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1. The role of HRS phosphorylation in endosomal trafficking and signalling

Author

Grimes, D. J.

Subjects
616.3
Abstract

Hepatocyte growth factor receptor substrate (HRS) is a component of the ESCRT-0 complex. It is involved in the sorting of ubiquitylated receptors into the lumen of multivesicular bodies (MVBs), thus targeting them for lysosomal degradation. HRS is highly phosphorylated in response to stimulation by various growth factors, but despite this, the functional role of its phosphorylation is still contentious. Preliminary data from our laboratory suggested that HRS may also act as a signalling adaptor, involved in the crosstalk between receptor tyrosine kinases (RTKs) and G protein couple receptors (GPCRs). In order to investigate this hypothesis, I first examined the EGF dependent interactors of HRS by mass spectrometry. I then developed tools for the measurement of endosomal cAMP production and PKA signalling. My data suggests that HRS interacts with the E3 ligase deltex3-like (DTX3L) in an EGF dependent manner. Although an association between these proteins has previously been made, its EGF dependence is novel. DTX3L has previously been shown to modulate the recruitment of HRS to endosomes in response to stimulation of the G-protein coupled receptor CXCR4. This new finding offers a theoretical means through which different receptor classes could crosstalk and elicit an integrated signalling response. I further show that GFP-HRS is recruited directly to newly formed vesicles containing EGF and its receptor. Recruitment of HRS to endosomes/vesicles in response to TGFα, but not EGF, is partly dependent on phospho-tyrosine residues Y329 and Y334. Furthermore, HRS has recently been implicated in the recruitment of the recycling complex WASH to endosomes. This, combined with the previous observation, suggests that phosphorylation of these two sites may be involved in receptor recycling. Overall, my thesis generates new tools for the study of HRS function and for the analysis of endosomal signalling. I provide evidence for the role of HRS in RTK and GPCR crosstalk alongside providing insights into the mechanisms governing recruitment of HRS.

Published
2019
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4. ASCEND: a randomised, double-blinded, placebo-controlled, phase II study of gemcitabine and nab-paclitaxel with LSTA1 in untreated metastatic pancreatic adenocarcinoma. An Australasian Gastro-Intestinal Trials Group (AGITG) trial

Author

Lee, J., primary, Dean, A., additional, Price, T., additional, Sjoquist, K., additional, Gebski, V., additional, Mumford, J., additional, Day, F., additional, Yip, S., additional, Wilson, K., additional, Jackson, C., additional, Padinharakam, S., additional, Lee, B., additional, Burge, M., additional, Siu, D., additional, Karapetis, C., additional, Chantrill, L., additional, Wong, Z.W., additional, Jennens, R., additional, Lomma, C., additional, Franscesconi, A., additional, Ackland, S., additional, Lynam, J., additional, Wahlroos, S., additional, So, J., additional, Jameson, M., additional, Tebbutt, N., additional, Gill, S., additional, Grimes, D., additional, Steer, C., additional, and Harris, M., additional

Published
2023
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6. The effects of applied water at various fractions of measured evapotranspiration on water relations and vegetative growth of Thompson Seedless grapevines

Author

Williams, L. E., Grimes, D. W., and Phene, C. J.

Subjects
Life Sciences, Climate Change, Sustainable Development, Waste Water Technology / Water Pollution Control / Water Management / Aquatic Pollution, Environment, general, Agriculture
Abstract

Vegetative growth and water relations of Thompson Seedless grapevines in response to applied water amounts at various fractions of measured grapevine ETc were quantified. Treatments ranged from no applied water up to 1.4 times the water used by vines growing in a weighing lysimeter. All treatments were irrigated at the same frequency as the vines in the lysimeter (whenever they used 2 mm of water), albeit at their respective fraction. Soil water content and midday leaf water potential (Ψl) were measured routinely in four of the irrigation treatments across years. The amount of water depleted in the soil profile ranged from 190 mm for the 0.2 treatment in 1993 to no water depletion for the 1.4 treatment in 1992. The irrigation treatments significantly affected midday Ψl, total shoot length, leaf area per vine, pruning weights and trunk diameter; as applied water decreased so did vegetative growth. Pruning weights were a linear function of the seasonal, mean midday Ψl across growing seasons. The application of water amounts in excess of evapotranspiration negatively affected vegetative growth some of the years. A companion paper will demonstrate that over-irrigation can negatively affect reproductive growth of this grape cultivar due to excess vegetative growth.

Published
2010

7. The effects of applied water at various fractions of measured evapotranspiration on reproductive growth and water productivity of Thompson Seedless grapevines

Author

Williams, Larry E., Grimes, D. W., and Phene, C. J.

Subjects
Life Sciences, Climate Change, Sustainable Development, Waste Water Technology / Water Pollution Control / Water Management / Aquatic Pollution, Environment, general, Agriculture
Abstract

The reproductive growth and water productivity (WPb) of Thompson Seedless grapevines were measured as a function of applied water amounts at various fractions of measured grapevine ETc for a total of eight irrigation treatments. Shoots were harvested numerous times during the growing season to calculate water productivity. Berry weight was maximized at the 0.6–0.8 applied water treatments across years. As applied water amounts increased soluble solids decreased. Berry weight measured at veraison and harvest was a linear function of the mean midday leaf water potential measured between anthesis and veraison and anthesis and harvest, respectively. As applied water amounts increased up to the 0.6–0.8 irrigation treatments there was a significant linear increase in yield. Yields at greater applied water amounts either leveled off or decreased. The reduction in yield on either side of the yearly maximum was due to fewer numbers of clusters per vine. Maximum yield occurred at an ETc ranging from 550 to 700 mm. Yield per unit applied water and WPb increased as applied water decreased. The results from this study demonstrated that Thompson Seedless grapevines can be deficit irrigated, increasing water use efficiency while maximizing yields.

Published
2010

10. Validation of the Rainbow Model of Integrated Care Measurement Tool in Parkinson's Disease.

Author

Valentijn, P.P., Eggers, C., Bloem, B.R., Grimes, D., Goldman, J., McGinley, J., Gardner, J., Piemonte, M.E.P., Dahodwala, N., Brennan, L., Iansek, R., Kovacs, N., Parashos, S., Hilel, A., Rajan, R., Valentijn, P.P., Eggers, C., Bloem, B.R., Grimes, D., Goldman, J., McGinley, J., Gardner, J., Piemonte, M.E.P., Dahodwala, N., Brennan, L., Iansek, R., Kovacs, N., Parashos, S., Hilel, A., and Rajan, R.

Abstract

01 juli 2023, Contains fulltext : 296073.pdf (Publisher’s version ) (Open Access), BACKGROUND: Integrated care is essential for improving the management and health outcomes for people with Parkinson's disease (PD); reliable and objective measures of care integration are few. OBJECTIVE: The aim of this study was to test the psychometric properties of the Rainbow Model of Integrated Care Measurement Tool (RMIC-MT, provider version) for healthcare professionals involved in PD care. METHODS: A cross-sectional survey was administered online to an international network representing 95 neurology centers across 41 countries and 588 healthcare providers. Exploratory factor analysis with principal axis extraction method was used to assess construct validity. Confirmatory factor analysis was used to evaluate model fit of the RMIC-MT provider version. Cronbach's alpha was used to assess the internal consistency reliability. RESULTS: Overall, 371 care providers (62% response rate) participated in this study. No item had psychometric sensitivity problems. Nine factors (professional coordination, cultural competence, triple aims outcome, system coordination, clinical coordination, technical competence, community-centeredness, person-centeredness, and organizational coordination) with 42 items were determined by exploratory factor analysis. Cronbach's alpha ranged from 0.76 (clinical coordination) to 0.94 (system coordination) and showed significant correlation among all items in the scale (>0.4), indicating good internal consistency reliability. The confirmatory factor analysis model passed most goodness-of-fit tests, thereby confirming the factor structure of nine categories with a total of 40 items. CONCLUSIONS: The results provide evidence for the construct validity and other psychometric properties of the provider version of the RMIC-MT to measure integrated care in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Published
2023

12. Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Task Force on Postovulatory Methods of Fertility Regulation.

Author

Grimes, D, von Hertzen, H, Piaggio, G, Van Look, PFA, Peregoudov, S, Vucurevic, M, Roberts, HE, Wu, SC, Bagshaw, SN, Otubu, JA, Ogedengbe, OK, Pretnar-Darovec, A, Kirkman, RJ, Ding, JH, Mittal, S, Leavesley, G, Austin, KL, Creinin, M, Adetoro, OO, Guilbert, E, Chen, JK, Bygdeman, M, Bartfai, G, Khomassuridze, A, Cheng, WY, Oyunbileg, A, Sparrow, M, and Reg, Task Force Postovulatory Methods Fertility

Subjects
Humans, Emergencies, Nausea, Vomiting, Ethinyl Estradiol, Levonorgestrel, Estradiol Congeners, Contraceptives, Oral, Combined, Contraceptives, Postcoital, Contraceptives, Oral, Synthetic, Risk, Double-Blind Method, Pregnancy, Pregnancy, Unwanted, Time Factors, Adult, Female, Contraceptives, Oral, Combined, Postcoital, Synthetic, Unwanted, General & Internal Medicine, Medical and Health Sciences
Abstract

BackgroundA previous randomised study suggested that the progestagen, levonorgestrel, given alone in two separate doses each of 0.75 mg caused nausea and vomiting in fewer women and might be more effective than the Yuzpe regimen of combined oral contraceptives for emergency contraception, although the difference was not significant. We compared these two regimens when started within 72 h of unprotected coitus.MethodsWe enrolled in the double-blind, randomised trial 1998 women at 21 centres worldwide. Women with regular menses, not using hormonal contraception, and requesting emergency contraception after one unprotected coitus, received levonorgestrel (0.75 mg, repeated 12 h later) or the Yuzpe regimen (ethinyloestradiol 100 microg plus levonorgestrel 0.5 mg, repeated 12 h later).FindingsOutcome was unknown for 43 women (25 assigned levonorgestrel, 18 assigned Yuzpe regimen). Among the remaining 1955 women, the crude pregnancy rate was 1.1% (11/976) in the levonorgestrel group compared with 3.2% (31/979) in the Yuzpe regimen group. The crude relative risk of pregnancy for levonorgestrel compared with the Yuzpe regimen was 0.36 (95% CI 0.18-0.70). The proportion of pregnancies prevented (compared with the expected number without treatment) was 85% (74-93) with the levonorgestrel regimen and 57% (39-71) with the Yuzpe regimen. Nausea (23.1 vs 50.5%) and vomiting (5.6 vs 18.8%) were significantly less frequent with the levonorgestrel regimen than with the Yuzpe regimen (p

Published
1998

18. Preparation of high orbital angular momentum Rydberg states by optical-millimeter-wave STIRAP.

Author

Barnum, T. J., Herburger, H., Grimes, D. D., Jiang, J., and Field, R. W.

Subjects
RYDBERG states, ANGULAR momentum (Mechanics)
Abstract

Rydberg states of molecules are intrinsically challenging to study due to the presence of fast non-radiative decay pathways, such as predissociation. However, selectively exciting Rydberg states with values of the orbital angular momentum (ℓ) ℓ ≳ 3 is a productive strategy to minimize this rapid decay and to populate molecular Rydberg states with lifetimes that approach those of atoms. In this proof-of-principle demonstration, we transfer population to an nf Rydberg state of the calcium atom by stimulated Raman adiabatic passage, in which an optical and a millimeter-wave field couple the initial and final states via an intermediate nd Rydberg state. Numerical simulations reproduce the observed time and frequency dependences of the population transfer and suggest the utility of this scheme to populate high-ℓ Rydberg states of molecules. [ABSTRACT FROM AUTHOR]

Published
2020
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22. Team Description: UW Huskies-01

Author

Azari, D., Burns, J.K., Deshmukh, K., Fox, D., Grimes, D., Kwok, C.T., Pitkanen, R., Shon, A.P., Tressel, P., Goos, G., editor, Hartmanis, J., editor, van Leeuwen, J., editor, Carbonell, Jaime G., editor, Siekmann, Jörg, editor, Birk, Andreas, editor, Coradeschi, Silvia, editor, and Tadokoro, Satoshi, editor

Published
2002
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24. Together through tough times: A qualitative study of community resilience to protect against mental health issues in the UK

Author

Southby, K, Bidey, T, Grimes, D, Khor, Z, South, J, Bagnall, AM, Southby, K, Bidey, T, Grimes, D, Khor, Z, South, J, and Bagnall, AM

Abstract

Purpose Living in an area experiencing economic and social disadvantage is a known risk factor to poor mental health and well-being. This paper aims to understand how some communities experiencing disadvantage appear to be more resilient to the enduring challenges they face and display better mental health outcomes. Design/methodology/approach A qualitative case study approach was used. Semi-structured interviews (total = 74) were undertaken remotely with residents (n = 39) and voluntary, community and social enterprise groups, community leaders and other local stakeholders (n = 35) in four case study areas. Data analysis was cross-case, thematic analysis. Community analysis workshops (n = 4) and resilience mapping workshops (n = 4) in each site corroborated emerging insights. Findings Four overlapping and interacting themes support community resilience: community hubs and local voluntary, community and social enterprise (VCSE) networks; opportunities to participate and make connections within communities; open and supportive environments to talk about mental health and well-being; and community identities and collective narratives. Differences in access to these resources was a cross-cutting theme. Originality/value Community resilience can be understood in terms of the amount of resources – articulated in terms of capital – that communities can draw on in response to challenges, and how well these resources are mobilised. A thriving VCSE sector is important for community resilience in communities experiencing disadvantage as a mechanism for both sustainably building and mobilising community resources in the face of daily and enduring challenges.

Published
2022

25. The role of the polycystin genes, Pkd1l1 and Pkd2, in the determination of left-right asymmetry

Author

Grimes, D, Robertson, E, Blum, M, Norris, D, and Srinivas, S

Subjects
Developmental biology
Abstract

Breaking bilateral symmetry is critical for vertebrate morphogenesis. In the mouse, overt left-right (L-R) asymmetries in the development of the organs is prefigured by asymmetric cascades of genes expression. The Nodal/Pitx2 pathway is active in the left lateral plate mesoderm (LPM) and remains absent from the right side of the embryo. Expression of Nodal in the left side is initiated downstream of a symmetry-breaking event that occurs in a midline structure called the node. Within the node, 200-300 posteriorly-tilted motile cilia rotate in the clockwise direction when viewed from the ventral aspect, and in so doing generate a unidirectional leftward flow of extra-cellular fluid across the surface of the node. This flow drives both an elevation in intracellular Ca2+ and changes in gene expression at the left side of the node, the first L-R asymmetrical chemical differences in the embryo. However, a major unanswered question concerns how leftward flow is sensed by the embryo, and what genes/pathways play a role in this process. Two mutant mouse lines were discovered as part of forward genetic screens for embryos with developmental defects. These two lines, called rks and lrm4, both exhibit severe L-R defects. Mapping of the mutants revealed lrm4 to be a new allele of Pkd2, a gene known to be required for the left-sided Ca2+ elevation which occurs downstream of flow in the node. In contrast, rks was mapped to a novel gene not previously associated with L-R determination. The protein encoded by this gene, Pkd1l1, was a candidate for being the elusive sensor of leftward flow. This thesis describes experiments aimed at testing the hypothesis that Pkd1l1 and Pkd2 act together to sense leftward flow in the node during the determination of L-R asymmetry in the mouse. The overt morphological and molecular L-R defects of Pkd1l1rks/rks and Pkd2lrm4/lrm4 mutants are compared and found to be highly similar when assessed on the same genetic background. Both mutants exhibit a loss of the normally left-sided Nodal/Pitx2 pathway and, as a consequence, right isomerism of the lungs. Pkd1l1 gene expression is localised to the ventral layer of the node where flow is generated and sensed, but neither Pkd1l1 nor Pkd2 are required for normal node morphogenesis or cilia structure/motility. Moreover, genetic experiments reveal that Pkd1l1 and Pkd2 both act downstream of leftward flow but upstream of early asymmetries in gene expression around the node. In contrast to Pkd1l1rks/rks mutants, Pkd1l1-null embryos exhibit left lung isomerism and bilateral activation of Pitx2. This surprising observation suggests that Pkd1l1 restricts Nodal to the left side during L-R determination, favouring a model in which leftward flow derepresses left-sided Nodal by inhibiting Pkd1l1. Bioinformatics and structural studies support a role for an extracellular polycystic kidney disease (PKD) domain within Pkd1l1 in the sensation of flow, whilst Pkd1l1 and Pkd2 are also shown to form physical associations mediated by intracellular coiled coil domains. Finally, Pkd2 is shown to be required within the cilial compartment for L-R determination. In conclusion, the results reported in this thesis support a model in which Pkd1l1 and Pkd2 act together for the sensation of leftward flow and specifically implicate Pkd1l1's extracellular PKD domain in the sensation mechanism.

Published
2022

35. Internal Bore Evolution Across the Shelf Near Pt. Sal CA interpreted as a Gravity Current

Author

Spydell, M. S., primary, Suanda, S. H., additional, Grimes, D. J., additional, Becherer, J., additional, McSweeney, J. M., additional, Chickadel, C., additional, Moulton, M., additional, Thomson, J., additional, Lerczak, J., additional, Barth, J., additional, MacMahan, J., additional, Colosi, J., additional, Romeiser, R., additional, Waterhouse, A. F., additional, Calantoni, J., additional, and Feddersen, Falk, additional

Published
2021
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46. The AGITG GAP Study: A Phase II Study of Perioperative Gemcitabine and Nab-Paclitaxel for Resectable Pancreas Cancer.

Author

Bagia S., Chua Y.J., Pavlakis N., Goldstein D., Aghmesheh M., Joubert W., Grimes D., Harris M., Burge M., Samra J.S., Haghighi K.S., Truskett P., Simes J., Jaber M., Gananadha S., O'Rourke N., Bryant R., Nathanson L., Cavallucci D., Barbour A., Fawcett J., O'Rourke T., Croagh D., Jones R., Chan H., Gebski V.J., Croagh D.G., Kench J.G., Hicks R., Coates A., Gurney H., Do V., Marschner I., Mitchell J., Donoghoe M., Goldstone S., Yip S., Barbour A.P., Donoghoe M.W., Harris M.T., Bagia S., Chua Y.J., Pavlakis N., Goldstein D., Aghmesheh M., Joubert W., Grimes D., Harris M., Burge M., Samra J.S., Haghighi K.S., Truskett P., Simes J., Jaber M., Gananadha S., O'Rourke N., Bryant R., Nathanson L., Cavallucci D., Barbour A., Fawcett J., O'Rourke T., Croagh D., Jones R., Chan H., Gebski V.J., Croagh D.G., Kench J.G., Hicks R., Coates A., Gurney H., Do V., Marschner I., Mitchell J., Donoghoe M., Goldstone S., Yip S., Barbour A.P., Donoghoe M.W., and Harris M.T.

Abstract

Background: While combination therapy with nab-paclitaxel/gemcitabine (nab-gem) is effective in pancreatic ductal adenocarcinoma (PDAC), its efficacy as perioperative chemotherapy is unknown. The primary objective of this multicenter, prospective, single-arm, phase II study was to determine whether neoadjuvant therapy with nab-gem was associated with higher complete resection rates (R0) in resectable PDAC, while the secondary objectives were to determine the utility of radiological assessment of response to preoperative chemotherapy and the safety and efficacy of nab-gem as perioperative therapy. Method(s): Patients were recruited from eight Australian sites, and 42 patients with radiologically defined resectable PDAC and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled. Participants received two cycles of preoperative nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on days 1, 8, and 15 (28-day cycle) presurgery, and four cycles postoperatively. Early response to chemotherapy was measured with fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scans on day 15. Result(s): Preoperative nab-gem was completed by 93% of participants, but only 63% postoperatively. Thirty-six patients had surgery: 6 (17%) were unresectable, 15 (52%) had R0 (>= 1 mm) resections, 14 (48%) had R1 (< 1 mm) resections, and 1 patient did not have PDAC. Median progression-free survival was 12.3 months and median overall survival (OS) was 23.5 months: R0 patients had an OS of 35 months versus 25.6 months for R1 patients after surgery. Seven patients had not progressed after 43 months. Conclusion(s): The GAP trial demonstrated that perioperative nab-gem was tolerable. Although the primary endpoint of an 85% R0 rate was not met, the R0 rate was similar to trials using a > 1 mm R0 resection definition, and survival rates were comparable with recent adjuvant studies.Copyright © 2020, Society of Surgical Oncology.

Published
2020

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