The expression of ADAM-9 and -10 in prostate cancer and their regulation by dihydrotestosterone, insulin-like growth Factor-1 and epidermal growth factor

Prostrate Cancer(PCa)is the most common cause of cancer death amongst Western males. PCa occurs in two distinct stages. In its early stage, growth and development is dependent primarily on male sex hormones (androgens) such as testosterone, although other growth factors have roles maintaining PCa cell survival in this stage. In the later stage of PCa development, growth and.maintenance is independent of androgen stimulation and growth factors including Insulin-like Growth Factor -1 (IGf.:·l) and Epidermal Growth Factor (EGF) are thought to have more crucial roles in cell survival and PCa progression. PCa, in its late stages, is highly aggressive and metastatic, that is, tumorigenic cells migrate from the primary site of the body (prostate) and travel via the systemic and lymphatic circulation, residing and colonising in the bone, lymph node, lung, and in more rare cases, the brain. Metastasis involves both cell migration and tissue degradation activities. The degradation of the extracellular matrix (ECM), the tissue surrounding the organ, is mediated in part by members of a family of 26 proteins called the Matrix Metalloproteases (MMPs), whilst ceil adhesion molecules, of which proteins known as Integrins are included, mediate ce11 migration. A family of proteins known as the ADAMs (A Disintegrin . And Metalloprotease domain) were a recently characterised family at the commencement of this study and now comprise 34 members. Because of their dual nature, possessing an active metaiioprotease domain, homologous to that of the MMPs, and an integrin-binding domain capable of regulating cell-cell and cell-ECM contacts, it was thought likely that members of the ADAMs family may have implications for the progression of aggressive cancers such as those ofthe prostate. This study focussed on two particular ADAMs -9 and -10. ADAM-9 has an active metalloprotease domain, which has been shown to degrade constituents of the ECM, including fibronectin, in vitro. It also has an integrin-binding capacity through association with key integrins involved in PCa progression, such as a6~1. ADAM-10 has no such integrin binding activities, but its bovine orthologue, MADM, is able to degrade coHagen type IV, a major component of basement membranes. It is likely human ADAM-10 has the same activity. It is also known to cleave Ll -a protein involved in cell anchorage activities - and collagen type XVII - which is a principal component of the hemidesmosomes of cellular tight junctions. The cleavage of these proteins enables the cell to be released from the surrounding environment and commence migratory activities, as required in metastasis. Previous studies in this laboratory showed the mRNA expression of the five ADAMs -9,- 10, -11, -15 and -17 in PCa cell lines, characteristic of androgen-dependent and androgen independent disease. These studies were furthered by the characterisation of AD AM-9, -10 and -17 mRNA regulation by Dihydrotestosterone (DHT) in the androgen-responsive cell line (LNCaP). ADAM-9 and -10 mRNA levels were elevated in response to DHT stimulation. Further to these observations, the expression of ADAM-9 and -10 was shown in primary prostate biopsies from patients with PCa. ADAM-1 0 was expressed in the cytoplasm and on the ceH membrane in epithelial and basal cells ofbenign prostate glands, but in high-grade PCa glands, ADAM-I 0 expression was localised to the nucleus and its expression levels appeared to be elevated when compared to low-grade PCa glands. These studies provided a strong background for the hypothesis that ADAM-9 and -10 have key roles in the development ofPCa and provided a basis for further studies.The aims of this study were to: 1) characterise the expression, localisation and levels, of ADAM-9 and -10 mRNA and protein in cell models representing characteristics of normal through androgen-dependent to androgen-independent PCa, as well as to expand the primary PCa biopsy data for ADAM-9 and ADAM-10 to encompass PCa bone metastases 2) establish an in vitro cell system, which could express elevated levels of ADAM-1 0 so that functional cell-based assays such as cell migration, invasion and attachment could be carried out, and 3) to extend the previous hormonal regulation data, to fully characterise the response of ADAM-9 and -10 mRNA and protein levels to DHT, IGF-1, DHT plus IGF-1 and EGF in the hormonal/growth factor responsive cell line LNCaP. For aim 1 (expression of ADAM-9 and -10 mRNA and protein), ADAM-9 and -10 mRNA were characterised by R T -PCR, while their protein products were analysed by Western blot. Both ADAM-9 and -10 mRNA and protein were expressed at readily detectable levels across progressively metastatic PCa cell lines model that represent characteristics of low-grade,. androgen-dependent (LNCaP and C4) to high-grade, androgen-independent (C4-2 and C4-2B) PCa. When the non-tumorigenic prostate cell line RWPE-1 was compared with the metastatic PCa cell line PC-3, differential expression patterns were seen by Western blot analysis. For ADAM-9, the active form was expressed at higher levels in RWPE-1, whilst subcellular fractionation showed that the active form of ADAM-9 was predominantly located in the cell nucleus. For ADAM-I 0, in both of the cell Jines, a nuclear specific isoform of the mature, catalytically active ADAM-I 0 was found. This isoforrn differed by -2 kDa in Mr (smaller) than the cytoplasmic specific isoform. Unprocessed ADAM-I 0 was readily detected in R WPE-1 cell lines but only occasionally detected in PC-3 cell lines. Immunocytochemistry using ADAM-9 and -10 specific antibodies confirmed nuclear, cytoplasmic and membrane expression of both ADAMs in these two cell lines. To examine the possibility of ADAM-9 and -10 being shed into the extracellular environment, membrane vesicles that are constitutively shed from the cell surface and contain membrane-associated proteins were collected from the media of the prostate cell lines RWPE-1, LNCaP and PC-3. ADAM-9 was readily detectable in RWPE- 1 and LNCaP cell membrane vesicles by Western blot analysis, but not in PC-3 cells, whilst the expression of ADAM-I 0 was detected in shed vesicles from each of these prostate cell lines. By Laser Capture Microdissection (LCM), secretory epithelial cells of primary prostate gland biopsies were isolated from benign and malignant glands. These secretory cells, by Western blot analysis, expressed similar Mr bands for ADAM-9 and -10 that were found in PCa cell lines in vitro, indicating that the nuclear specific isoforrn of ADAM-I 0 was present in PCa primary tumours and may represent the predominantly nuclear form of ADAM-I 0 expression, previously shown in high-grade PCa by immunohistochemistry (IHC). ADAM-9 and -10 were also examined by IHC in bone metastases taken from PCa patients at biopsy. Both ADAMs could be detected at levels similar to those shown for Prostate Specific Antigen (PSA) in these biopsies. Furthermore, both ADAM-9 and -10 were predominantly membrane- bound with occasional nuclear expression. For aim 2, to establish a cell system that over-expressed levels of ADAM-10, two fulllength ADAM-I 0 mammalian expression vectors were constructed; ADAM-I 0 was cloned into pcDNA3.1, which contains a CMV promoter, and into pMEP4, containing an inducible metallothionine promoter, whose activity is stimulated by the addition of CdC}z. The efficiency of these two constructs was tested by way of transient transfection in the PCa cell line PC-3, whilst the pcDNA3.1 construct was also tested in the RWPE-1 prostate cell line. Resultant Western blot analysis for all transient transfection assays showed that levels of ADAM-I 0 were not significantly elevated in any case, when compared to levels of the housekeeping gene ~-Tubulin, despite testing various levels of vector DNA, and, for pMEP4, the induction of the transfected cell system with different degrees of stimulation with CdCh to activate the metallothionine promoter post-transfection. Another study in this laboratory found similar results when the same full length ADAM-10 sequence was cloned into a Green Fluorescent Protein (GFP) expressing vector, as no fluorescence was observed by means of transient tran sfection in the same, and other, PCa cell lines. It was hypothesised that the Kozak sequence included in the full-length construct (human ADAMI 0 naturally occurring sequence) is not strong enough to initiate translation in an artificial system, in cells, which, as described in Aim 1, are already expressing readily detectable levels of endogenous ADAM-10. As a result, time constraints prevented any further progress with Aim 2 and functional studies including cell attachment, invasion and migration were unable to be explored. For Aim 3, to characterise the response of ADAM-9 and -10 mRNA and protein levels to DHT, IGF-1, DHT plus IGF-1 and EGF in LNCaP cells, the levels of ADAM-9 and -10 mRNA were not stimulated by DHT or IGF-I alone, despite our previous observations that initially characterised ADAM-9 and -10 mRNA as being responsive to DHT. However, IGF-1 in synergy with DHT did significantly elevate mRNA levels ofboth ADAMs. In the case of ADAM-9 and -10 protein, the same trends of stimulation as found at the rnRNA level were shown by Western blot analysis when ADAM-9 and -10 signal intensity was normalised with the housekeeping protein ~-Tubulin. For EGF treatment, both ADAM-9 and -10 mRNA and protein levels were significantly elevated, and further investigation vm found this to be the case for each of these ADAMs proteins in the nuclear fractions of LNCaP cells. These studies are the first to describe extensively, the expression and hormonal/growth factor regulation of two members of the ADAMs family ( -9 and -1 0) in PCa. These observations imply that the expression of ADAM-9 and -10 have varied roles in PCa whilst it develops from androgen-sensitive (early stage disease), through to an androgeninsensitive (late-stage), metastatic disease. Further studies are now required to investigate the several key areas of focus that this research has revealed, including: • Investigation of the cellular mechanisms that are involved in actively transporting the ADAMs to the cell's nuclear compartment and the ADAMs functional roles in the cell nucleus. • The construction of a full-length human ADAM-10 mammalian expression construct with the introduction of a new Kozak sequence, that elevates ADAM-I 0 expression in an in vitro cell system are required, so that functional assays such as cell invasion, migration and attachment may be carried out to fmd the functional consequences of ADAM expression on cellular behaviour. • The regulation studies also need to be extended by confirming the preliminary observations that the nuclear levels of ADAMs may also be elevated by hormones and growth factors such as DHT, IGF-1 and EGF, as well as the regulation of levels of plasma membrany vesicle associated ADAM expression. Given the data presented in this study, it is likely the ADAMs have differential roles throughout the development of PCa due to their differential cellular localisation and synergistic growth-factor regulation. These observations, along with those further studies outlined above, are necessary in identifying these specific components ofPCa metastasis to which the ADAMs may contribute.

Analytical modeling and sensitivity analysis for travel time estimation on signalized urban networks

This paper presents a model for estimation of average travel time and its variability on signalized urban networks using cumulative plots. The plots are generated based on the availability of data: a) case-D, for detector data only; b) case-DS, for detector data and signal timings; and c) case-DSS, for detector data, signal timings and saturation flow rate. The performance of the model for different degrees of saturation and different detector detection intervals is consistent for case-DSS and case-DS whereas, for case-D the performance is inconsistent. The sensitivity analysis of the model for case-D indicates that it is sensitive to detection interval and signal timings within the interval. When detection interval is integral multiple of signal cycle then it has low accuracy and low reliability. Whereas, for detection interval around 1.5 times signal cycle both accuracy and reliability are high.

TCSC control design for transient stability improvement of a multi-machine power system using trajectory sensitivity

This paper discusses the effects of thyristor controlled series compensator (TCSC), a series FACTS controller, on the transient stability of a power system. Trajectory sensitivity analysis (TSA) has been used to measure the transient stability condition of the system. The TCSC is modeled by a variable capacitor, the value of which changes with the firing angle. It is shown that TSA can be used in the design of the controller. The optimal locations of the TCSC-controller for different fault conditions can also be identified with the help of TSA. The paper depicts the advantage of the use of TCSC with a suitable controller over fixed capacitor operation.

Sensitivity of the lane change test as a measure of in-vehicle system demand

The Lane Change Test (LCT) is one of the growing number of methods developed to quantify driving performance degradation brought about by the use of in-vehicle devices. Beyond its validity and reliability, for such a test to be of practical use, it must also be sensitive to the varied demands of individual tasks. The current study evaluated the ability of several recent LCT lateral control and event detection parameters to discriminate between visual-manual and cognitive surrogate In-Vehicle Information System tasks with different levels of demand. Twenty-seven participants (mean age 24.4 years) completed a PC version of the LCT while performing visual search and math problem solving tasks. A number of the lateral control metrics were found to be sensitive to task differences, but the event detection metrics were less able to discriminate between tasks. The mean deviation and lane excursion measures were able to distinguish between the visual and cognitive tasks, but were less sensitive to the different levels of task demand. The other LCT metrics examined were less sensitive to task differences. A major factor influencing the sensitivity of at least some of the LCT metrics could be the type of lane change instructions given to participants. The provision of clear and explicit lane change instructions and further refinement of its metrics will be essential for increasing the utility of the LCT as an evaluation tool.

Does physical protection of soil organic matter attenuate temperature sensitivity?

Global climate change may induce accelerated soil organic matter (SOM) decomposition through increased soil temperature, and thus impact the C balance in soils. We hypothesized that compartmentalization of substrates and decomposers in the soil matrix would decrease SOM sensitivity to temperature. We tested our hypothesis with three short-term laboratory incubations with differing physical protection treatments conducted at different temperatures. Overall, CO2 efflux increased with temperature, but responses among physical protection treatments were not consistently different. Similar respiration quotient (Q(10)) values across physical protection treatments did not support our original hypothesis that the largest Q(10) values would be observed in the treatment with the least physical protection. Compartmentalization of substrates and decomposers is known to reduce the decomposability of otherwise labile material, but the hypothesized attenuation of temperature sensitivity was not detected, and thus the sensitivity is probably driven by the thermodynamics of biochemical reactions as expressed by Arrhenius-type equations.

Experimental warming shows that decomposition temperature sensitivity increases with soil organic matter recalcitrance

Soil C decomposition is sensitive to changes in temperature, and even small increases in temperature may prompt large releases of C from soils. But much of what we know about soil C responses to global change is based on short-term incubation data and model output that implicitly assumes soil C pools are composed of organic matter fractions with uniform temperature sensitivities. In contrast, kinetic theory based on chemical reactions suggests that older, more-resistant C fractions may be more temperature sensitive. Recent research on the subject is inconclusive, indicating that the temperature sensitivity of labile soil organic matter (OM) decomposition could either be greater than, less than, or equivalent to that of resistant soil OM. We incubated soils at constant temperature to deplete them of labile soil OM and then successively assessed the CO2-C efflux in response to warming. We found that the decomposition response to experimental warming early during soil incubation (when more labile C remained) was less than that later when labile C was depleted. These results suggest that the temperature sensitivity of resistant soil OM pools is greater than that for labile soil OM and that global change-driven soil C losses may be greater than previously estimated.

Sensitivity of organic matter decomposition to warming varies with its quality

The relationship between organic matter (OM) lability and temperature sensitivity is disputed, with recent observations suggesting that responses of relatively more resistant OM to increased temperature could be greater than, equivalent to, or less than responses of relatively more labile OM. This lack of clear understanding limits the ability to forecast carbon (C) cycle responses to temperature changes. Here, we derive a novel approach (denoted Q(10-q)) that accounts for changes in OM quality during decomposition and use it to analyze data from three independent sources. Results from new laboratory soil incubations (labile Q(10-q)=2.1 +/- 0.2; more resistant Q(10-q)=3.8 +/- 0.3) and reanalysis of data from other soil incubations reported in the literature (labile Q(10-q)=2.3; more resistant Q(10-q)=3.3) demonstrate that temperature sensitivity of soil OM decomposition increases with decreasing soil OM lability. Analysis of data from a cross-site, field litter bag decomposition study (labile Q(10-q)=3.3 +/- 0.2; resistant Q(10-q)=4.9 +/- 0.2) shows that litter OM follows the same pattern, with greater temperature sensitivity for more resistant litter OM. Furthermore, the initial response of cultivated soils, presumably containing less labile soil OM (Q(10-q)=2.4 +/- 0.3) was greater than that for undisturbed grassland soils (Q(10-q)=1.7 +/- 0.1). Soil C losses estimated using this approach will differ from previous estimates as a function of the magnitude of the temperature increase and the proportion of whole soil OM comprised of compounds sensitive to temperature over that temperature range. It is likely that increased temperature has already prompted release of significant amounts of C to the atmosphere as CO2. Our results indicate that future losses of litter and soil C may be even greater than previously supposed.

Indentation size effect and strain rate sensitivity of nanocrystalline Mg-Al alloys

Deformation Behaviour of microcrystalline (mc) and nanocrystalline (nc) Mg-5%Al alloys produced by hot extrusion of ball-milled powders were investigated using instrumented indentation tests. The hardness values of the mc and nc metals exhibited indentation size effect (ISE), with nc alloys showing weaker ISE. The highly localized dislocation activities resulted in a small activation volume, hence enhanced strain rate sensitivity. Relative higher strain rate sensitivity and the negative Hall-Petch Relationship suggested the increasingly important role of grain boundary mediated mechanisms when the grain size decreased to nanometer region.

Cigarette smoking in young adults : the influence of the HTR2A T102C polymorphism and punishment sensitivity

Background: The C allele of a common polymorphism of the serotonin 2A receptor (HTR2A) gene, T102C, results in reduced synthesis of 5-HT2A receptors and has been associated with current smoking status in adults. The -1438A/G polymorphism, located in the regulatory region of this gene, is in linkage disequilibrium with T102C, and the A allele is associated with increased promoter activity and with smoking in adult males. We investigated the contributions of the HTR2A gene, chronic psychological stress, and impulsivity to the prediction of cigarette smoking status and dependence in young adults. Methods: T102C and -1438A/G genotyping was conducted on 132 healthy Caucasian young adults (47 smokers) who completed self-report measures of chronic stress, depressive symptoms, impulsive personality and cigarette use. Results: A logistic regression analysis of current cigarette smoker user status, after adjusting for gender, depressive symptom severity and chronic stress, indicated that the T102C TT genotype relative to the CC genotype (OR = 7.53), and lower punishment sensitivity (OR = 0.91) were each significant predictive risk factors. However, for number of cigarettes smoked, only lower punishment sensitivity was a significant predictor (OR = 0.81). Conclusions: These data indicate the importance of the T102C polymorphism to tobacco use but not number of cigarettes smoked for Caucasian young adults. Future studies should examine whether this is explained by effects of nicotine on the serotonin system. Lower punishment sensitivity increased risk of both smoking and of greater consumption, perhaps via a reduced sensitivity to cigarette health warnings and negative physiological effects.

Mild systemic hypoxia and photopic visual field sensitivity

Purpose: Flickering stimuli increase the metabolic demand of the retina,making it a sensitive perimetric stimulus to the early onset of retinal disease. We determine whether flickering stimuli are a sensitive indicator of vision deficits resulting from to acute, mild systemic hypoxia when compared to standard static perimetry. Methods: Static and flicker visual perimetry were performed in 14 healthy young participants while breathing 12% oxygen (hypoxia) under photopic illumination. The hypoxia visual field data were compared with the field data measured during normoxia. Absolute sensitivities (in dB) were analysed in seven concentric rings at 1°, 3°, 6°, 10°, 15°, 22° and 30° eccentricities as well as mean defect (MD) and pattern defect (PD) were calculated. Preliminary data are reported for mesopic light levels. Results: Under photopic illumination, flicker and static visual field sensitivities at all eccentricities were not significantly different between hypoxia and normoxia conditions. The mean defect and pattern defect were not significantly different for either test between the two oxygenation conditions. Conclusion: Although flicker stimulation increases cellular metabolism, flicker photopic visual field impairment is not detected during mild hypoxia. These findings contrast with electrophysiological flicker tests in young participants that show impairment at photopic illumination during the same levels of mild hypoxia. Potential mechanisms contributing to the difference between the visual fields and electrophysiological flicker tests including variability in perimetric data, neuronal adaptation and vascular autoregulation, are considered. The data have implications for the use of visual perimetry in the detection of ischaemic/hypoxic retinal disorders under photopic and mesopic light levels.

EduBuilding: material selection from life cycle costing sensitivity

Life Cycle Cost Analysis provides a form of synopsis of the initial and consequential costs of building related decisions. These cost figures may be implemented to justify higher investments, for example, in the quality or flexibility of building solutions through a long term cost reduction. The emerging discipline of asset mnagement is a promising approach to this problem, because it can do things that techniques such as balanced scorecards and total quantity cannot. Decisions must be made about operating and maintaining infrastructure assets. An injudicious sensitivity of life cycle costing is that the longer something lasts, the less it costs over time. A life cycle cost analysis will be used as an economic evaluation tool and collaborate with various numbers of analyses. LCCA quantifies incurring costs commonly overlooked (by property and asset managers and designs) as replacement and maintenance costs. The purpose of this research is to examine the Life Cycle Cost Analysis on building floor materials. By implementing the life cycle cost analysis, the true cost of each material will be computed projecting 60 years as the building service life and 5.4% as the inflation rate percentage to classify and appreciate the different among the materials. The analysis results showed the high impact in selecting the floor materials according to the potential of service life cycle cost next.

Sensitivity of Dot-ELISA on Nitrocellulose Membranes in Comparison with ELISA on Polystyrene Plates for the Detection of Four Plant Viruses

ABSTR.4CT Senitivity of dot-immunobindinding ELf SA on nitrocellulose membrane (DotELISA)was compared with double-antibody sandwich ELISA (DAS-ELlSA) on polystyrene plates for the detection of bean yellow mosaic virus (BYMV), broad bean stain virus (WMV-2). Dot-ELISA was 2 and 1O times more sensitive than DAS-ELISA for the detection of BBSV and WMV-2, respectively, whereas DAS-ELISA was more sensitive than Dot-ELiSA for {he detection of BYMV. Both techniques were equally sensitive for the detection of BYDV. Using one day instead uf the two-day procedure, the four viruses were still detectable and the ralative sensitivity of both techniques remained the same.

Corneal sensitivity as an ophthalmic marker of diabetic neuropathy

Purpose. The objective of this study was to explore the discriminative capacity of non-contact corneal esthesiometry (NCCE) when compared with the neuropathy disability score (NDS) score—a validated, standard method of diagnosing clinically significant diabetic neuropathy. Methods. Eighty-one participants with type 2 diabetes, no history of ocular disease, trauma, or surgery and no history of systemic disease that may affect the cornea were enrolled. Participants were ineligible if there was history of neuropathy due to non-diabetic cause or current diabetic foot ulcer or infection. Corneal sensitivity threshold was measured on the eye of dominant hand side at a distance of 10 mm from the center of the cornea using a stimulus duration of 0.9 s. The NDS was measured producing a score ranging from 0 to 10. To determine the optimal cutoff point of corneal sensitivity that identified the presence of neuropathy (diagnosed by NDS), the Youden index and “closest-to-(0,1)” criteria were used. Results. The receiver-operator characteristic curve for NCCE for the presence of neuropathy (NDS ≥3) had an area under the curve of 0.73 (p = 0.001) and, for the presence of moderate neuropathy (NDS ≥6), area of 0.71 (p = 0.003). By using the Youden index, for an NDS ≥3, the sensitivity of NCCE was 70% and specificity was 75%, and a corneal sensitivity threshold of 0.66 mbar or higher indicated the presence of neuropathy. When NDS ≥6 (indicating risk of foot ulceration) was applied, the sensitivity was 52% with a specificity of 85%. Conclusions. NCCE is a sensitive test for the diagnosis of minimal and more advanced diabetic neuropathy and may serve as a useful surrogate marker for diabetic and perhaps other neuropathies.

Insulin-like growth factor-i : vitronectin complex-induced changes in gene expression effect breast cell survival and migration

Recent studies have demonstrated that IGF-I associates with VN through IGF-binding proteins (IGFBP) which in turn modulate IGF-stimulated biological functions such as cell proliferation, attachment and migration. Since IGFs play important roles in transformation and progression of breast tumours, we aimed to describe the effects of IGF-I:IGFBP:VN complexes on breast cell function and to dissect mechanisms underlying these responses. In this study we demonstrate that substrate-bound IGF-I:IGFBP:VN complexes are potent stimulators of MCF-7 breast cell survival, which is mediated by a transient activation of ERK/MAPK and sustained activation of PI3-K/AKT pathways. Furthermore, use of pharmacological inhibitors of the MAPK and PI3-K pathways confirms that both pathways are involved in IGF-I:IGFBP:VN complex-mediated increased cell survival. Microarray analysis of cells stimulated to migrate in response to IGF-I:IGFBP:VN complexes identified differential expression of genes with previously reported roles in migration, invasion and survival (Ephrin-B2, Sharp-2, Tissue-factor, Stratifin, PAI-1, IRS-1). These changes were not detected when the IGF-I analogue (\[L24]\[A31]-IGF-I), which fails to bind to the IGF-I receptor, was substituted; confirming the IGF-I-dependent differential expression of genes associated with enhanced cell migration. Taken together, these studies have established that IGF-I:IGFBP:VN complexes enhance breast cell migration and survival, processes central to facilitating metastasis. This study highlights the interdependence of ECM and growth factor interactions in biological functions critical for metastasis and identifies potential novel therapeutic targets directed at preventing breast cancer progression.

Hall-petch relationship and strain rate sensitivity of nanocrystalline Mg - 5wt% A1 alloy

This study investigated the grain size dependence of mechanical properties and deformation mechanisms of microcrystalline (mc) and nanocrystalline (nc: grain size below 100 nm) Mg-5wt% Al alloys. The Hall-Petch relationship was investigated by both instrumented indentation tests and compression tests. The test results from the indentation tests and compression tests match well with each other. The breakdown of Hall-Petch relationship and the elevated strain rate sensitivity (SRS) of present Mg-5wt% Al alloys when the grain size was reduced below 58nm indicated the more significant role of GB mediated mechanisms in plastic deformation process. However, the relatively smaller SRS values compared to GB sliding and coble creep process suggested the plastic deformation in the current study is still dislocation mediated mechanism dominant.