Publications

Stratton-Powell, AA & Tipper, JL 2016, 'Characterization of UHMWPE Wear Particles' in UHMWPE Biomaterials Handbook, Elsevier, pp. 635-653.
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© 2016 Elsevier Inc. All rights reserved. Although most total joint prostheses remain stable for many years, a significant proportion experience loosening, with about 10% requiring revision 10 years after primary arthroplasty. It is generally accepted that osteolysis, among other causes, is initiated by the biological response to wear particles, which are released from ultra high molecular weight polyethylene acetabular liners and tibial trays. Wear particles up to 10 μm in size are predicted to be phagocytosed by resident macrophages and cause the release of inflammatory cytokines and chemokines, including tumor necrosis factor alpha (TNF-α), interleukin-1beta (IL-1β, IL-6, and IL-8. These cytokines stimulate the release of other mediators and the ensuing inflammatory cascade results in the formation of a periprosthetic granulomatous tissue reaction. Histopathological studies have revealed that these inflammatory cytokines facilitate osteoclastagenesis, which results in resorption of bone and a painfully loose implant. Revision surgery is currently the only option for the patient and surgeon.

Ahadi, A, Brennan, S, Kennedy, PJ, Hutvagner, G & Tran, N 2016, 'Long non-coding RNAs harboring miRNA seed regions are enriched in prostate cancer exosomes', Scientific Reports, vol. 6, no. 1, pp. 1-14.
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AbstractLong non-coding RNAs (lncRNAs) form the largest transcript class in the human transcriptome. These lncRNA are expressed not only in the cells, but they are also present in the cell-derived extracellular vesicles such as exosomes. The function of these lncRNAs in cancer biology is not entirely clear, but they appear to be modulators of gene expression. In this study, we characterize the expression of lncRNAs in several prostate cancer exosomes and their parental cell lines. We show that certain lncRNAs are enriched in cancer exosomes with the overall expression signatures varying across cell lines. These exosomal lncRNAs are themselves enriched for miRNA seeds with a preference for let-7 family members as well as miR-17, miR-18a, miR-20a, miR-93 and miR-106b. The enrichment of miRNA seed regions in exosomal lncRNAs is matched with a concomitant high expression of the same miRNA. In addition, the exosomal lncRNAs also showed an over representation of RNA binding protein binding motifs. The two most common motifs belonged to ELAVL1 and RBMX. Given the enrichment of miRNA and RBP sites on exosomal lncRNAs, their interplay may suggest a possible function in prostate cancer carcinogenesis.

Alarkawi, D, Bliuc, D, Nguyen, TV, Eisman, JA & Center, JR 2016, 'Contribution of Lumbar Spine BMD to Fracture Risk in Individuals With T-Score Discordance', Journal of Bone and Mineral Research, vol. 31, no. 2, pp. 274-280.
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ABSTRACT   Fracture risk estimates are usually based on femoral neck (FN) BMD. It is unclear how to address T-score discordance, where lumbar spine (LS) T-score is lower than FN T-score. The objective of this work was to examine the impact of LS BMD on fracture risk, in individuals with lower LS T-score than FN T-score. Participants aged 60+ years from the Dubbo Osteoporosis Epidemiology Study with LS and FN BMD measured at first visit, and were followed from 1989 to 2014. Five-hundred and seventy-three (573) of 2270 women and 131 of 1373 men had lower LS than FN T-score by ≥0.6 standard deviation (SD) (low-LS group based on least significant change). In low-LS women, each 1 SD lower LS T-score than FN was associated with a 30% increase in fracture risk (hazard ratio [HR] 1.30; 95% CI, 1.11 to 1.45). For low-LS men there was a 20% nonsignificant increase in fracture risk for each 1 SD lower LS than FN T-score (HR 1.20; 95% CI, 0.10 to 1.67). Low-LS women had greater absolute fracture risks than the rest of the women. This increased risk was more apparent for lower levels of FN T-score and in older age groups. At an FN T-score of –2, low-LS women had a 3%, 10%, and 23% higher 5-year absolute fracture risk than non-low LS women in the 60 to 69 year, 70 to 79 year, and 80+ years age-groups, respectively. Furthermore, an osteoporotic LS T-score increased 5-year absolute fracture risk for women with normal or osteopenic FN T-score by 10% to 13%. Men in the low-LS group had very few fractures; therefore, a meaningful analyses of fracture risk could not be conducted. This study shows the significant contribution of lower LS BMD to fracture risk over and above FN BMD in women. A LS BMD lower than FN BMD should be incorporated into fracture risk calculators at least for women in older age-groups. © 2015 American Society for Bone and Mineral Res...

Asadnia, M, Kottapalli, AGP, Karavitaki, KD, Warkiani, ME, Miao, J, Corey, DP & Triantafyllou, M 2016, 'From Biological Cilia to Artificial Flow Sensors: Biomimetic Soft Polymer Nanosensors with High Sensing Performance', Scientific Reports, vol. 6, no. 1, p. 32955.
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AbstractWe report the development of a new class of miniature all-polymer flow sensors that closely mimic the intricate morphology of the mechanosensory ciliary bundles in biological hair cells. An artificial ciliary bundle is achieved by fabricating bundled polydimethylsiloxane (PDMS) micro-pillars with graded heights and electrospinning polyvinylidenefluoride (PVDF) piezoelectric nanofiber tip links. The piezoelectric nature of a single nanofiber tip link is confirmed by X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). Rheology and nanoindentation experiments are used to ensure that the viscous properties of the hyaluronic acid (HA)-based hydrogel are close to the biological cupula. A dome-shaped HA hydrogel cupula that encapsulates the artificial hair cell bundle is formed through precision drop-casting and swelling processes. Fluid drag force actuates the hydrogel cupula and deflects the micro-pillar bundle, stretching the nanofibers and generating electric charges. Functioning with principles analogous to the hair bundles, the sensors achieve a sensitivity and threshold detection limit of 300 mV/(m/s) and 8 μm/s, respectively. These self-powered, sensitive, flexible, biocompatibale and miniaturized sensors can find extensive applications in navigation and maneuvering of underwater robots, artificial hearing systems, biomedical and microfluidic devices.

Avellino, R, Havermans, M, Erpelinck, C, Sanders, MA, Hoogenboezem, R, van de Werken, HJG, Rombouts, E, van Lom, K, van Strien, PMH, Gebhard, C, Rehli, M, Pimanda, J, Beck, D, Erkeland, S, Kuiken, T, de Looper, H, Gröschel, S, Touw, I, Bindels, E & Delwel, R 2016, 'An autonomous CEBPA enhancer specific for myeloid-lineage priming and neutrophilic differentiation', Blood, vol. 127, no. 24, pp. 2991-3003.
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Key Points The CEBPA locus harbors 14 enhancers of which distinct combinations are active in different CEBPA-expressing tissues. A +42-kb enhancer is required for myeloid-lineage priming to drive adequate CEBPA expression levels necessary for neutrophilic maturation.

Bernabé-Rubio, M, Andrés, G, Casares-Arias, J, Fernández-Barrera, J, Rangel, L, Reglero-Real, N, Gershlick, DC, Fernández, JJ, Millán, J, Correas, I, Miguez, DG & Alonso, MA 2016, 'Novel role for the midbody in primary ciliogenesis by polarized epithelial cells', Journal of Cell Biology, vol. 214, no. 3, pp. 259-273.
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The primary cilium is a membrane protrusion that is crucial for vertebrate tissue homeostasis and development. Here, we investigated the uncharacterized process of primary ciliogenesis in polarized epithelial cells. We show that after cytokinesis, the midbody is inherited by one of the daughter cells as a remnant that initially locates peripherally at the apical surface of one of the daughter cells. The remnant then moves along the apical surface and, once proximal to the centrosome at the center of the apical surface, enables cilium formation. The physical removal of the remnant greatly impairs ciliogenesis. We developed a probabilistic cell population–based model that reproduces the experimental data. In addition, our model explains, solely in terms of cell area constraints, the various observed transitions of the midbody, the beginning of ciliogenesis, and the accumulation of ciliated cells. Our findings reveal a biological mechanism that links the three microtubule-based organelles—the midbody, the centrosome, and the cilium—in the same cellular process.

Bliuc, D, Tran, T, Alarkawi, D, Nguyen, TV, Eisman, JA & Center, JR 2016, 'Secular Changes in Postfracture Outcomes Over 2 Decades in Australia: A Time-Trend Comparison of Excess Postfracture Mortality in Two Birth Controls Over Two Decades', The Journal of Clinical Endocrinology & Metabolism, vol. 101, no. 6, pp. 2475-2483.
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Abstract Context: Hip fracture incidence has been declining and life expectancy improving. However, trends of postfracture outcomes are unknown. Objectives: The objective of the study was to compare the refracture risk and excess mortality after osteoporotic fracture between two birth cohorts, over 2 decades. Design: Prospective birth cohorts were followed up over 2 decades (1989–2004 and 2000–2014). Setting: The study was conducted in community-dwelling participants in Dubbo, Australia. Participants: Women and men aged 60–80 years, participating in Dubbo Osteoporosis Epidemiology Study 1 (DOES 1; born before 1930) and Dubbo Osteoporosis Epidemiology Study 2 (DOES 2; born after 1930) participated in the study. Main Outcome Measure: Age-standardized fracture and mortality over two time intervals: (1989–2004 [DOES 1] and 2000–2014 [DOES 2]) were measured. Results: The DOES 2 cohort had higher body mass index and bone mineral density and lower initial fracture rate than DOES 1, but similar refracture rates [age-standardized refracture rates per 1000 person-years: wome...

Botezatu, L, Michel, LC, Makishima, H, Schroeder, T, Germing, U, Haas, R, van der Reijden, B, Marneth, AE, Bergevoet, SM, Jansen, JH, Przychodzen, B, Wlodarski, M, Niemeyer, C, Platzbecker, U, Ehninger, G, Unnikrishnan, A, Beck, D, Pimanda, J, Hellström-Lindberg, E, Malcovati, L, Boultwood, J, Pellagatti, A, Papaemmanuil, E, Le Coutre, P, Kaeda, J, Opalka, B, Möröy, T, Dührsen, U, Maciejewski, J & Khandanpour, C 2016, 'GFI136N as a therapeutic and prognostic marker for myelodysplastic syndrome', Experimental Hematology, vol. 44, no. 7, pp. 590-595.e1.
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Carter, DR, Sutton, SK, Pajic, M, Murray, J, Sekyere, EO, Fletcher, J, Beckers, A, De Preter, K, Speleman, F, George, RE, Haber, M, Norris, MD, Cheung, BB & Marshall, GM 2016, 'Glutathione biosynthesis is upregulated at the initiation of MYCN‐driven neuroblastoma tumorigenesis', Molecular Oncology, vol. 10, no. 6, pp. 866-878.
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The MYCN gene is amplified and overexpressed in a large proportion of high stage neuroblastoma patients and has been identified as a key driver of tumorigenesis. However, the mechanism by which MYCN promotes tumor initiation is poorly understood. Here we conducted metabolic profiling of pre‐malignant sympathetic ganglia and tumors derived from the TH‐MYCN mouse model of neuroblastoma, compared to non‐malignant ganglia from wildtype littermates. We found that metabolites involved in the biosynthesis of glutathione, the most abundant cellular antioxidant, were the most significantly upregulated metabolic pathway at tumor initiation, and progressively increased to meet the demands of tumorigenesis. A corresponding increase in the expression of genes involved in ribosomal biogenesis suggested that MYCN‐driven transactivation of the protein biosynthetic machinery generated the necessary substrates to drive glutathione biosynthesis. Pre‐malignant sympathetic ganglia from TH‐MYCN mice had higher antioxidant capacity and required glutathione upregulation for cell survival, when compared to wildtype ganglia. Moreover, in vivo administration of inhibitors of glutathione biosynthesis significantly delayed tumorigenesis when administered prophylactically and potentiated the anticancer activity of cytotoxic chemotherapy against established tumors. Together these results identify enhanced glutathione biosynthesis as a selective metabolic adaptation required for initiation of MYCN‐driven neuroblastoma, and suggest that glutathione‐targeted agents may be used as a potential preventative strategy, or as an adjuvant to existing chemotherapies in established disease.

Chandrakanthan, V, Yeola, A, Kwan, JC, Oliver, RA, Qiao, Q, Kang, YC, Zarzour, P, Beck, D, Boelen, L, Unnikrishnan, A, Villanueva, JE, Nunez, AC, Knezevic, K, Palu, C, Nasrallah, R, Carnell, M, Macmillan, A, Whan, R, Yu, Y, Hardy, P, Grey, ST, Gladbach, A, Delerue, F, Ittner, L, Mobbs, R, Walkley, CR, Purton, LE, Ward, RL, Wong, JWH, Hesson, LB, Walsh, W & Pimanda, JE 2016, 'PDGF-AB and 5-Azacytidine induce conversion of somatic cells into tissue-regenerative multipotent stem cells', PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 113, no. 16, pp. E2306-E2315.
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Chaudhuri, PK, Ebrahimi Warkiani, M, Jing, T, Kenry, K & Lim, CT 2016, 'Microfluidics for research and applications in oncology', The Analyst, vol. 141, no. 2, pp. 504-524.
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Cancer is currently one of the top non-communicable human diseases, and continual research and developmental efforts, particularly in microfluidics technology, are being made to better understand and manage this disease.

Chen, Y, Zhou, Y, Yang, S, Li, JJ, Li, X, Ma, Y, Hou, Y, Jiang, N, Xu, C, Zhang, S, Zeng, R, Tu, M & Yu, B 2016, 'Novel bone substitute composed of chitosan and strontium-doped α-calcium sulfate hemihydrate: Fabrication, characterisation and evaluation of biocompatibility', Materials Science and Engineering: C, vol. 66, pp. 84-91.
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Calcium sulfate is in routine clinical use as a bone substitute, offering the benefits of biodegradability, biocompatibility and a long history of use in bone repair. The osteoconductive properties of calcium sulfate may be further improved by doping with strontium ions. Nevertheless, the high degradation rate of calcium sulfate may impede bone healing as substantial material degradation may occur before the healing process is complete. The purpose of this study is to develop a novel composite bone substitute composed of chitosan and strontium-doped α-calcium sulfate hemihydrate in the form of microcapsules, which can promote osteogenesis while matching the natural rate of bone healing. The developed microcapsules exhibited controlled degradation that facilitated the sustained release of strontium ions. In vitro testing showed that the microcapsules had minimal cytotoxicity and ability to inhibit bacterial growth. In vivo testing in a mouse model showed the absence of genetic toxicity and low inflammatory potential of the microcapsules. The novel microcapsules developed in this study demonstrated suitable degradation characteristics for bone repair as well as favourable in vitro and in vivo behaviour, and hold promise for use as an alternative bone substitute in orthopaedic surgery.

Clement, S, Deng, W, Camilleri, E, Wilson, BC & Goldys, EM 2016, 'X-ray induced singlet oxygen generation by nanoparticle-photosensitizer conjugates for photodynamic therapy: determination of singlet oxygen quantum yield', Scientific Reports, vol. 6, no. 1, p. 19954.
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AbstractSinglet oxygen is a primary cytotoxic agent in photodynamic therapy. We show that CeF3 nanoparticles, pure as well as conjugated through electrostatic interaction with the photosensitizer verteporfin, are able to generate singlet oxygen as a result of UV light and 8 keV X-ray irradiation. The X-ray stimulated singlet oxygen quantum yield was determined to be 0.79 ± 0.05 for the conjugate with 31 verteporfin molecules per CeF3 nanoparticle, the highest conjugation level used. From this result we estimate the singlet oxygen dose generated from CeF3-verteporfin conjugates for a therapeutic dose of 60 Gy of ionizing radiation at energies of 6 MeV and 30 keV to be (1.2 ± 0.7) × 108 and (2.0 ± 0.1) × 109 singlet oxygen molecules per cell, respectively. These are comparable with cytotoxic doses of 5 × 107–2 × 109 singlet oxygen molecules per cell reported in the literature for photodynamic therapy using light activation. We confirmed that the CeF3-VP conjugates enhanced cell killing with 6 MeV radiation. This work confirms the feasibility of using X- or γ- ray activated nanoparticle-photosensitizer conjugates, either to supplement the radiation treatment of cancer, or as an independent treatment modality.

Connerty, P, Bajan, S, Remenyi, J, Fuller-Pace, FV & Hutvagner, G 2016, 'The miRNA biogenesis factors, p72/DDX17 and KHSRP regulate the protein level of Ago2 in human cells', Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, vol. 1859, no. 10, pp. 1299-1305.
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© 2016 Elsevier B.V. MicroRNAs (miRNAs) are short (21–23 nt long) RNAs that post-transcriptionally regulate gene expression in plants and animals. They are key regulators in all biological processes. In mammalian cells miRNAs are loaded into one of the four members of the Argonaute (Ago) protein family to form the RNA-induced silencing complex (RISC). RISCs inhibit the translation of mRNAs that share sequence complementarity with their loaded miRNAs. miRNA processing and miRNA-mediated gene regulation are highly regulated processes and involve many RNA-binding proteins as auxiliary factors. Here we show that the two RNA-binding proteins, p72 and KHSRP, both with known roles in promoting miRNA biogenesis, regulate the protein level of human Ago2 in transformed human cells. We determined that p72 and KHSRP influence Ago2 stability by regulating miRNA levels in the cell and that loss of p72/KHSRP results in a decrease of unloaded Ago2.

Cropley, JE, Eaton, SA, Aiken, A, Young, PE, Giannoulatou, E, Ho, JWK, Buckland, ME, Keam, SP, Hutvagner, G, Humphreys, DT, Langley, KG, Henstridge, DC, Martin, DIK, Febbraio, MA & Suter, CM 2016, 'Male-lineage transmission of an acquired metabolic phenotype induced by grand-paternal obesity', Molecular Metabolism, vol. 5, no. 8, pp. 699-708.
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© 2016 The Author(s) Objective Parental obesity can induce metabolic phenotypes in offspring independent of the inherited DNA sequence. Here we asked whether such non-genetic acquired metabolic traits can be passed on to a second generation that has never been exposed to obesity, even as germ cells. Methods We examined the F1, F2, and F3 a/a offspring derived from F0 matings of obese prediabetic Avy/a sires and lean a/a dams. After F0, only lean a/a mice were used for breeding. Results We found that F1 sons of obese founder males exhibited defects in glucose and lipid metabolism, but only upon a post-weaning dietary challenge. F1 males transmitted these defects to their own male progeny (F2) in the absence of the dietary challenge, but the phenotype was largely attenuated by F3. The sperm of F1 males exhibited changes in the abundance of several small RNA species, including the recently reported diet-responsive tRNA-derived fragments. Conclusions These data indicate that induced metabolic phenotypes may be propagated for a generation beyond any direct exposure to an inducing factor. This non-genetic inheritance likely occurs via the actions of sperm noncoding RNA.

Dehbari, N, Tavakoli, J, Zhao, J & Tang, Y 2016, 'Enhancing water swelling ability and mechanical properties of water‐swellable rubber by PAA/SBS nanofiber mats', Journal of Applied Polymer Science, vol. 133, no. 47.
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ABSTRACTInvestigation of the potential use of nanofibers to reinforce composites has gained significance in many applications. In this article, the nanofiber mats of poly(acrylic acid) (PAA) and styrene–butadiene–styrene (SBS) triblock copolymer with composites structure were interweaved by double needle electrospinning process. The multiple nanofiber mats were added to conventional water‐swellable rubber (WSR). Improved mechanical and physical properties of WSR were obtained. Enhancement of the swellability of WSR + PAA/SBS nanofiber mats was derived from the PAA constituent absorbing water from the surface into the bulk and introducing random internal water channels between discontinuous superabsorbent polymers. The role of SBS nanofibers in the composite of WSR + PAA/SBS nanofiber mats was more related to the mechanical properties, where the breaking force of the composite increased to twice that of the conventional WSR. Interestingly, after immersion of the WSR + PAA/SBS nanofiber mats in water for 1 week, there was only a slight decrease in their mechanical properties of less than 5% compared to the dry state. The mechanisms and effects of the nanofiber mats in enhancing the mechanical and water swelling properties of WSR are also discussed. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 44213.

Deng, W, Kautzka, Z, Chen, W & Goldys, EM 2016, 'PLGA nanocomposites loaded with verteporfin and gold nanoparticles for enhanced photodynamic therapy of cancer cells', RSC Advances, vol. 6, no. 113, pp. 112393-112402.
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Enhanced ¹O₂ generation from PLGA loaded with verteporfin and gold nanoparticles under light illumination has the potential to improve cancer cell-killing effect.

Du, W, Su, QP, Chen, Y, Zhu, Y, Jiang, D, Rong, Y, Zhang, S, Zhang, Y, Ren, H, Zhang, C, Wang, X, Gao, N, Wang, Y, Sun, L, Sun, Y & Yu, L 2016, 'Kinesin 1 Drives Autolysosome Tubulation', Developmental Cell, vol. 37, no. 4, pp. 326-336.
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© 2016 Elsevier Inc. Autophagic lysosome reformation (ALR) plays an important role in maintaining lysosome homeostasis. During ALR, lysosomes are reformed by recycling lysosomal components from autolysosomes. The most noticeable step of ALR is autolysosome tubulation, but it is currently unknown how the process is regulated. Here, using an approach combining in vivo studies and in vitro reconstitution, we found that the kinesin motor protein KIF5B is required for autolysosome tubulation and that KIF5B drives autolysosome tubulation by pulling on the autolysosomal membrane. Furthermore, we show that KIF5B directly interacts with PtdIns(4,5)P2. Kinesin motors are recruited and clustered on autolysosomes via interaction with PtdIns(4,5)P2 in a clathrin-dependent manner. Finally, we demonstrate that clathrin promotes formation of PtdIns(4,5)P2-enriched microdomains, which are required for clustering of KIF5B. Our study reveals a mechanism by which autolysosome tubulation was generated.

Entezari, A, Fang, J, Sue, A, Zhang, Z, Swain, MV & Li, Q 2016, 'Yielding behaviors of polymeric scaffolds with implications to tissue engineering', Materials Letters, vol. 184, pp. 108-111.
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Entezari, A, Roohani-Esfahani, S-I, Zhang, Z, Zreiqat, H, Dunstan, CR & Li, Q 2016, 'Fracture behaviors of ceramic tissue scaffolds for load bearing applications', Scientific Reports, vol. 6, no. 1.
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AbstractHealing large bone defects, especially in weight-bearing locations, remains a challenge using available synthetic ceramic scaffolds. Manufactured as a scaffold using 3D printing technology, Sr-HT-Gahnite at high porosity (66%) had demonstrated significantly improved compressive strength (53 ± 9 MPa) and toughness. Nevertheless, the main concern of ceramic scaffolds in general remains to be their inherent brittleness and low fracture strength in load bearing applications. Therefore, it is crucial to establish a robust numerical framework for predicting fracture strengths of such scaffolds. Since crack initiation and propagation plays a critical role on the fracture strength of ceramic structures, we employed extended finite element method (XFEM) to predict fracture behaviors of Sr-HT-Gahnite scaffolds. The correlation between experimental and numerical results proved the superiority of XFEM for quantifying fracture strength of scaffolds over conventional FEM. In addition to computer aided design (CAD) based modeling analyses, XFEM was conducted on micro-computed tomography (μCT) based models for fabricated scaffolds, which took into account the geometric variations induced by the fabrication process. Fracture strengths and crack paths predicted by the μCT-based XFEM analyses correlated well with relevant experimental results. The study provided an effective means for the prediction of fracture strength of porous ceramic structures, thereby facilitating design optimization of scaffolds.

Erami, Z, Herrmann, D, Warren, SC, Nobis, M, McGhee, EJ, Lucas, MC, Leung, W, Reischmann, N, Mrowinska, A, Schwarz, JP, Kadir, S, Conway, JRW, Vennin, C, Karim, SA, Campbell, AD, Gallego-Ortega, D, Magenau, A, Murphy, KJ, Ridgway, RA, Law, AM, Walters, SN, Grey, ST, Croucher, DR, Zhang, L, Herzog, H, Hardeman, EC, Gunning, PW, Ormandy, CJ, Evans, TRJ, Strathdee, D, Sansom, OJ, Morton, JP, Anderson, KI & Timpson, P 2016, 'Intravital FRAP Imaging using an E-cadherin-GFP Mouse Reveals Disease- and Drug-Dependent Dynamic Regulation of Cell-Cell Junctions in Live Tissue', Cell Reports, vol. 14, no. 1, pp. 152-167.
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Fabian, J, Opitz, D, Althoff, K, Lodrini, M, Hero, B, Volland, R, Beckers, A, de Preter, K, Decock, A, Patil, N, Abba, M, Kopp-Schneider, A, Astrahantseff, K, Wünschel, J, Pfeil, S, Ercu, M, Künkele, A, Hu, J, Thole, T, Schweizer, L, Mechtersheimer, G, Carter, D, Cheung, BB, Popanda, O, von Deimling, A, Koster, J, Versteeg, R, Schwab, M, Marshall, GM, Speleman, F, Erb, U, Zoeller, M, Allgayer, H, Simon, T, Fischer, M, Kulozik, AE, Eggert, A, Witt, O, Schulte, JH & Deubzer, HE 2016, 'MYCN and HDAC5 transcriptionally repress CD9 to trigger invasion and metastasis in neuroblastoma', Oncotarget, vol. 7, no. 41, pp. 66344-66359.
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The systemic and resistant nature of metastatic neuroblastoma renders it largely incurable with current multimodal treatment. Clinical progression stems mainly from the increasing burden of metastatic colonization. Therapeutically inhibiting the migration-invasion-metastasis cascade would be of great benefit, but the mechanisms driving this cycle are as yet poorly understood. In-depth transcriptome analyses and ChIP-qPCR identified the cell surface glycoprotein, CD9, as a major downstream player and direct target of the recently described GRHL1 tumor suppressor. CD9 is known to block or facilitate cancer cell motility and metastasis dependent upon entity. High-level CD9 expression in primary neuroblastomas correlated with patient survival and established markers for favorable disease. Low-level CD9 expression was an independent risk factor for adverse outcome. MYCN and HDAC5 colocalized to the CD9 promoter and repressed transcription. CD9 expression diminished with progressive tumor development in the TH-MYCN transgenic mouse model for neuroblastoma, and CD9 expression in neuroblastic tumors was far below that in ganglia from wildtype mice. Primary neuroblastomas lacking MYCN amplifications displayed differential CD9 promoter methylation in methyl-CpG-binding domain sequencing analyses, and high-level methylation was associated with advanced stage disease, supporting epigenetic regulation. Inducing CD9 expression in a SH-EP cell model inhibited migration and invasion in Boyden chamber assays. Enforced CD9 expression in neuroblastoma cells transplanted onto chicken chorioallantoic membranes strongly reduced metastasis to embryonic bone marrow. Combined treatment of neuroblastoma cells with HDAC/DNA methyltransferase inhibitors synergistically induced CD9 expression despite hypoxic, metabolic or cytotoxic stress. Our results show CD9 is a critical and indirectly druggable suppressor of the invasion-metastasis cycle in neuroblastoma.

Frost, SA & Nguyen, TV 2016, 'Uncertain effects of calcium and vitamin D supplementation on fracture risk reduction', Osteoporosis International, vol. 27, no. 8, pp. 2647-2648.
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Gentile, C 2016, 'Filling the Gaps between the In Vivo and In Vitro Microenvironment: Engineering of Spheroids for Stem Cell Technology', Current Stem Cell Research & Therapy, vol. 11, no. 8, pp. 652-665.
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Engineering of in vitro three-dimensional cultures of stem cells and their progenies has offered promising alternatives to recapitulate the in vivo microenvironment, or stem cell niche, and has provided more specific cues for proper stem cell differentiation, maintenance and culture. In particular, tissue spheroids are cellular aggregates with defined cellular and extracellular features and have provided optimal conditions for stem cell technology, both in culture and for potential engraftment. Recent studies have focused on spheroid formation and the developmental roles played by cellular and extracellular signals necessary for cellular aggegation into spheroids. This review will provide insights into the factors that regulate in vitro spheroid formation by comparing them with their developmental counterparts in vivo. At the same time, we will identify cellular and extracellular signals that could be used to bioengineer spheroids with improved features according to their application. Finally, this review will provide an overview of the applications to date of spheroid cultures of stem cells and their progenies, providing insights for future studies.

Gerami, A, Mostaghimi, P, Armstrong, RT, Zamani, A & Warkiani, ME 2016, 'A microfluidic framework for studying relative permeability in coal', International Journal of Coal Geology, vol. 159, pp. 183-193.
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A significant unconventional energy resource is methane gas stored in shallow coal beds, known as coal seam gas. The flow and transport of fluid in coal beds occur in a well-developed system of natural fractures, called cleats. In this study, we developed an efficient workflow for the fabrication of microfluidic chips based on X-ray micro-Computed Tomography (micro-CT) images of coal. A dry and wet micro-CT imaging technique is utilized to image coal cleats that would be otherwise non-resolvable. The obtained image of the cleat network is then etched into silicon wafers and used to fabricate poly dimethyl siloxane (PDMS) microfluidic devices. Fluid transport and displacement efficiency are visualized and quantified in real time by injecting water with a flow rate of 1 μl min-1 into the fabricated cleat structure initially saturated with air. A microfluidic approach is used to measure the relative permeability of a realistic coal cleat system by monitoring the liquid recovery at recorded saturations after the breakthrough. Relative permeability curves show the cross and end point values for the water and gas flow, and predict a maximum relative permeability of 0.15 for the water phase. Understanding the relationship between coal cleat structure and the resulting relative permeability is crucial for the optimization of methane gas extraction and to reduce the environmental concerns of excess surface water production. Also, pore network modelling based on the Maximal Ball (MB) concept is applied to predict relative permeability curves numerically. Our experimental results are in good agreement with pore network modelling outcomes and provide consistent and smooth macro-scale relationships along with direct observation of the pore-scale physics. Therefore not only can the microfluidic approach be used as a validation tool for multiphase flow numerical models but it can also provide direct visualization of transport properties unique to coals. Overall, our d...

Gourlay, ML, Overman, RA, Fine, JP, Filteau, G, Cawthon, PM, Schousboe, JT, Orwoll, ES, Wilt, TJ, Nguyen, TV, Lane, NE, Szulc, P, Taylor, BC, Dam, T-T, Nielson, CM, Cauley, JA, Barrett-Connor, E, Fink, HA, Lapidus, JA, Kado, DM, Diem, SJ & Ensrud, KE 2016, 'Time to Osteoporosis and Major Fracture in Older Men', American Journal of Preventive Medicine, vol. 50, no. 6, pp. 727-736.
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© 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved. Introduction For older men who undergo bone mineral density (BMD) testing, the optimal osteoporosis screening schedule is unknown. Time-to-disease estimates are necessary to inform screening intervals. Methods A prospective cohort study of 5,415 community-dwelling men aged ≥65 years without hip or clinical vertebral fracture or antifracture treatment at baseline was conducted. Participants had concurrent BMD and fracture follow-up between 2000 and 2009, and additional fracture follow-up through 2014. Data were analyzed in 2015. Time to incident osteoporosis (lowest T-score ≤ -2.50) for men without baseline osteoporosis, and time to hip or clinical vertebral fracture or major osteoporotic fracture for men without or with baseline osteoporosis, were estimated. Results Nine men (0.2%) with BMD T-scores >-1.50 at baseline developed osteoporosis during follow-up. The adjusted estimated time for 10% to develop osteoporosis was 8.5 (95% CI=6.7, 10.9) years for those with moderate osteopenia (lowest T-score, -1.50 to -1.99) and 2.7 (95% CI=2.1, 3.4) years for those with advanced osteopenia (lowest T-score, -2.00 to -2.49) at baseline. The adjusted times for 3% to develop a first hip or clinical vertebral fracture ranged from 7.1 (95% CI=6.0, 8.3) years in men with baseline T-scores > -1.50 to 1.7 (95% CI=1.0, 3.1) years in men with baseline osteoporosis. Conclusions Men aged 65 years and older with femoral neck, total hip, and lumbar spine BMD T-scores >-1.50 on a first BMD test were very unlikely to develop osteoporosis during follow-up. Additional BMD testing may be most informative in older men with T-scores ≤-1.50.

Han, S, Middleton, PF, Tran, TS & Crowther, CA 2016, 'Assessing use of a printed lifestyle intervention tool by women with borderline gestational diabetes and their achievement of diet and exercise goals: a descriptive study', BMC Pregnancy and Childbirth, vol. 16, no. 1.
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Hassanzadeh-Barforoushi, A, Shemesh, J, Farbehi, N, Asadnia, M, Yeoh, GH, Harvey, RP, Nordon, RE & Warkiani, ME 2016, 'A rapid co-culture stamping device for studying intercellular communication', Scientific Reports, vol. 6, no. 1, p. 35618.
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AbstractRegulation of tissue development and repair depends on communication between neighbouring cells. Recent advances in cell micro-contact printing and microfluidics have facilitated the in-vitro study of homotypic and heterotypic cell-cell interaction. Nonetheless, these techniques are still complicated to perform and as a result, are seldom used by biologists. We report here development of a temporarily sealed microfluidic stamping device which utilizes a novel valve design for patterning two adherent cell lines with well-defined interlacing configurations to study cell-cell interactions. We demonstrate post-stamping cell viability of >95%, the stamping of multiple adherent cell types, and the ability to control the seeded cell density. We also show viability, proliferation and migration of cultured cells, enabling analysis of co-culture boundary conditions on cell fate. We also developed an in-vitro model of endothelial and cardiac stem cell interactions, which are thought to regulate coronary repair after myocardial injury. The stamp is fabricated using microfabrication techniques, is operated with a lab pipettor and uses very low reagent volumes of 20 μl with cell injection efficiency of >70%. This easy-to-use device provides a general strategy for micro-patterning of multiple cell types and will be important for studying cell-cell interactions in a multitude of applications.

Hesari, Z, Soleimani, M, Atyabi, F, Sharifdini, M, Nadri, S, Warkiani, ME, Zare, M & Dinarvand, R 2016, 'A hybrid microfluidic system for regulation of neural differentiation in induced pluripotent stem cells', Journal of Biomedical Materials Research Part A, vol. 104, no. 6, pp. 1534-1543.
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AbstractControlling cellular orientation, proliferation, and differentiation is valuable in designing organ replacements and directing tissue regeneration. In the present study, we developed a hybrid microfluidic system to produce a dynamic microenvironment by placing aligned PDMS microgrooves on surface of biodegradable polymers as physical guidance cues for controlling the neural differentiation of human induced pluripotent stem cells (hiPSCs). The neuronal differentiation capacity of cultured hiPSCs in the microfluidic system and other control groups was investigated using quantitative real time PCR (qPCR) and immunocytochemistry. The functionally of differentiated hiPSCs inside hybrid system's scaffolds was also evaluated on the rat hemisected spinal cord in acute phase. Implanted cell's fate was examined using tissue freeze section and the functional recovery was evaluated according to the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale. Our results confirmed the differentiation of hiPSCs to neuronal cells on the microfluidic device where the expression of neuronal‐specific genes was significantly higher compared to those cultured on the other systems such as plain tissue culture dishes and scaffolds without fluidic channels. Although survival and integration of implanted hiPSCs did not lead to a significant functional recovery, we believe that combination of fluidic channels with nanofiber scaffolds provides a great microenvironment for neural tissue engineering, and can be used as a powerful tool for in situ monitoring of differentiation potential of various kinds of stem cells. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 1534–1543, 2016.

Hesson, LB, Ng, B, Zarzour, P, Srivastava, S, Kwok, C-T, Packham, D, Nunez, AC, Beck, D, Ryan, R, Dower, A, Ford, CE, Pimanda, JE, Sloane, MA, Hawkins, NJ, Bourke, MJ, Wong, JWH & Ward, RL 2016, 'Integrated Genetic, Epigenetic, and Transcriptional Profiling Identifies Molecular Pathways in the Development of Laterally Spreading Tumors', MOLECULAR CANCER RESEARCH, vol. 14, no. 12, pp. 1217-1228.
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Ho-Pham, LT, Hans, D, Doan, MC, Mai, LD & Nguyen, TV 2016, 'Genetic determinant of trabecular bone score (TBS) and bone mineral density: A bivariate analysis', Bone, vol. 92, pp. 79-84.
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Ho-Pham, LT, Lai, TQ, Mai, LD, Doan, MC & Nguyen, TV 2016, 'Body Composition in Individuals with Asymptomatic Osteoarthritis of the Knee', Calcified Tissue International, vol. 98, no. 2, pp. 165-171.
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© 2015, Springer Science+Business Media New York. Greater body mass index (BMI) is associated with a greater risk of osteoarthritis (OA). This study sought to investigate whether the association is mediated by fat mass or lean mass. The study involved 170 men and 488 women aged between 20 and 90 (average age: 55) who were randomly recruited from Ho Chi Minh City, Vietnam. The presence of knee OA was radiographically diagnosed based on the Kellgren–Lawrence criteria. Lean mass (LM) and fat mass (FM) were obtained from the DXA whole body scan (Hologic QDR-4500). The relationship between OA, LM, and FM was analyzed by a series of multiple linear regression models which take into account the effects of gender and age. As expected, men and women with knee OA were older than those without OA (65 vs 51 year in men, and 64 vs 52 year in women). After adjusting for age, OA was associated with greater FM and percent body fat (PBF), but the association was only observed in women, not in men. There was no statistically significant difference in LM between OA and non-OA individuals. Moreover, after adjusting for age and BMI or PBF, bone density in OA patients was not significantly different from non-OA individuals. Women with OA of the knee have greater fat mass than non-OA individuals, and that there is no significant difference in bone density between OA and non-OA individuals. Thus, the association between body mass index and OA is mainly mediated by fat mass.

Hosseinzadeh Adli, A, Karami, C, Zhand, S, Talei, R & Moradi, A 2016, 'Mutations in the Basal Core Promoter and Precore/Core Regions of Hepatitis B Virus in Patients Co-Infected With Human Immunodeficiency Virus', Medical Laboratory Journal, vol. 10, no. 4, pp. 32-39.
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Huang, Y, Thoms, JAI, Tursky, ML, Knezevic, K, Beck, D, Chandrakanthan, V, Suryani, S, Olivier, J, Boulton, A, Glaros, EN, Thomas, SR, Lock, RB, MacKenzie, KL, Bushweller, JH, Wong, JWH & Pimanda, JE 2016, 'MAPK/ERK2 phosphorylates ERG at serine 283 in leukemic cells and promotes stem cell signatures and cell proliferation', LEUKEMIA, vol. 30, no. 7, pp. 1552-1561.
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© 2016 Macmillan Publishers Limited. Aberrant ERG (v-ets avian erythroblastosis virus E26 oncogene homolog) expression drives leukemic transformation in mice and high expression is associated with poor patient outcomes in acute myeloid leukemia (AML) and T-acute lymphoblastic leukemia (T-ALL). Protein phosphorylation regulates the activity of many ETS factors but little is known about ERG in leukemic cells. To characterize ERG phosphorylation in leukemic cells, we applied liquid chromatography coupled tandem mass spectrometry and identified five phosphorylated serines on endogenous ERG in T-ALL and AML cells. S283 was distinct as it was abundantly phosphorylated in leukemic cells but not in healthy hematopoietic stem and progenitor cells (HSPCs). Overexpression of a phosphoactive mutant (S283D) increased expansion and clonogenicity of primary HSPCs over and above wild-type ERG. Using a custom antibody, we screened a panel of primary leukemic xenografts and showed that ERG S283 phosphorylation was mediated by mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling and in turn regulated expression of components of this pathway. S283 phosphorylation facilitates ERG enrichment and transactivation at the ERG +85 HSPC enhancer that is active in AML and T-ALL with poor prognosis. Taken together, we have identified a specific post-translational modification in leukemic cells that promotes progenitor proliferation and is a potential target to modulate ERG-driven transcriptional programs in leukemia.

Karami, C, H Adli, A, Zhand, S, Tabarraei, A, Talei, R, Saeidi, M & Moradi, A 2016, 'Study of Genotype, Subtype and Mutation in the S Gene in Hepatitis B Patients Co-infected with HIV in Iran', Jundishapur Journal of Microbiology, vol. 9, no. 12, pp. 1-5.
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Background: Co-infection with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) is common due to shared routes of transmission, as reported approximately 10% of 33 million HIV-infected patients worldwide are chronically infected with HBV. Mutations of HBsAg especially within the “a” determinant could alter the antigenicity of the protein, causing failure of HBsAg neutralization and escaping from the host’s immune system. This results in active viral replication and liver disease. Objectives: The aim of the survey was to identify HBV genotype and subtype, and different mutations in HBV S gene in hepatitis B patients co-infected with HIV in Iran. Methods: PCR performance and HBV-DNA extraction from plasma of 124 samples obtained from treatment naive HIV/HBV coinfected participants were according to the protocol. Direct sequencing and alignment of surface gene were carried out using reference sequences from the Gene Bank database. Results: From 124 HIV/HBV ELISA positive samples, 40 were HBV DNA-positive. Themean age of patients was 33.88 years. 20% of them were female and 80% were male. All isolates belonged to the sub genotype D1/ayw2 and genotype D. There were 50 point mutations including 23 (46%) missense and 27 (54%) silent mutations in amino acid level. Twenty three amino acid mutations occurred in different immune epitopes such as 11 (47.82%) in B cell, 6 (26.08%) in T helper and 2 (%8.6) in CTL. The prevalence of mutations in both “a” determinant region and Major Hydrophilic Region (MHR) was 5 (21.73%). Conclusions: Our findings showed that P127T and A70P (Outside of MHR) were the most frequently occurring substitution mutations. P127T, P132T, G130R, and S136Y substitutions placed in the first loop of the “a” determinant and the other substitutions of P142T and D144N occurred in the second loop of “a” determinant. The results of our study showed that most of the mutations occurred in B cell epitopes. The mutation in a surface gene of H...

Karimi Galougahi, K, Liu, C, Garcia, A, Gentile, C, Fry, NA, Hamilton, EJ, Hawkins, CL & Figtree, GA 2016, 'β3 Adrenergic Stimulation Restores Nitric Oxide/Redox Balance and Enhances Endothelial Function in Hyperglycemia', Journal of the American Heart Association, vol. 5, no. 2.
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Background Perturbed balance between NO and O 2 •− . (ie, NO/redox imbalance) is central in the pathobiology of diabetes‐induced vascular dysfunction. We examined whether stimulation of β 3 adrenergic receptors (β 3 ARs), coupled to endothelial nitric oxide synthase (eNOS) activation, would re‐establish NO/redox balance, relieve oxidative inhibition of the membrane proteins eNOS and Na + ‐K + (NK) pump, and improve vascular function in a new animal model of hyperglycemia. Methods and Results We established hyperglycemia in male White New Zealand rabbits by infusion of S961, a competitive high‐affinity peptide inhibitor of the insulin receptor. Hyperglycemia impaired endothelium‐dependent vasorelaxation by “uncoupling” of eNOS via glutathionylation (eNOS‐GSS) that was dependent on NADPH oxidase activity. Accordingly, NO levels were lower while O 2 •− levels were higher in hyperglycemic rabbits. Infusion of the β 3 AR agonist CL316243 (CL) decreased eNOS‐GSS, reduced O 2 •− , restored NO levels, and improved endothelium‐dependent relaxation. CL decreased hyperglycemia‐induced NADPH oxidase activation as suggested by co‐immunoprecipitation experiments, and it increased eNOS co‐immunoprecipitation w...

Khoo, BL, Chaudhuri, PK, Ramalingam, N, Tan, DSW, Lim, CT & Warkiani, ME 2016, 'Single‐cell profiling approaches to probing tumor heterogeneity', International Journal of Cancer, vol. 139, no. 2, pp. 243-255.
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Tumor heterogeneity is a major hindrance in cancer classification, diagnosis and treatment. Recent technological advances have begun to reveal the true extent of its heterogeneity. Single‐cell analysis (SCA) is emerging as an important approach to detect variations in morphology, genetic or proteomic expression. In this review, we revisit the issue of inter‐ and intra‐tumor heterogeneity, and list various modes of SCA techniques (cell‐based, nucleic acid‐based, protein‐based, metabolite‐based and lipid‐based) presently used for cancer characterization. We further discuss the advantages of SCA over pooled cell analysis, as well as the limitations of conventional techniques. Emerging trends, such as high‐throughput sequencing, are also mentioned as improved means for cancer profiling. Collectively, these applications have the potential for breakthroughs in cancer treatment.

Kulasinghe, A, Perry, C, Warkiani, ME, Blick, T, Davies, A, O'Byrne, K, Thompson, EW, Nelson, CC, Vela, I & Punyadeera, C 2016, 'Short term ex-vivo expansion of circulating head and neck tumour cells', Oncotarget, vol. 7, no. 37, pp. 60101-60109.
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Minimally invasive techniques are required for the identification of head and neck cancer (HNC) patients who are at an increased risk of metastasis, or are not responding to therapy. An approach utilised in other solid cancers is the identification and enumeration of circulating tumour cells (CTCs) in the peripheral blood of patients. Low numbers of CTCs has been a limiting factor in the HNC field to date. Here we present a methodology to expand HNC patient derived CTCs ex-vivo. As a proof of principle study, 25 advanced stage HNC patient bloods were enriched for circulating tumour cells through negative selection and cultured in 2D and 3D culture environments under hypoxic conditions (2% O2, 5% CO2). CTCs were detected in 14/25 (56%) of patients (ranging from 1-15 CTCs/5 mL blood). Short term CTC cultures were successfully generated in 7/25 advanced stage HNC patients (5/7 of these cultures were from HPV+ patients). Blood samples from which CTC culture was successful had higher CTC counts (p = 0.0002), and were predominantly from HPV+ patients (p = 0.007). This is, to our knowledge, the first pilot study to culture HNC CTCs ex-vivo. Further studies are warranted to determine the use of short term expansion in HNC and the role of HPV in promoting culture success.

Lal, S, Hall, RM & Tipper, JL 2016, 'A novel method for isolation and recovery of ceramic nanoparticles and metal wear debris from serum lubricants at ultra-low wear rates', Acta Biomaterialia, vol. 42, pp. 420-428.
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Li, JJ, Roohani-Esfahani, S-I, Dunstan, CR, Quach, T, Steck, R, Saifzadeh, S, Pivonka, P & Zreiqat, H 2016, 'Efficacy of novel synthetic bone substitutes in the reconstruction of large segmental bone defects in sheep tibiae', Biomedical Materials, vol. 11, no. 1, pp. 015016-015016.
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The treatment of large bone defects, particularly those with segmental bone loss, remains a significant clinical challenge as current approaches involving surgery or bone grafting often do not yield satisfactory long-term outcomes. This study reports the evaluation of novel ceramic scaffolds applied as bone graft substitutes in a clinically relevant in vivo model. Baghdadite scaffolds, unmodified or modified with a polycaprolactone coating containing bioactive glass nanoparticles, were implanted into critical-sized segmental bone defects in sheep tibiae for 26 weeks. Radiographic, biomechanical, μ-CT and histological analyses showed that both unmodified and modified baghdadite scaffolds were able to withstand physiological loads at the defect site, and induced substantial bone formation in the absence of supplementation with cells or growth factors. Notably, all samples showed significant bridging of the critical-sized defect (average 80%) with evidence of bone infiltration and remodelling within the scaffold implant. The unmodified and modified baghdadite scaffolds achieved similar outcomes of defect repair, although the latter may have an initial mechanical advantage due to the nanocomposite coating. The baghdadite scaffolds evaluated in this study hold potential for use as purely synthetic bone graft substitutes in the treatment of large bone defects while circumventing the drawbacks of autografts and allografts.

Liu, D, Xu, X, Du, Y, Qin, X, Zhang, Y, Ma, C, Wen, S, Ren, W, Goldys, EM, Piper, JA, Dou, S, Liu, X & Jin, D 2016, 'Three-dimensional controlled growth of monodisperse sub-50 nm heterogeneous nanocrystals', Nature Communications, vol. 7, no. 1, pp. 1-8.
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AbstractThe ultimate frontier in nanomaterials engineering is to realize their composition control with atomic scale precision to enable fabrication of nanoparticles with desirable size, shape and surface properties. Such control becomes even more useful when growing hybrid nanocrystals designed to integrate multiple functionalities. Here we report achieving such degree of control in a family of rare-earth-doped nanomaterials. We experimentally verify the co-existence and different roles of oleate anions (OA−) and molecules (OAH) in the crystal formation. We identify that the control over the ratio of OA− to OAH can be used to directionally inhibit, promote or etch the crystallographic facets of the nanoparticles. This control enables selective grafting of shells with complex morphologies grown over nanocrystal cores, thus allowing the fabrication of a diverse library of monodisperse sub-50 nm nanoparticles. With such programmable additive and subtractive engineering a variety of three-dimensional shapes can be implemented using a bottom–up scalable approach.

Liu, D, Xu, X, Wang, F, Zhou, J, Mi, C, Zhang, L, Lu, Y, Ma, C, Goldys, E, Lin, J & Jin, D 2016, 'Emission stability and reversibility of upconversion nanocrystals', Journal of Materials Chemistry C, vol. 4, no. 39, pp. 9227-9234.
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We report the emission stability and reversibility of NaYF₄:Yb³⁺,Er³⁺ core and core–shell nanocrystals at different temperatures and pH values.

Ma, C, Xu, X, Wang, F, Zhou, Z, Wen, S, Liu, D, Fang, J, Lang, CI & Jin, D 2016, 'Probing the Interior Crystal Quality in the Development of More Efficient and Smaller Upconversion Nanoparticles', The Journal of Physical Chemistry Letters, vol. 7, no. 16, pp. 3252-3258.
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© 2016 American Chemical Society. Optical biomedical imaging using luminescent nanoparticles as contrast agents prefers small size, as they can be used at high dosages and efficiently cleared from body. Reducing nanoparticle size is critical for the stability and specificity for the fluorescence nanoparticles probes for in vitro diagnostics and subcellular imaging. The development of smaller and brighter upconversion nanoparticles (UCNPs) is accordingly a goal for complex imaging in bioenvironments. At present, however, small UCNPs are reported to exhibit less emission intensity due to increased surface deactivation and decreased number of dopants. Here we show that smaller and more efficient UCNPs can be made by improving the interior crystal quality via controlling heating rate during synthesis. We further developed a unique quantitative method for optical characterizations on the single UCNPs with varied sizes and the corresponding shell passivated UCNPs, confirming that the internal crystal quality dominates the relative emission efficiency of the UCNPs.

Nasrallah, R, Fast, EM, Solaimani, P, Knezevic, K, Eliades, A, Patel, R, Thambyrajah, R, Unnikrishnan, A, Thoms, J, Beck, D, Vink, CS, Smith, A, Wong, J, Shepherd, M, Kent, D, Roychoudhuri, R, Paul, F, Klippert, J, Hammes, A, Willnow, T, Göttgens, B, Dzierzak, E, Zon, LI, Lacaud, G, Kouskoff, V & Pimanda, JE 2016, 'Identification of novel regulators of developmental hematopoiesis using Endoglin regulatory elements as molecular probes', Blood, vol. 128, no. 15, pp. 1928-1939.
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Key PointsENG regulatory elements target hemogenic mesoderm and hemogenic endothelium. Hemogenic progenitors can be enriched using these elements as molecular probes to discover novel regulators of hematopoiesis.

Pavesi, A, Adriani, G, Tay, A, Warkiani, ME, Yeap, WH, Wong, SC & Kamm, RD 2016, 'Engineering a 3D microfluidic culture platform for tumor-treating field application', Scientific Reports, vol. 6, no. 1, p. 26584.
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AbstractThe limitations of current cancer therapies highlight the urgent need for a more effective therapeutic strategy. One promising approach uses an alternating electric field; however, the mechanisms involved in the disruption of the cancer cell cycle as well as the potential adverse effects on non-cancerous cells must be clarified. In this study, we present a novel microfluidic device with embedded electrodes that enables the application of an alternating electric field therapy to cancer cells in a 3D extracellular matrix. To demonstrate the potential of our system to aid in designing and testing new therapeutic approaches, cancer cells and cancer cell aggregates were cultured individually or co-cultured with endothelial cells. The metastatic potential of the cancer cells was reduced after electric field treatment. Moreover, the proliferation rate of the treated cancer cells was lower compared with that of the untreated cells, whereas the morphologies and proliferative capacities of the endothelial cells were not significantly affected. These results demonstrate that our novel system can be used to rapidly screen the effect of an alternating electric field on cancer and normal cells within an in vivo-like microenvironment with the potential to optimize treatment protocols and evaluate synergies between tumor-treating field treatment and chemotherapy.

Perera, D, Poulos, RC, Shah, A, Beck, D, Pimanda, JE & Wong, JWH 2016, 'Differential DNA repair underlies mutation hotspots at active promoters in cancer genomes', NATURE, vol. 532, no. 7598, pp. 259-+.
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© 2016 Macmillan Publishers Limited. Promoters are DNA sequences that have an essential role in controlling gene expression. While recent whole cancer genome analyses have identified numerous hotspots of somatic point mutations within promoters, many have not yet been shown to perturb gene expression or drive cancer development. As such, positive selection alone may not adequately explain the frequency of promoter point mutations in cancer genomes. Here we show that increased mutation density at gene promoters can be linked to promoter activity and differential nucleotide excision repair (NER). By analysing 1,161 human cancer genomes across 14 cancer types, we find evidence for increased local density of somatic point mutations within the centres of DNase I-hypersensitive sites (DHSs) in gene promoters. Mutated DHSs were strongly associated with transcription initiation activity, in which active promoters but not enhancers of equal DNase I hypersensitivity were most mutated relative to their flanking regions. Notably, analysis of genome-wide maps of NER shows that NER is impaired within the DHS centre of active gene promoters, while XPC-deficient skin cancers do not show increased promoter mutation density, pinpointing differential NER as the underlying cause of these mutation hotspots. Consistent with this finding, we observe that melanomas with an ultraviolet-induced DNA damage mutation signature show greatest enrichment of promoter mutations, whereas cancers that are not highly dependent on NER, such as colon cancer, show no sign of such enrichment. Taken together, our analysis has uncovered the presence of a previously unknown mechanism linking transcription initiation and NER as a major contributor of somatic point mutation hotspots at active gene promoters in cancer genomes.

Pham, HM, Nguyen, ND, Center, JR, Eisman, JA & Nguyen, TV 2016, 'Contribution of Quadriceps Weakness to Fragility Fracture: A Prospective Study', Journal of Bone and Mineral Research, vol. 31, no. 1, pp. 208-214.
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ABSTRACT   The association between muscle weakness and fracture is not well understood. This study sought to examine the contribution of muscle strength at baseline and change in muscle strength to the observed risk of fragility fracture in older people. The study involved 595 men and 1066 women aged 60+ years (median 69 years) who had been followed for a median of 11 years (range, 4 to 22 years). Quadriceps isometric muscle strength (MS) measured at baseline and biennially was adjusted for height. Femoral neck bone mineral density (FNBMD) was measured by DXA. Low-trauma fracture was ascertained from X-ray reports and interview. The relationship between baseline MS and serial MS and fracture assessed by time-invariant and time-variant Cox's regression models was expressed as hazard ratio (HR) and 95% confidence interval (CI). During the follow-up period, 282 (26%) women and 89 (15%) men sustained a fragility fracture. From age 60 years, women lost 0.28 kg/m (1.6%) of MS per year, whereas men lost 0.39 kg/m (1.5%) of MS per year. In the time-variant model, using serial MS, each 1 SD (4.7 kg/m) lower MS was associated with a 27% increase in the risk of fracture in women (HR 1.27; 95% CI, 1.11 to 1.43); and 46% increase in men (HR 1.46; 95% CI, 1.22 to 1.75). After adjusting for FNBMD, age and prior fracture, history of fall and smoking, HR per SD of lower MS was 1.13 (95% CI, 0.99 to 1.28) for women and 1.35 (95% CI, 1.18 to 1.64) for men. These data indicate that muscle weakness is an independent determinant of fracture risk in men, but not in women. This sex difference suggests that apart from mechanical load effect of muscle on bone, there are other muscle-bone interactions that need to be investigated in future studies. The accuracy of fracture risk prediction for men may be improved by incorporating muscle strength. © 2015 American ...

Piggin, CL, Roden, DL, Gallego-Ortega, D, Lee, HJ, Oakes, SR & Ormandy, CJ 2016, 'ELF5 isoform expression is tissue-specific and significantly altered in cancer', Breast Cancer Research, vol. 18, no. 1, p. 4.
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BACKGROUND: E74-like factor 5 (ELF5) is an epithelial-specific member of the E26 transforming sequence (ETS) transcription factor family and a critical regulator of cell fate in the placenta, pulmonary bronchi, and milk-producing alveoli of the mammary gland. ELF5 also plays key roles in malignancy, particularly in basal-like and endocrine-resistant forms of breast cancer. Almost all genes undergo alternative transcription or splicing, which increases the diversity of protein structure and function. Although ELF5 has multiple isoforms, this has not been considered in previous studies of ELF5 function. METHODS: RNA-sequencing data for 6757 samples from The Cancer Genome Atlas were analyzed to characterize ELF5 isoform expression in multiple normal tissues and cancers. Extensive in vitro analysis of ELF5 isoforms, including a 116-gene quantitative polymerase chain reaction panel, was performed in breast cancer cell lines. RESULTS: ELF5 isoform expression was found to be tissue-specific due to alternative promoter use but altered in multiple cancer types. The normal breast expressed one main isoform, while in breast cancer there were subtype-specific alterations in expression. Expression of other ETS factors was also significantly altered in breast cancer, with the basal-like subtype demonstrating a distinct ETS expression profile. In vitro inducible expression of the full-length isoforms 1 and 2, as well as isoform 3 (lacking the Pointed domain) had similar phenotypic and transcriptional effects. CONCLUSIONS: Alternative promoter use, conferring differential regulatory responses, is the main mechanism governing ELF5 action rather than differential transcriptional activity of the isoforms. This understanding of expression and function at the isoform level is a vital first step in realizing the potential of transcription factors such as ELF5 as prognostic markers or therapeutic targets in cancer.

Polonchuk, L, Chabria, M, Davies, MJ & Gentile, C 2016, 'Doxorubicin-Mediated Toxic Effects Are Mediated Via NO/eNOS in a Novel 3D in Vitro Model of the Human Heart', Free Radical Biology and Medicine, vol. 100, pp. S142-S142.
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Rafeie, M, Zhang, J, Asadnia, M, Li, W & Warkiani, ME 2016, 'Multiplexing slanted spiral microchannels for ultra-fast blood plasma separation', Lab on a Chip, vol. 16, no. 15, pp. 2791-2802.
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Blood and blood products are critical components of health care.

Ramalingam, N, Warkiani, ME, Ramalingam, N, Keshavarzi, G, Hao-Bing, L & Hai-Qing, TG 2016, 'Numerical and experimental study of capillary-driven flow of PCR solution in hybrid hydrophobic microfluidic networks', Biomedical Microdevices, vol. 18, no. 4, p. 68.
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Capillary-driven microfluidics is essential for development of point-of-care diagnostic micro-devices. Polymerase chain reaction (PCR)-based micro-devices are widely developed and used in such point-of-care settings. It is imperative to characterize the fluid parameters of PCR solution for designing efficient capillary-driven microfluidic networks. Generally, for numeric modelling, the fluid parameters of PCR solution are approximated to that of water. This procedure leads to inaccurate results, which are discrepant to experimental data. This paper describes mathematical modeling and experimental validation of capillary-driven flow inside Poly-(dimethyl) siloxane (PDMS)-glass hybrid micro-channels. Using experimentally measured PCR fluid parameters, the capillary meniscus displacement in PDMS-glass microfluidic ladder network is simulated using computational fluid dynamic (CFD), and experimentally verified to match with the simulated data.

Remenyi, J, Bajan, S, Fuller-Pace, FV, Arthur, JSC & Hutvagner, G 2016, 'The loop structure and the RNA helicase p72/DDX17 influence the processing efficiency of the mice miR-132', Scientific Reports, vol. 6, no. 1.
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AbstractmiRNAs are small RNAs that are key regulators of gene expression in eukaryotic organisms. The processing of miRNAs is regulated by structural characteristics of the RNA and is also tightly controlled by auxiliary protein factors. Among them, RNA binding proteins play crucial roles to facilitate or inhibit miRNA maturation and can be controlled in a cell, tissue and species-specific manners or in response to environmental stimuli. In this study we dissect the molecular mechanism that promotes the overexpression of miR-132 in mice over its related, co-transcribed and co-regulated miRNA, miR-212. We have shown that the loop structure of miR-132 is a key determinant for its efficient processing in cells. We have also identified a range of RNA binding proteins that recognize the loop of miR-132 and influence both miR-132 and miR-212 processing. The DEAD box helicase p72/DDX17 was identified as a factor that facilitates the specific processing of miR-132.

Richmond, J, Robbins, A, Evans, K, Beck, D, Kurmasheva, RT, Billups, CA, Carol, H, Heatley, S, Sutton, R, Marshall, GM, White, D, Pimanda, J, Houghton, PJ, Smith, MA & Lock, RB 2016, 'Acute Sensitivity of Ph-like Acute Lymphoblastic Leukemia to the SMAC-Mimetic Birinapant', Cancer Research, vol. 76, no. 15, pp. 4579-4591.
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Abstract Ph-like acute lymphoblastic leukemia (ALL) is a genetically defined high-risk ALL subtype with a generally poor prognosis. In this study, we evaluated the efficacy of birinapant, a small-molecule mimetic of the apoptotic regulator SMAC, against a diverse set of ALL subtypes. Birinapant exhibited potent and selective cytotoxicity against B-cell precursor ALL (BCP-ALL) cells that were cultured ex vivo or in vivo as patient-derived tumor xenografts (PDX). Cytotoxicity was consistently most acute in Ph-like BCP-ALL. Unbiased gene expression analysis of BCP-ALL PDX specimens identified a 68-gene signature associated with birinapant sensitivity, including an enrichment for genes involved in inflammatory response, hematopoiesis, and cell death pathways. All Ph-like PDXs analyzed clustered within this 68-gene classifier. Mechanistically, birinapant sensitivity was associated with expression of TNF receptor TNFR1 and was abrogated by interfering with the TNFα/TNFR1 interaction. In combination therapy, birinapant enhanced the in vivo efficacy of an induction-type regimen of vincristine, dexamethasone, and L-asparaginase against Ph-like ALL xenografts, offering a preclinical rationale to further evaluate this SMAC mimetic for BCP-ALL treatment. Cancer Res; 76(15); 4579–91. ©2016 AACR.

Seeman, E & Nguyen, TV 2016, 'Bone remodeling markers: so easy to measure, so difficult to interpret', Osteoporosis International, vol. 27, no. 1, pp. 33-35.
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Shen, M, Zhang, N, Zheng, S, Zhang, W-B, Zhang, H-M, Lu, Z, Su, QP, Sun, Y, Ye, K & Li, X-D 2016, 'Calmodulin in complex with the first IQ motif of myosin-5a functions as an intact calcium sensor', Proceedings of the National Academy of Sciences, vol. 113, no. 40, pp. E5812-E5820.
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Significance Myosin-5a is a molecular motor that functions as a cargo transporter in cells. The motor function of myosin-5a is regulated by calcium via the calmodulin bound to the first isoleucine-glutamine (IQ) motif (IQ1) of myosin-5a. Here, we solve the crystal structure of a truncated myosin-5a containing the motor domain and the IQ1 complexed with calcium-bound calmodulin. Comparison of the structures of the IQ1 complexed with calmodulin with or without bound calcium reveals the calcium-induced conformational changes of calmodulin. We demonstrated that calmodulin continuously associates with the IQ1 during that calcium transition and that the IQ1 binding substantially changes the thermodynamic and kinetics of calcium transition in calmodulin. These findings provide insight into the mechanism by which calcium regulates myosin-5a.

Shields, BJ, Jackson, JT, Metcalf, D, Shi, W, Huang, Q, Garnham, AL, Glaser, SP, Beck, D, Pimanda, JE, Bogue, CW, Smyth, GK, Alexander, WS & McCormack, MP 2016, 'Acute myeloid leukemia requires Hhex to enable PRC2-mediated epigenetic repression of Cdkn2a', Genes & Development, vol. 30, no. 1, pp. 78-91.
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Unlike clustered HOX genes, the role of nonclustered homeobox gene family members in hematopoiesis and leukemogenesis has not been extensively studied. Here we found that the hematopoietically expressed homeobox gene Hhex is overexpressed in acute myeloid leukemia (AML) and is essential for the initiation and propagation of MLL-ENL-induced AML but dispensable for normal myelopoiesis, indicating a specific requirement for Hhex for leukemic growth. Loss of Hhex leads to expression of the Cdkn2a-encoded tumor suppressors p16INK4a and p19ARF, which are required for growth arrest and myeloid differentiation following Hhex deletion. Mechanistically, we show that Hhex binds to the Cdkn2a locus and directly interacts with the Polycomb-repressive complex 2 (PRC2) to enable H3K27me3-mediated epigenetic repression. Thus, Hhex is a potential therapeutic target that is specifically required for AML stem cells to repress tumor suppressor pathways and enable continued self-renewal.

Stratton-Powell, AA, Pasko, KM, Brockett, CL & Tipper, JL 2016, 'The Biologic Response to Polyetheretherketone (PEEK) Wear Particles in Total Joint Replacement: A Systematic Review', Clinical Orthopaedics & Related Research, vol. 474, no. 11, pp. 2394-2404.
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Styrkarsdottir, U, Thorleifsson, G, Eiriksdottir, B, Gudjonsson, SA, Ingvarsson, T, Center, JR, Nguyen, TV, Eisman, JA, Christiansen, C, Thorsteinsdottir, U, Sigurdsson, G & Stefansson, K 2016, 'Two Rare Mutations in the COL1A2 Gene Associate With Low Bone Mineral Density and Fractures in Iceland', Journal of Bone and Mineral Research, vol. 31, no. 1, pp. 173-179.
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ABSTRACT   We conducted a genome-wide association study of low bone mineral density (BMD) at the hip and spine utilizing sequence variants found through whole-genome sequencing of 2636 Icelanders. We found two rare missense mutations, p.Gly496Ala and p.Gly703Ser, in the COL1A2 gene that associate with measures of osteoporosis in Icelanders. Mutations in COL1A2 are known to cause the autosomal dominant disorder osteogenesis imperfecta. Both variants associate with low BMD and with osteoporotic fractures. p.Gly496Ala (frequency of 0.105%) shows the strongest association with low BMD at the spine (p = 1.8 × 10−7, odds ratio [OR] = 4.61 [95% confidence interval (CI) 2.59, 8.18]), whereas p.Gly703Ser (frequency of 0.050%) is most strongly associated with low BMD at the hip (p = 1.9 × 10−8, OR = 9.34 [95% CI 4.28, 20.3]). Association with fractures was p = 2.2 × 10−5, OR = 3.75 (95% CI 2.03, 6.93) and p = 0.0023, OR = 4.32 (95% CI 1.69, 11.1), respectively. The carriers of these variants do not have signs of osteogenesis imperfecta other than low BMD, demonstrating that similar mutations in COL1A2 can affect skeletal phenotypes in more than one way. © 2015 American Society for Bone and Mineral Research.

Styrkarsdottir, U, Thorleifsson, G, Gudjonsson, SA, Sigurdsson, A, Center, JR, Lee, SH, Nguyen, TV, Kwok, TCY, Lee, JSW, Ho, SC, Woo, J, Leung, P-C, Kim, B-J, Rafnar, T, Kiemeney, LA, Ingvarsson, T, Koh, J-M, Tang, NLS, Eisman, JA, Christiansen, C, Sigurdsson, G, Thorsteinsdottir, U & Stefansson, K 2016, 'Sequence variants in the PTCH1 gene associate with spine bone mineral density and osteoporotic fractures', Nature Communications, vol. 7, no. 1, pp. 1-8.
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AbstractBone mineral density (BMD) is a measure of osteoporosis and is useful in evaluating the risk of fracture. In a genome-wide association study of BMD among 20,100 Icelanders, with follow-up in 10,091 subjects of European and East-Asian descent, we found a new BMD locus that harbours the PTCH1 gene, represented by rs28377268 (freq. 11.4–22.6%) that associates with reduced spine BMD (P=1.0 × 10−11, β=−0.09). We also identified a new spine BMD signal in RSPO3, rs577721086 (freq. 6.8%), that associates with increased spine BMD (P=6.6 × 10−10, β=0.14). Importantly, both variants associate with osteoporotic fractures and affect expression of the PTCH1 and RSPO3 genes that is in line with their influence on BMD and known biological function of these genes. Additional new BMD signals were also found at the AXIN1 and SOST loci and a new lead SNP at the EN1 locus.

Su, QP, Du, W, Ji, Q, Xue, B, Jiang, D, Zhu, Y, Ren, H, Zhang, C, Lou, J, Yu, L & Sun, Y 2016, 'Vesicle Size Regulates Nanotube Formation in the Cell', Scientific Reports, vol. 6, no. 1, pp. 24002-24002.
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AbstractIntracellular membrane nanotube formation and its dynamics play important roles for cargo transportation and organelle biogenesis. Regarding the regulation mechanisms, while much attention has been paid on the lipid composition and its associated protein molecules, effects of the vesicle size has not been studied in the cell. Giant unilamellar vesicles (GUVs) are often used for in vitro membrane deformation studies, but they are much larger than most intracellular vesicles and the in vitro studies also lack physiological relevance. Here, we use lysosomes and autolysosomes, whose sizes range between 100 nm and 1 μm, as model systems to study the size effects on nanotube formation both in vivo and in vitro. Single molecule observations indicate that driven by kinesin motors, small vesicles (100–200 nm) are mainly transported along the tracks while a remarkable portion of large vesicles (500–1000 nm) form nanotubes. This size effect is further confirmed by in vitro reconstitution assays on liposomes and purified lysosomes and autolysosomes. We also apply Atomic Force Microscopy (AFM) to measure the initiation force for nanotube formation. These results suggest that the size-dependence may be one of the mechanisms for cells to regulate cellular processes involving membrane-deformation, such as the timing of tubulation-mediated vesicle recycling.

Sutton, SK, Carter, DR, Kim, P, Tan, O, Arndt, GM, Zhang, XD, Baell, J, Noll, BD, Wang, S, Kumar, N, McArthur, GA, Cheung, BB & Marshall, GM 2016, 'A novel compound which sensitizes BRAF wild-type melanoma cells to vemurafenib in a TRIM16-dependent manner', Oncotarget, vol. 7, no. 32, pp. 52166-52178.
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There is an urgent need for better therapeutic options for advanced melanoma patients, particularly those without the BRAFV600E/K mutation. In melanoma cells, loss of TRIM16 expression is a marker of cell migration and metastasis, while the BRAF inhibitor, vemurafenib, induces melanoma cell growth arrest in a TRIM16-dependent manner. Here we identify a novel small molecule compound which sensitized BRAF wild-type melanoma cells to vemurafenib. High throughput, cell-based, chemical library screening identified a compound (C012) which significantly reduced melanoma cell viability, with limited toxicity for normal human fibroblasts. When combined with the BRAFV600E/K inhibitor, vemurafenib, C012 synergistically increased vemurafenib potency in 5 BRAFWT and 4 out of 5 BRAFV600E human melanoma cell lines (Combination Index: CI < 1), and, dramatically reduced colony forming ability. In addition, this drug combination was significantly anti-tumorigenic in vivo in a melanoma xenograft mouse model. The combination of vemurafenib and C012 markedly increased expression of TRIM16 protein, and knockdown of TRIM16 significantly reduced the growth inhibitory effects of the vemurafenib and C012 combination. These findings suggest that the combination of C012 and vemurafenib may have therapeutic potential for the treatment of melanoma, and, that reactivation of TRIM16 may be an effective strategy for patients with this disease.

Tavakoli, J, Elliott, DM & Costi, JJ 2016, 'Structure and mechanical function of the inter‐lamellar matrix of the annulus fibrosus in the disc', Journal of Orthopaedic Research, vol. 34, no. 8, pp. 1307-1315.
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ABSTRACTThe inter‐lamellar matrix (ILM) has an average thickness of less than 30 µm and lies between adjacent lamellae in the annulus fibrosus (AF). The microstructure and composition of the ILM have been studied in various anatomic regions of the disc; however, their contribution to AF mechanical properties and structural integrity is unknown. It was suggested that the ILM components, mainly elastic fibers and cross‐bridges, play a role in providing mechanical integrity of the AF. Therefore, the manner in which they respond to different loadings and stabilize adjacent lamellae structure will influence AF tear formation and subsequent herniation. This review paper summarizes the composition, microstructure, and potential role of the ILM in the progression of disc herniation, clarifies the micromechanical properties of the ILM, and proposes critical areas for future studies. There are a number of unknown characteristics of the ILM, such as its mechanical role, impact on AF integrity, and ultrastructure of elastic fibers at the ILM‐lamella boundary. Determining these characteristics will provide important information for tissue engineering, repair strategies, and the development of more‐physiological computational models to study the initiation and propagation of AF tears that lead to herniation and degeneration. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1307–1315, 2016.

Tay, A, Pavesi, A, Yazdi, SR, Lim, CT & Warkiani, ME 2016, 'Advances in microfluidics in combating infectious diseases', Biotechnology Advances, vol. 34, no. 4, pp. 404-421.
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One of the important pursuits in science and engineering research today is to develop low-cost and user-friendly technologies to improve the health of people. Over the past decade, research efforts in microfluidics have been made to develop methods that can facilitate low-cost diagnosis of infectious diseases, especially in resource-poor settings. Here, we provide an overview of the recent advances in microfluidic devices for point-of-care (POC) diagnostics for infectious diseases and emphasis is placed on malaria, sepsis and AIDS/HIV. Other infectious diseases such as SARS, tuberculosis, and dengue are also briefly discussed. These infectious diseases are chosen as they contribute the most to disability-adjusted life-years (DALYs) lost according to the World Health Organization (WHO). The current state of research in this area is evaluated and projection toward future applications and accompanying challenges are also discussed.

Warkiani, ME, Khoo, BL, Wu, L, Tay, AKP, Bhagat, AAS, Han, J & Lim, CT 2016, 'Ultra-fast, label-free isolation of circulating tumor cells from blood using spiral microfluidics', Nature Protocols, vol. 11, no. 1, pp. 134-148.
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Circulating tumor cells (CTCs) are rare cancer cells that are shed from primary or metastatic tumors into the peripheral blood circulation. Phenotypic and genetic characterization of these rare cells can provide important information to guide cancer staging and treatment, and thus further research into their characteristics and properties is an area of considerable interest. In this protocol, we describe detailed procedures for the production and use of a label-free spiral microfluidic device to allow size-based isolation of viable CTCs using hydrodynamic forces that are present in curvilinear microchannels. This spiral system enables us to achieve ≥ 85% recovery of spiked cells across multiple cancer cell lines and 99.99% depletion of white blood cells in whole blood. The described spiral microfluidic devices can be produced at an extremely low cost using standard microfabrication and soft lithography techniques (2-3 d), and they can be operated using two syringe pumps for lysed blood samples (7.5 ml in 12.5 min for a three-layered multiplexed chip). The fast processing time and the ability to collect CTCs from a large patient blood volume allows this technique to be used experimentally in a broad range of potential genomic and transcriptomic applications.

Yan, L, Zhao, B, Liu, X, Li, X, Zeng, C, Shi, H, Xu, X, Lin, T, Dai, L & Liu, Y 2016, 'Aligned Nanofibers from Polypyrrole/Graphene as Electrodes for Regeneration of Optic Nerve via Electrical Stimulation', ACS APPLIED MATERIALS & INTERFACES, vol. 8, no. 11, pp. 6834-6840.
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© 2016 American Chemical Society. The damage of optic nerve will cause permanent visual field loss and irreversible ocular diseases, such as glaucoma. The damage of optic nerve is mainly derived from the atrophy, apoptosis or death of retinal ganglion cells (RGCs). Though some progress has been achieved on electronic retinal implants that can electrically stimulate undamaged parts of RGCs or retina to transfer signals, stimulated self-repair/regeneration of RGCs has not been realized yet. The key challenge for development of electrically stimulated regeneration of RGCs is the selection of stimulation electrodes with a sufficient safe charge injection limit (Qinj, i.e., electrochemical capacitance). Most traditional electrodes tend to have low Qinj values. Herein, we synthesized polypyrrole functionalized graphene (PPy-G) via a facile but efficient polymerization-enhanced ball milling method for the first time. This technique could not only efficiently introduce electron-acceptor nitrogen to enhance capacitance, but also remain a conductive platform-the π-π conjugated carbon plane for charge transportation. PPy-G based aligned nanofibers were subsequently fabricated for guided growth and electrical stimulation (ES) of RGCs. Significantly enhanced viability, neurite outgrowth and antiaging ability of RGCs were observed after ES, suggesting possibilities for regeneration of optic nerve via ES on the suitable nanoelectrodes.

Yang, Y, Ciampi, S, Zhu, Y & Gooding, JJ 2016, 'Light-Activated Electrochemistry for the Two-Dimensional Interrogation of Electroactive Regions on a Monolithic Surface with Dramatically Improved Spatial Resolution', The Journal of Physical Chemistry C, vol. 120, no. 24, pp. 13032-13038.
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The concept of light-activated electrochemistry (LAE) was recently presented where faradaic electrochemistry could be spatially resolved on a monolithic silicon electrode by illuminating the specific region with light. A major implication from the previous study using illumination from the nonsolution side, or backside, is that the spatial resolution is limited by the finite thickness of silicon wafer. To overcome this restriction, and enable the further application of LAE, in combination with optical imaging for example, herein the spatial resolution of LAE using topside illumination (illumination from the solution side) is explored. The applied potential and irradiated light intensity are found to have significant effects on the spatial resolution. A spatial resolution of ∼30 μm was achieved with optimal parameters, which is a 20 times improvement compared with the previously reported backside illumination design, demonstrating the potential application of the strategy including microarray patterning of silicon or for single cell analysis.

Young, AIJ, Law, AMK, Castillo, L, Chong, S, Cullen, HD, Koehler, M, Herzog, S, Brummer, T, Lee, EF, Fairlie, WD, Lucas, MC, Herrmann, D, Allam, A, Timpson, P, Watkins, DN, Millar, EKA, O’Toole, SA, Gallego-Ortega, D, Ormandy, CJ & Oakes, SR 2016, 'MCL-1 inhibition provides a new way to suppress breast cancer metastasis and increase sensitivity to dasatinib', Breast Cancer Research, vol. 18, no. 1, p. 125.
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BACKGROUND: Metastatic disease is largely resistant to therapy and accounts for almost all cancer deaths. Myeloid cell leukemia-1 (MCL-1) is an important regulator of cell survival and chemo-resistance in a wide range of malignancies, and thus its inhibition may prove to be therapeutically useful. METHODS: To examine whether targeting MCL-1 may provide an effective treatment for breast cancer, we constructed inducible models of BIMs2A expression (a specific MCL-1 inhibitor) in MDA-MB-468 (MDA-MB-468-2A) and MDA-MB-231 (MDA-MB-231-2A) cells. RESULTS: MCL-1 inhibition caused apoptosis of basal-like MDA-MB-468-2A cells grown as monolayers, and sensitized them to the BCL-2/BCL-XL inhibitor ABT-263, demonstrating that MCL-1 regulated cell survival. In MDA-MB-231-2A cells, grown in an organotypic model, induction of BIMs2A produced an almost complete suppression of invasion. Apoptosis was induced in such a small proportion of these cells that it could not account for the large decrease in invasion, suggesting that MCL-1 was operating via a previously undetected mechanism. MCL-1 antagonism also suppressed local invasion and distant metastasis to the lung in mouse mammary intraductal xenografts. Kinomic profiling revealed that MCL-1 antagonism modulated Src family kinases and their targets, which suggested that MCL-1 might act as an upstream modulator of invasion via this pathway. Inhibition of MCL-1 in combination with dasatinib suppressed invasion in 3D models of invasion and inhibited the establishment of tumors in vivo. CONCLUSION: These data provide the first evidence that MCL-1 drives breast cancer cell invasion and suggests that MCL-1 antagonists could be used alone or in combination with drugs targeting Src kinases such as dasatinib to suppress metastasis.

Zarepour, E, Hassan, M, Chou, CT & Ebrahimi Warkiani, M 2016, 'Characterizing terahertz channels for monitoring human lungs with wireless nanosensor networks', Nano Communication Networks, vol. 9, pp. 43-57.
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We characterize terahertz wireless channels for extracting data from nanoscale sensors deployed within human lungs. We discover that the inhalation and exhalation of oxygen and carbon dioxide causes periodic variation of the absorption coefficient of the terahertz channel. Channel absorption drops to its minimum near the end of inhalation, providing a window of opportunity to extract data with minimum transmission power. We propose an algorithm for nanosensors to estimate the periodic channel by observing signal-to-noise ratio of the beacons transmitted from the data sink. Using real respiration data from multiple subjects, we demonstrate that the proposed algorithm can estimate the minimum absorption interval of the periodic channel with 98.5% accuracy. Our analysis shows that by confining all data collections during the estimated low-absorption window of the periodic channel, nanosensors can reduce power consumption by six orders of magnitude. Finally, we demonstrate that for wireless communications within human lungs, 0.1–0.12 THz is the least absorbing spectrum within the terahertz band.

Zhand, S, Rostamian, G, Tabarraei, A & Moradi, A 2016, 'Study of Hepatitis B Virus Genotypes and Mutation in 1762 &amp; 1764 Nucleotides of X Gene in Chronic HBV Patients from Golestan Province—Iran', Health, vol. 08, no. 13, pp. 1397-1401.
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Zhang, J, Yan, S, Yuan, D, Alici, G, Nguyen, N-T, Ebrahimi Warkiani, M & Li, W 2016, 'Fundamentals and applications of inertial microfluidics: a review', Lab on a Chip, vol. 16, no. 1, pp. 10-34.
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We provide a comprehensive review describing the fundamental mechanisms of inertial microfluidics, structure design and applications in biology, medicine and industry.

Zhao, W, Li, J, Jin, K, Liu, W, Qiu, X & Li, C 2016, 'Fabrication of functional PLGA-based electrospun scaffolds and their applications in biomedical engineering', Materials Science and Engineering: C, vol. 59, pp. 1181-1194.
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Zhu, Y, Kekalo, K, NDong, C, Huang, Y, Shubitidze, F, Griswold, KE, Baker, I & Zhang, JXJ 2016, 'Magnetic‐Nanoparticle‐Based Immunoassays‐on‐Chip: Materials Synthesis, Surface Functionalization, and Cancer Cell Screening', Advanced Functional Materials, vol. 26, no. 22, pp. 3953-3972.
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The unique properties of magnetic nanoparticles (MNPs), coupled with versatile surface engineering techniques, have led to a rising class of screening methods that enable separation of specific cell populations from complex biological samples. The growing sophistication and efficiency of these methods have far reaching implications for both fundamental research and clinical applications. In this study, the synthesis and surface engineering of MNPs is reviewed. Here, a model is introduced to illustrate how MNP morphology and particle–particle interactions influence magnetization, which is a key consideration in designing and selecting MNPs for efficient cell separations. Building upon these themes, immunomagnetic assays for capturing, isolating, and characterizing rare cell types from complex biological mixtures are reviewed. Although the focus of this study is on circulating tumor cells, these same techniques can be applied in screening for other rare cells of interest, such as various stem cell populations. In conclusion, current challenges and future directions for magnetic ‐nanomaterial‐based cell screening systems are discussed.

Attwater, DJ, Stenzel, MH, Min, EH, Zhao, J, Hutvagner, GJ & Ting, SRSIMON 1970, 'Cationic Polymers based on Fructose and Galactose Moieties for Nucleic Acids Delivery', 36th Australasian Polymer Symposium, 36th Australasian Polymer Symposium, Lorne, Australia.
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Cationic polymers and glycopolymers were synthesised using the RAFT technique. Combining cationic polymers with glycopolymers has great potential in targeted nucleic acid delivery.1,2 However, many obstacles prevent the use of cationic glycopolymers as vectors including low success in nucleic acid delivery and high toxicity of the cationic polymer. This project aims to investigate RAFT synthesis of cationic glycopolymers with galactose or fructose carbohydrates, their binding ability with their specific lectins and with negatively charged nucleic acids.The cationic polymer poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) was synthesised using RAFT polymerisation. The galactose monomer, 2-(2’,3’,4’,6’-tetra-O-acetyl-β-D-galactosyloxy)ethyl methacrylate (AcGalEMA), and the fructose monomer, 1-O-methacryloyl-2,3:4,5-di-O-isopropylidene--D-fructopyranose (1-O-MAiPFru)3, were polymerised with PDMAEMA to form cationic glycopolymers. Chain extension was confirmed using proton nuclear magnetic spectroscopy (NMR) and gel permeation chromatography (GPC). Gel permeation chromatography was also performed to determine the polydispersity index (uniformity) of the polymers. The protected glycopolymer blocks were modified by deacetylation of the galactose block and acid deprotection of the fructose block. Characterisation of the modified cationic glycopolymers was achieved using proton nuclear magnetic spectroscopy for confirmation of deacetylation/deprotection, and dynamic light scattering to determine the sizes of the diblock copolymers. The zeta potential (ionic charge) of the diblock copolymers was recorded.Aggregation assays between the cationic glycopolymers and plant lectins were assessed. The galactose-containing glycopolymers were conjugated with peanut agglutinin lectin and the fructose-containing glycopolymers were conjugated with lectin from Ulex europaeus. The assays were analysed using dynamic light spectroscopy and ultraviolet-visible spectroscopy...

Barforoushi, AH, Shemesh, J, Farbehi, N, Asadnia, M, Yeoh, GH, Nordon, RE & Warkiani, ME 1970, 'A rapid microfluidic stamping device for studying cardiac stem cells and endothelial cells co-culture', 20th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2016, pp. 1069-1070.
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Many biological processes in the body are regulated by synchronized activity between two cell types. Recent advances in cell μcontact printing have facilitated the in-vitro study of homotypic and heterotypic cell-cell interaction. However, these techniques are still complicated to perform and are seldom used by biologists. We report here development of a novel microfluidic stamping device for patterning two adherent cell lines with well-defined interlacing configurations to study cell-cell spatial interactions. To demonstrate the stamp's capabilities, we developed an in-vitro model of endothelial and cardiac mesenchymal stem cell interactions, which are thought to regulate coronary repair after myocardial injury.

Bazaz, SR, Mehrizi, AA & Hesari, AZ 1970, 'A novel microfluidic design for blood plasma separation', 2016 23rd Iranian Conference on Biomedical Engineering and 2016 1st International Iranian Conference on Biomedical Engineering (ICBME), 2016 23rd Iranian Conference on Biomedical Engineering and 2016 1st International Iranian Conference on Biomedical Engineering (ICBME), IEEE, pp. 97-101.
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one of the most crucial materials used in detection and diagnosis field is blood. The effects of blood components on the diagnosis process are significant. To avoid the disturbance of the experiments, the first step of blood analysis is to separate plasma from blood. Two dominant factors influence on this procedure are blood plasma skimming and Zweifach-Fung effect. In order to evaluate the separation device, two major criteria including separation and purity efficiency are introduced. The main drawback of these two factors is that they have reverse effect on each other which means that correcting one of them have destructive effect on the other one. Therefore, a trade-off between them should have happened. In this study, a novel microfluidic separation device is designed based on momentum definition and acceleration-deceleration effect. The computational CFD package, Ansys Fluent is used to simulate and solve this study. The Lagrangian approach is utilized for particle trajectory and the effect of the forces acting on each blood cell is considered. The results are then analyzed and shown that by using momentum and acceleration-deceleration effects, the purity efficiency would be increased by 15% with the same separation efficiency as before which was 70% on the average flow rate of 100 μl/min, approximately and it is completely providing for future use of this kind of device.

Beck, D, Thoms, J, Palu, C, Herold, T, Shah, A, Olivier, J, Boelen, L, Huang, Y, Chacon, D, Brown, A, Babic, M, Hahn, C, Perugini, M, Zhou, X, Huntly, B, Berdel, W, Woermann, B, Buechner, T, Hiddemann, W, Bohlander, S, Scott, H, Lewis, I, D'Andrea, R, Wong, J & Pimanda, J 1970, 'INTEGRATIVE ANALYSIS OF LINCRNA EXPRESSION IN 922 ACUTE MYELOID LEUKEMIA PATIENTS REVEALS MULTIPLE PROGNOSTIC GENE SIGNATURES', HAEMATOLOGICA, pp. 208-209.

Chen, W, Deng, W & Goldys, EM 1970, 'Enhanced gene silencing mediated by photoresponsive liposomes', SPIE Proceedings, SPIE BioPhotonics Australasia, SPIE.
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Clement, S, Deng, W, Camilleri, E, Wilson, B & Goldys, E 1970, 'Towards photodynamic therapy with ionizing radiation: nanoparticle-mediated singlet oxygen generation(Conference Presentation)', Colloidal Nanoparticles for Biomedical Applications XI, Colloidal Nanoparticles for Biomedical Applications XI, SPIE, San Francisco, CA.
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Deng, W, Kautzka, Z & Goldys, EM 1970, 'Enhanced singlet oxygen generation from PLGA loaded with verteporfin and gold nanoparticles', SPIE Proceedings, SPIE BioPhotonics Australasia, SPIE, Adelaide, AUSTRALIA.
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Hadgraft, R, Lowe, D & Lawson, J 1970, 'Enhancing Mechanics Education through Shared Assessment Design', 2016 ASEE Annual Conference & Exposition Proceedings, 2016 ASEE Annual Conference & Exposition, ASEE Conferences, New Orleans, Louisiana, United States.
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© American Society for Engineering Education, 2016. There is considerable commonality between engineering undergraduate programs in terms of content, pedagogies, course structures and assessment practices, particularly in terms of engineering fundamentals such as mechanics. Despite this, and the availability of an array of online resources, there seems to be limited commitment to sharing learning resources among teaching academics and between institutions. Further, there seems to be a specific resistance to sharing those materials that support the teaching and learning of technical content1. Collaborations seen in research networks seem not to have equivalent presence in teaching and learning, despite a literature that points to the benefits of sharing curriculum resources 2,3. A few projects funded by the Federal Office for Learning and Teaching (OLT) in Australia have made freely available resources as deliverables (A proactive approach to addressing student learning diversity in engineering mechanics 4; Promoting student engagement and continual improvement: Integrating professional quality management practice into engineering curricula5; Remotely accessible laboratories: Enhancing learning outcomes6 and many more 7). There has been varied uptake of these, however, and the long-term maintenance of online resources is problematic. There is also a literature that identifies sustainability challenges with open educational resources including funding and intellectual property rights 3. It could be argued that failure to provide resources and, concomitantly the uptake by teaching academics of such resources impedes student access to these resources and therefore impacts their learning. It also contributes to inefficiencies brought about by work duplication. The reasons for limited uptake of resources are both institutional and individual. However, there are nuances to what is meant by a resource, how resources are modified by academics and where in a prog...

Mahmoodi, L, Bazaz, SR, Mohammadnejad, J, Mehrizi, AA & Soleimani, M 1970, 'Size-tunable alginate nanoparticles synthesis using T-junction microfluidic chip', 2016 23rd Iranian Conference on Biomedical Engineering and 2016 1st International Iranian Conference on Biomedical Engineering (ICBME), 2016 23rd Iranian Conference on Biomedical Engineering and 2016 1st International Iranian Conference on Biomedical Engineering (ICBME), IEEE, pp. 271-275.
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nanoparticles have manifold applications in the disease detection, diagnosis, and drug delivery. The precise control of an amount of particle that delivers on each organ depends on the size of the particle and its residual time. Microfluidic has a major rule on the control size of the nanoparticles. Usually, a T-junction microchip is used for the synthesis of the nanoparticles by changing the related velocity between the core and shear flow. In this experimental study, alginate solution in water uses as the core flow and an efficient cross-linker which is CaCl2 uses as the shear flow. The different related velocity of core flow to shear flow is examined. The range of these two streams varies from 0.2 to 0.01. It should be noted that decrease of the velocity rate between two streams leads to decrease in the size of the nanoparticles. Therefore, it is shown that the smallest nanoparticle is made on the least relative stream which is 0.01. By scanning electron microscope and image processing techniques, it is found that the nanoparticle with 97 nm is produced during this process. Due to the various application fields of nanoparticles, this experimental procedure could be a promising one for the biologist in the future.

Rafeie, M, Zhang, J, Asadnia, M, Li, W & Warkiani, ME 1970, 'Multiplexing slanted spiral microchannels for ultra-fast blood plasma separation', 20th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2016, pp. 906-907.
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The ability to efficiently fractionate blood into its individual components is crucial for therapeutic and diagnostic purposes. Here, we developed an inertial microfluidic system for cell focusing and blood plasma separation. First, polystyrene beads and blood cells were used to investigate the inertial focusing performance of a single slanted spiral microchannel as a function of particle size, flow rate, and the haematocrit (HCT) concentration. Next, we built a high-throughput system consisted of 16 interconnected spiral channels which can process diluted samples at 24 mL/min. The proposed multiplexed system surmounts shortcomings of previously-reported microfluidic systems concerning throughput, yield and operation efficiency.

Wen, S, Li, D, Liu, D, Xu, X, Du, Y, Mitchell, DRG, Shi, B, Shi, X & Jin, D 1970, 'Seed mediated one-pot growth of versatile heterogeneous upconversion nanocrystals for multimodal bioimaging', SPIE Proceedings, SPIE BioPhotonics Australasia, SPIE, Adelaide, South Australia, Australia.
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© 2016 SPIE. The rapid development of a variety of molecular contrast agents makes the multimodality bioimaging highly attractive towards higher resolution, more sensitive, informative diagnosis. The key lies in the development of facile material synthesis that allows the integration of multiple contrast agents, ideally in a way that each of the components should be logically assembled to maximize their performances. Here, we report the one-pot programmable growth of multifunctional heterogeneous nanocrystal with tunable size, shape, composition, and properties. We demonstrated a facile one-pot hot-injection method to enable the highly selectively controlled growth of different sodium lanthanide fluoride nanomaterials in either longitudinal or transversal directions with atomic scale precision. This technique allows the upconversion luminescence signal, MRI signal and x-ray signal logically integrated and optimized within one single versatile nanoplatform for multimode bioimaging. These findings suggest that the facile strategy developed here have the promising to get the desired heterogeneous nanocrystals as an all-in-one contrast agent for integrated and self-correlative multimodal bioimaging.