice may have entered on straying sheep. The model showed that a flock should be treated if the probability of infestation is greater than 10%. It was projected that acceptance of a risk level greater than 10% would reduce treatment of flocks where no lice were present, thus reducing treatment costs. This higher risk level, however, would increase the proportion of louse-infested flocks that remained untreated, resulting in increased direct lice costs and an increase in the regional prevalence of lice, but little overall change in costs to the sheep industry. The model indicated that treatment of sheep at lower levels of risk (less than 10%) would incur unnecessary costs due to treatment of flocks where no lice were present and would not reduce the regional prevalence of lice more effectively than a 10% intervention level. The model suggested that more accurate methods of detecting lice at shearing would allow higher levels of risk, reduce the use of treatment and hence reduce overall costs associated with managing lice, without increasing the prevalence of lice.
Publisher: Springer Science and Business Media LLC
Date: 14-06-2019
DOI: 10.1007/S12035-018-1189-3
Abstract: The original version of this article unfortunately contained mistake. The old version of Fig. 3 was published.
Publisher: CSIRO Publishing
Date: 2015
DOI: 10.1071/AN14509
Abstract: The application of preventive treatment against flystrike early in spring (before strike occurs) may reduce the reproductive success of the sheep blowfly, thereby maintaining a low risk of flystrike throughout the fly season. This hypothesis has been examined using a weather-driven model of flystrike (incorporating a reduced risk due to early treatment), based on previous experimental studies. The model indicates that in the Gunning area (with a high flystrike risk), this reduction in seasonal risk would reduce total costs related to flystrike, reduce the overall use of preventive chemical treatment and reduce the number of sheep struck. However, in a lower risk area (Flinders Island), the value of early treatment would depend on the date of shearing and the local risk of flystrike. Under some conditions, no preventive treatment would be necessary in most years because of a regional low risk of flystrike, so there would be no economic benefit from always using early treatment. Early treatment is least likely to be cost-effective when shearing is required soon after the optimal date for early treatment. Further experimental studies are recommended to fully examine whether the previously reported reduction in flystrike resulting from early treatment is consistent over a wider range of climatic conditions.
Publisher: Wiley
Date: 2014
DOI: 10.1111/AVJ.12138
Abstract: This study used a model of the development of wool damage caused by lice in long wool to examine the conditions under which treatment of the sheep is advisable on an economic basis. The model uses the proportion of a flock showing visible signs of rubbing and the number of days until the next shearing to compare the cost of treatment (product plus labour) with production losses because of the reduction in wool value caused by lice. From the model output, guidelines are provided to inform producers of the most cost-effective option for lice control. Under normal conditions, if there are any signs of rubbing ≥140 days before shearing, then treatment was the best option. If signs of wool damage are not observed until there are ≤70 days before shearing, then the most cost-effective option is to not treat at all. Between these two periods, the time period in which not treating is the most cost-effective option decreases as the number of sheep visibly affected by lice increases. At higher wool values (A$70/head vs A$35), the option to treat is brought forward approximately 25 days, whereas at a low wool value (A$17.50/head) the period in which no treatment is the most cost-effective is extended by approximately 25 days. Treating only the visibly affected sheep is the best option only for a very short time for all wool values and treatment costs. The model provides guidelines for control of lice in long wool to minimise the net cost of infestation and limit unnecessary pesticide use.
Publisher: Wiley
Date: 07-2016
Publisher: MDPI AG
Date: 16-11-2018
DOI: 10.3390/ANI8110210
Abstract: Free-range laying hen systems provide in iduals a choice between indoor and outdoor areas where range use may be socially influenced. This study used radio-frequency identification technology to track the ranging of in idually-tagged hens housed in six experimental free-range pens from 28 to 38 weeks of age (46–50 hens en). All daily visits to the range were used to study group behaviour. Results showed that 67.6% (SD = 5.0%) of all hen movements through the pop-holes outdoors or indoors were following the movement of another hen (‘pop-hole-following’) compared to only 50.5% of movements in simulated random data. The percentage overlap in time that all combinations of hen pairs within each pen spent simultaneously outdoors or indoors showed a median value of overlap greater than the 90th percentile of random data. Pens housing hens that had been provided variable enrichments from 4 to 21 days (n = 3 pens) showed higher ‘pop-hole-following’ behaviour and a higher percentage of hen-pair association compared to hens reared in non-enriched conditions (n = 3 pens). These results show that birds in each free-range pen were primarily a cohesive flock and early enrichment improved this social cohesiveness. These results have implications for understanding free-range flock-level behaviour.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.BBALIP.2017.03.012
Abstract: The ATP-binding cassette transporter A7 (ABCA7), which is highly expressed in the brain, is associated with the pathogenesis of Alzheimer's disease (AD). However, the physiological function of ABCA7 and its transport substrates remain unclear. Immunohistochemical analyses of human brain sections from AD and non-AD subjects revealed that ABCA7 is expressed in neuron and microglia cells in the cerebral cortex. The transport substrates and acceptors were identified in BHK/ABCA7 cells and compared with those of ABCA1. Like ABCA1, ABCA7 exported choline phospholipids in the presence of apoA-I and apoE however, unlike ABCA1, cholesterol efflux was marginal. Lipid efflux by ABCA7 was saturated by 5μg/ml apoA-I and was not dependent on apoE isoforms, whereas efflux by ABCA1 was dependent on apoA-I up to 20μg/ml and apoE isoforms. Liquid chromatography-tandem mass spectrometry analyses revealed that the two proteins had different preferences for phospholipid export: ABCA7 preferred phosphatidylcholine (PC)≥lysoPC>sphingomyelin (SM)=phosphatidylethanolamine (PE), whereas ABCA1 preferred PC>>SM>PE=lysoPC. The major difference in the pattern of lipid peaks between ABCA7 and ABCA1 was the high lysoPC/PC ratio of ABCA7. These results suggest that lysoPC is one of the major transport substrates for ABCA7 and that lysoPC export may be a physiologically important function of ABCA7 in the brain.
Publisher: CSIRO Publishing
Date: 2016
DOI: 10.1071/AN14426
Abstract: Merino sheep infested with lice (Bovicola ovis) and with 8 months’ wool were hand jetted with a commercial spinosad formulation or treated with an α-cypermethrin backline product to examine the effect of long wool treatment on lice numbers and wool damage, relative to untreated controls. Mean lice numbers were reduced significantly (P 0.05) by treatment and then remained relatively constant until shearing 20 weeks later. Treatment with either product resulted in significant improvements in mean clean and greasy wool cut, yield, staple length, both visually assessed and measured colour, and the proportion of fleeces classed into the main fleece line. There was no significant difference between the two treatments in either efficacy in reducing louse numbers or on production characters. Wool rub score and cotting assessed on the sheep increased slightly after treatment and then did not change until shearing whereas both scores increased significantly in the untreated group. There was a strong relationship between the visual rub score and the loss of wool at shearing, indicating that rub score can be a good predictor of lice-induced reduction in fleece weights.
Publisher: Springer Science and Business Media LLC
Date: 30-04-2020
Publisher: MDPI AG
Date: 29-03-2022
Abstract: Plasminogen activator inhibitor type-2 (PAI-2), a member of the serpin family, is dramatically upregulated during pregnancy and in response to inflammation. Although PAI-2 exists in glycosylated and non-glycosylated forms in vivo, the majority of in vitro studies of PAI-2 have exclusively involved the intracellular non-glycosylated form. This study shows that exposure to inflammation-associated hypochlorite induces the oligomerisation of PAI-2 via a mechanism involving dityrosine formation. Compared to plasminogen activator inhibitor type-1 (PAI-1), both forms of PAI-2 are more resistant to hypochlorite-induced inactivation of its protease inhibitory activity. Holdase-type extracellular chaperone activity plays a putative non-canonical role for PAI-2. Our data demonstrate that glycosylated PAI-2 more efficiently inhibits the aggregation of Alzheimer’s disease and preecl sia-associated amyloid beta peptide (Aβ), compared to non-glycosylated PAI-2 in vitro. However, hypochlorite-induced modification of non-glycosylated PAI-2 dramatically enhances its holdase activity by promoting the formation of very high-molecular-mass chaperone-active PAI-2 oligomers. Both PAI-2 forms protect against Aβ-induced cytotoxicity in the SH-SY5Y neuroblastoma cell line in vitro. In the villous placenta, PAI-2 is localised primarily to syncytiotrophoblast with wide interpersonal variation in women with preecl sia and in gestational-age-matched controls. Although intracellular PAI-2 and Aβ staining localised to different placental cell types, some PAI-2 co-localised with Aβ in the extracellular plaque-like aggregated deposits abundant in preecl tic placenta. Thus, PAI-2 potentially contributes to controlling aberrant fibrinolysis and the accumulation of misfolded proteins in states characterised by oxidative and proteostasis stress, such as in Alzheimer’s disease and preecl sia.
Publisher: Wiley
Date: 07-2015
Publisher: Elsevier BV
Date: 04-2021
Publisher: Elsevier BV
Date: 07-2023
No related grants have been discovered for Noralyn Mañucat-Tan.