Publications

Kashaninejad, N, Yaghoobi, M, Pourhassan‐Moghaddam, M, Bazaz, SR, Jin, D & Warkiani, ME 2020, 'Biological Diagnosis Based on Microfluidics and Nanotechnology' in Nanotechnology for Microfluidics, Wiley, USA, pp. 211-238.
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This chapter discusses the integrations of the nanoparticles with microfluidic platforms for biological diagnosis. It evaluates the applications of two emerging formats of microfluidics, digital microfluidics and paper-based microfluidics, for biological diagnosis. Microfluidics is an enabling technology that can be employed in numerous biological studies because of its high-throughput, precision, sample efficiency, portability, and low-cost production. Many investigations are currently underway concerning the imaging of the biological molecules and cellular components using fluorescent nanomaterials. The main problems associated with fluorescence methods can be addressed by using semiconductor quantum dots (Qdots) possessing unique optical properties. Their surface is capable of being modified with various biomolecules making them selective to different analytes. In the bioanalysis with Qdots, these nanoparticles are conjugated with biomolecules for the detection of analytes. In the case of a disease, the target analytes can be viruses, antigens, and cancer biomarkers, whose concentration is also of interest.

Aboulkheyr Es, H, Zhand, S, Thiery, JP & Warkiani, ME 2020, 'Pirfenidone reduces immune-suppressive capacity of cancer-associated fibroblasts through targeting CCL17 and TNF-beta', Integrative Biology, vol. 12, no. 7, pp. 188-197.
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Abstract Various factors in the tumor microenvironment (TME) regulate the expression of PD-L1 in carcinoma cells. The cancer-associated fibroblasts (CAFs) play a crucial role in regulating and rewiring TME to enhance their immune suppressive function and to favor the invasion of the malignant cells. Tumor progression may be retarded by targeting CAFs in the TME. Various studies highlighted the ability of targeting CAF with pirfenidone (PFD), leading to increased efficacy of chemotherapy. However, its potential for the reduction of immune-suppression capacity of CAFs remains to be elusive. Here, we assessed the effect of PFD on the expression of PD-L1 on CAF cells. Besides migration inhibitory effects of PFD on CAFs, the expression level of PD-L1 reduced in CAFs after treatment with PFD. The downstream analysis of released cytokines from CAFs showed that PFD significantly dropped the secretion of CCL17 and TNF-β, where a positive association between PFD-targeted proteins and PD-L1 was observed. These data suggest that the treatment of CAF within TME through the PFD may reduce the acquisition of CAF-mediated invasive and immune-suppressive capacity of breast carcinoma cells.

Alghalayini, A, Jiang, L, Gu, X, Yeoh, GH, Cranfield, CG, Timchenko, V, Cornell, BA & Valenzuela, SM 2020, 'Real-time monitoring of heat transfer between gold nanoparticles and tethered bilayer lipid membranes', Biochimica et Biophysica Acta (BBA) - Biomembranes, vol. 1862, no. 9, pp. 183334-183334.
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Plasmon resonance frequency irradiated gold nanoparticles (GNPs) have gained interest as a laser-targeted treatment for infections, tumors and for the controlled release of drugs in situ. Questions still remain, however, as to the efficiency of heat delivery within biological tissues and how this can be reliably determined. Here, we demonstrate how a nanomaterial-electrode interface that mimics cell membranes can detect the localized heat transfer characteristics arising from plasmon resonance frequency-matched laser excitation of GNPs. We demonstrate that the lipid bilayer membrane can be affected by conjugated GNP induced hyperthermia when irradiated with a laser power output as low as 135 nW/μm². This is four orders of magnitude lower power than previously reported. By restricting the lateral movement of the lipids in the bilayer membrane, it was shown that the change in membrane conductance as a result of the heat transfer was due to the creation of transient lipidic toroidal pores within the membrane. We further demonstrate that the heat transfer from the GNPs alters diffusion rates of monomers of the gramicidin-A peptide within the lipid leaflets. This work highlights how targeted low laser power GNP hyperthermia treatments, in vivo, could play a dual role of interfering with both cell membrane morphology and dynamics, along with membrane protein function.

Alghalayini, A, Jiang, L, Gu, X, Yeoh, GH, Cranfield, CG, Timchenko, V, Cornell, BA & Valenzuela, SM 2020, 'Tethered Bilayer Lipid Membranes to Monitor Heat Transfer between Gold Nanoparticles and Lipid Membranes', Journal of Visualized Experiments, no. 166.
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Aneman, I, Pienaar, D, Suvakov, S, Simic, TP, Garovic, VD & McClements, L 2020, 'Mechanisms of Key Innate Immune Cells in Early- and Late-Onset Preeclampsia', Frontiers in Immunology, vol. 11.
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Preeclampsia is a complex cardiovascular disorder of pregnancy with underlying multifactorial pathogeneses; however, its etiology is not fully understood. It is characterized by the new onset of maternal hypertension after 20 weeks of gestation, accompanied by proteinuria, maternal organ damage, and/or uteroplacental dysfunction. Preeclampsia can be subdivided into early- and late-onset phenotypes (EOPE and LOPE), diagnosed before 34 weeks or from 34 weeks of gestation, respectively. Impaired placental development in early pregnancy and subsequent growth restriction is often associated with EOPE, while LOPE is associated with maternal endothelial dysfunction. The innate immune system plays an essential role in normal progression of physiological pregnancy and fetal development. However, inappropriate or excessive activation of this system can lead to placental dysfunction or poor maternal vascular adaptation and contribute to the development of preeclampsia. This review aims to comprehensively outline the mechanisms of key innate immune cells including macrophages, neutrophils, natural killer (NK) cells, and innate B1 cells, in normal physiological pregnancy, EOPE and LOPE. The roles of the complement system, syncytiotrophoblast extracellular vesicles and mesenchymal stem cells (MSCs) are also discussed in the context of innate immune system regulation and preeclampsia. The outlined molecular mechanisms, which represent potential therapeutic targets, and associated emerging treatments, are evaluated as treatments for preeclampsia. Therefore, by addressing the current understanding of innate immunity in the pathogenesis of EOPE and LOPE, this review will contribute to the body of research that could lead to the development of better diagnosis, prevention, and treatment strategies. Importantly, it will delineate the differences in the mechanisms of the innate immune system in two different types of preeclampsia, which is necessary for a more personalized ...

Annett, S, Moore, G, Short, A, Marshall, A, McCrudden, C, Yakkundi, A, Das, S, McCluggage, WG, Nelson, L, Harley, I, Moustafa, N, Kennedy, CJ, deFazio, A, Brand, A, Sharma, R, Brennan, D, O’Toole, S, O’Leary, J, Bates, M, O’Riain, C, O’Connor, D, Furlong, F, McCarthy, H, Kissenpfennig, A, McClements, L & Robson, T 2020, 'FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer', British Journal of Cancer, vol. 122, no. 3, pp. 361-371.
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Abstract Background ALM201 is a therapeutic peptide derived from FKBPL that has previously undergone preclinical and clinical development for oncology indications and has completed a Phase 1a clinical trial in ovarian cancer patients and other advanced solid tumours. Methods In vitro, cancer stem cell (CSC) assays in a range of HGSOC cell lines and patient samples, and in vivo tumour initiation, growth delay and limiting dilution assays, were utilised. Mechanisms were determined by using immunohistochemistry, ELISA, qRT-PCR, RNAseq and western blotting. Endogenous FKBPL protein levels were evaluated using tissue microarrays (TMA). Results ALM201 reduced CSCs in cell lines and primary samples by inducing differentiation. ALM201 treatment of highly vascularised Kuramochi xenografts resulted in tumour growth delay by disruption of angiogenesis and a ten-fold decrease in the CSC population. In contrast, ALM201 failed to elicit a strong antitumour response in non-vascularised OVCAR3 xenografts, due to high levels of IL-6 and vasculogenic mimicry. High endogenous tumour expression of FKBPL was associated with an increased progression-free interval, supporting the protective role of FKBPL in HGSOC. Conclusion FKBPL-based therapy can (i) dually target angiogenesis and CSCs, (ii) target the CD44/STAT3 pathway in tumours and (iii) is effective in highly vascularised HGSOC tumours with low levels of IL-6.

Ariawan, AD, Sun, B, Wojciechowski, JP, Lin, I, Du, EY, Goodchild, SC, Cranfield, CG, Ittner, LM, Thordarson, P & Martin, AD 2020, 'Effect of polar amino acid incorporation on Fmoc-diphenylalanine-based tetrapeptides', Soft Matter, vol. 16, no. 20, pp. 4800-4805.
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The incorporation of polar amino acids into the Fmoc-FF motif yields tetrapeptide hydrogels whose biocompatibility in the gel state is inversely proportional to their biocompatibility in the solution state.

Asadniaye Fardjahromi, M, Razmjou, A, Vesey, G, Ejeian, F, Banerjee, B, Chandra Mukhopadhyay, S & Ebrahimi Warkiani, M 2020, 'Mussel inspired ZIF8 microcarriers: a new approach for large-scale production of stem cells', RSC Advances, vol. 10, no. 34, pp. 20118-20128.
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Mussel inspired ZIF8 microcarriers with high surface area, biocompatibility, and nanoscale surface roughness are applied to enhance mesenchymal stem cell attachment and proliferation in 3D cell culture.

Azadi, S, Aboulkheyr Es, H, Kulasinghe, A, Bordhan, P & Ebrahimi Warkiani, M 2020, 'Application of microfluidic technology in cancer research and therapy', Advances in Clinical Chemistry, vol. 99, pp. 193-235.
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Cancer is a heterogeneous disease that requires a multimodal approach to diagnose, manage and treat. A better understanding of the disease biology can lead to identification of novel diagnostic/prognostic biomarkers and the discovery of the novel therapeutics with the goal of improving patient outcomes. Employing advanced technologies can facilitate this, enabling better diagnostic and treatment for cancer patients. In this regard, microfluidic technology has emerged as a promising tool in the studies of cancer, including single cancer cell analysis, modeling angiogenesis and metastasis, drug screening and liquid biopsy. Microfluidic technologies have opened new ways to study tumors in the preclinical and clinical settings. In this chapter, we highlight novel application of this technology in area of fundamental, translational and clinical cancer research.

Bao, G 2020, 'Lanthanide complexes for drug delivery and therapeutics', Journal of Luminescence, vol. 228, pp. 117622-117622.
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© 2020 Elsevier B.V. Lanthanide complex-based medicine combining organic ligands and individual lanthanide ions is proving successful in therapeutics, especially in drug delivery, chemotherapy, and photodynamic therapy. In this review, I discuss the coordination chemistry, antenna effect, and chelating ligands of lanthanide complexes and their key features benefiting the therapeutical monitoring and performance, such as fingerprint emissions, large pseudo-Stokes’ shifts, long lifetimes, two-photon excitations and magnetic resonance responses. While illustrating their pharmaceutical applications in drug delivery, chemotherapy and photodynamic therapy, I identify the challenges and prospective opportunities in clinical translation of the lanthanide complex-based medicine.

Chang, M, Hou, Z, Jin, D, Zhou, J, Wang, M, Wang, M, Shu, M, Ding, B, Li, C & Lin, J 2020, 'Colorectal Tumor Microenvironment‐Activated Bio‐Decomposable and Metabolizable Cu₂O@CaCO₃ Nanocomposites for Synergistic Oncotherapy', Advanced Materials, vol. 32, no. 43, pp. 1-11.
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AbstractRational design of tumor microenvironment (TME)‐activated nanocomposites provides an innovative strategy to construct responsive oncotherapy. In colorectal cancer (CRC), the specific physiological features are the overexpressed endogenous H2S and slightly acidic microenvironment. Here, a core–shell Cu2O@CaCO3 nanostructure for CRC “turn‐on” therapy is reported. With CaCO3 responsive to pH decomposition and Cu2O responsive to H2S sulfuration, Cu2O@CaCO3 can be triggered “on” into the therapeutic mode by the colorectal TME. When the CaCO3 shell decomposes and releases calcium in acidic colorectal TME, the loss of protection from the CaCO3 shell exposes the Cu2O core to be sulfuretted by H2S to form metabolizable Cu31S16 nanocrystals that gain remarkably strong near‐infrared absorption. After modifying hyaluronic acid, Cu2O@CaCO3 can achieve synergistic CRC‐targeted and TME‐triggered photothermal/photodynamic/chemodynamic/calcium‐overload‐mediated therapy. Moreover, it is found that the generation of hyperthermia and oxidative stress from Cu2O@CaCO3 nanocomposites can efficiently reprogram the macrophages from the M2 phenotype to the M1 phenotype and initiate a vaccine‐like immune effect after primary tumor removal, which further induces an immune‐favorable TME and intense immune responses for anti‐CD47 antibody to simultaneously inhibit CRC distant metastasis and recurrence by immunotherapy.

Changani, Z, Razmjou, A, Taheri-Kafrani, A, Warkiani, ME & Asadnia, M 2020, 'Surface modification of polypropylene membrane for the removal of iodine using polydopamine chemistry', Chemosphere, vol. 249, pp. 126079-126079.
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The development of stable and effective iodine removal systems would be highly desirable in addressing environmental issues relevant to water contamination. In the present research, a novel iodine adsorbent was synthesized by self-polymerization of dopamine (PDA) onto inert polypropylene (PP) membrane. This PP/PDA membrane was thoroughly characterized and its susrface propeties was analyzed by various analytical techniques indcluding field emission scanning electron microscopy (FESEM), atomic force microscopy (AFM), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR), Brunauer-Emmett-Teller (BET) and Barrett-Joyner-Halenda (BJH), contact angle, and surface free energy measurement. The PP/PDA membranes were subsequently used for batchwise removal of iodine at different temperatures (25-70 °C), pH (2-7), and surface areas (1-10 cm2) to understand the underlying adsorption phenomena and to estimate the membrane capacity for iodine uptake. The increase in temperature and pH both led to higher adsorption of iodine. The present approach showed a removal efficiency of over 75% for iodine using 10 cm2 PP/PDA membrane (18.87 m2 g-1) within 2 h at moderate temperatures (∼50 °C) and pH > 4, about 15 fold compared to the PP control membrane. The adsorption kinetics and isotherms were well fitted to the pseudo-second-order kinetic and Langmuir isotherm models (R2 > 0.99). This adsorbent can be recycled and reused at least six times with stable iodine adsorption. These findings were attributed to the homogenous monolayer adsorption of the iodide on the surface due to the presence of catechol and amine groups in the PP/PDA membrane. This study proposes an efficient adsorbent for iodine removal.

Chen, H, McGrath, K, Rayner, B & McClements, L 2020, '054 Potential New Treatment Based on FKBPL for Hypertension-Induced Cardiac Hypertrophy', Heart, Lung and Circulation, vol. 29, pp. S62-S62.
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Chen, Y, D'Amario, C, Gee, A, Duong, HTT, Shimoni, O & Valenzuela, SM 2020, 'Dispersion stability and biocompatibility of four ligand-exchanged NaYF4: Yb, Er upconversion nanoparticles', Acta Biomaterialia, vol. 102, pp. 384-393.
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Surface modification to obtain high dispersion stability and biocompatibility is a key factor for bio-application of upconversion nanoparticles (UCNPs). A systematic study of UCNPs modified with four hydrophilic molecules separately, comparing their dispersion stability in biological buffers and cellular biocompatibility is reported here. The results show that carboxyl-functionalized UCNPs (modified by 3,4-dihydrocinnamic acid (DHCA) or poly(monoacryloxyethyl phosphate (MAEP)) with negative surface charge have superior even-distribution in biological buffers compared to amino-functionalized UCNPs (modified by (aminomethyl)phosphonic (AMPA) or (3-Aminopropyl)triethoxysilane (APTES)) with positive surface charge. Subsequent investigation of cellular interactions revealed high levels of non-targeted cellular uptake of the particles modified with either of the three small molecules (AMPA, APTES, DHCA) and high levels of cytotoxicity when used at high concentrations. The particles were seen to be trapped as particle-aggregates within the cellular cytoplasm, leading to reduced cell viability and cell proliferation, along with dysregulation of the cell cycle as assessed by DNA content measurements. The dramatically reduced proportion of cells in G1 phase and the slightly increased proportion in G2 phase indicates inhibition of M phase, and the appearance of sub-G1 phase reflects cell necrosis. In contrast, MAEP-modified UCNPs are bio-friendly with increased dispersion stability in biological buffers, are non-cytotoxic, with negligible levels of non-specific cellular uptake and no effect on the cell cycle at both low and high concentrations. MAEP-modified UCNPs were further functionalized with streptavidin for intracellular microtubule imaging, and showed clear cytoskeletal structures via their upconversion luminescence. STATEMENT OF SIGNIFICANCE: Upconversion nanoparticles (UCNP) are an exciting potential nanomaterial for bio-applications. Their anti-Stokes lu...

Chrzanowski, W, Kim, SY & McClements, L 2020, 'Can Stem Cells Beat COVID-19: Advancing Stem Cells and Extracellular Vesicles Toward Mainstream Medicine for Lung Injuries Associated With SARS-CoV-2 Infections', Frontiers in Bioengineering and Biotechnology, vol. 8.
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A number of medicines are currently under investigation for the treatment of COVID-19 disease including anti-viral, anti-malarial, and anti-inflammatory agents. While these treatments can improve patient's recovery and survival, these therapeutic strategies do not lead to unequivocal restoration of the lung damage inflicted by this disease. Stem cell therapies and, more recently, their secreted extracellular vesicles (EVs), are emerging as new promising treatments, which could attenuate inflammation but also regenerate the lung damage caused by COVID-19. Stem cells exert their immunomodulatory, anti-oxidant, and reparative therapeutic effects likely through their EVs, and therefore, could be beneficial, alone or in combination with other therapeutic agents, in people with COVID-19. In this review article, we outline the mechanisms of cytokine storm and lung damage caused by SARS-CoV-2 virus leading to COVID-19 disease and how mesenchymal stem cells (MSCs) and their secreted EVs can be utilized to tackle this damage by harnessing their regenerative properties, which gives them potential enhanced clinical utility compared to other investigated pharmacological treatments. There are currently 17 clinical trials evaluating the therapeutic potential of MSCs for the treatment of COVID-19, the majority of which are administered intravenously with only one clinical trial testing MSC-derived exosomes via inhalation route. While we wait for the outcomes from these trials to be reported, here we emphasize opportunities and risks associated with these therapies, as well as delineate the major roadblocks to progressing these promising curative therapies toward mainstream treatment for COVID-19.

Deplazes, E, Hartmann, LM, Cranfield, CG & Garcia, A 2020, 'Structural Characterization of a Cation-Selective, Self-Assembled Peptide Pore in Planar Phospholipid Bilayers', The Journal of Physical Chemistry Letters, vol. 11, no. 19, pp. 8152-8156.
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GALA is a 30-residue amphipathic peptide that self-assembles into multimeric transmembrane pores in a pH-dependent fashion. In this study, we characterize the size, multimeric structure, and cation selectivity of GALA pores in planar phospholipid bilayers using electrical impedance spectroscopy and molecular dynamics simulations. We demonstrate that in planar bilayers GALA pores are likely formed by six peptide monomers rather than eight to 12 monomers as previously reported for lipid vesicles. We further show that in planar bilayers, GALA pores exhibit previously unreported cation selectivity. We propose that the difference between the predicted pore structures in planar bilayers and lipid vesicles exemplifies the importance of phospholipid bilayer structural properties on the aggregation of transmembrane helical structures.

Deplazes, E, Tafalla, BD, Cranfield, CG & Garcia, A 2020, 'Role of Ion–Phospholipid Interactions in Zwitterionic Phospholipid Bilayer Ion Permeation', The Journal of Physical Chemistry Letters, vol. 11, no. 15, pp. 6353-6358.
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Despite the central role of Na+ and K+ in physiological processes, it is still unclear whether they interact or alter the physical properties of simple zwitterionic phospholipid bilayers at physiologically relevant concentrations. Here we report a difference in membrane permeability between Na+ and K+, as measured with electrical impedance spectroscopy and tethered bilayer lipid membranes. We reveal that the differences in membrane permeability originate from distinct ion coordination by carbonyl oxygens at the phospholipid-water interface, altering the propensity for bilayer pore formation. Molecular dynamics simulations showed differences in the coordination of Na+ and K+ at the phospholipid-water interface of zwitterionic phospholipid bilayers. The ability of Na+ to conscript more phospholipids with a greater number of coordinating interactions causes a higher localized energy barrier for pore formation. These results provide evidence that ion-specific interactions at the phospholipid-water interface can modulate the physical properties of zwitterionic phospholipid bilayers.

Di, X, Wang, D, Zhou, J, Zhang, L, Stenzel, M, Su, QP & Jin, D 2020, 'Quantitatively Monitoringin situMitochondrial Thermal Dynamics by Upconversion Nanoparticles', p. 2020.11.29.402818.
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AbstractTemperature dynamics reflect the physiological conditions of cells and organisms. Mitochondria regulates temperature dynamics in living cells, as they oxidize the respiratory substrates and synthesize ATP, with heat being released as a by-product of active metabolism. Here, we report an upconversion nanoparticles based thermometer that allowsin situthermal dynamics monitoring of mitochondria in living cells. We demonstrate that the upconversion nanothermometers can efficiently target mitochondria and the temperature responsive feature is independent of probe concentration and medium conditions. The relative sensing sensitivity of 3.2% K−1in HeLa cells allows us to measure the mitochondrial temperature difference through the stimulations of high glucose, lipid, Ca2+shock and the inhibitor of oxidative phosphorylation. Moreover, cells display distinct response time and thermal dynamic profiles under different stimulations, which highlights the potential applications of this thermometer to studyin situvital processes related to mitochondrial metabolism pathways and interactions between organelles.

Ejeian, F, Razmjou, A, Nasr-Esfahani, MH, Mohammad, M, Karamali, F, Ebrahimi Warkiani, M, Asadnia, M & Chen, V 2020, '<p>ZIF-8 Modified Polypropylene Membrane: A Biomimetic Cell Culture Platform with a View to the Improvement of Guided Bone Regeneration</p>', International Journal of Nanomedicine, vol. Volume 15, pp. 10029-10043.
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Purpose

Despite the significant advances in modeling of biomechanical aspects of cell microenvironment, it remains a major challenge to precisely mimic the physiological condition of the particular cell niche. Here, the metal-organic frameworks (MOFs) have been introduced as a feasible platform for multifactorial control of cell-substrate interaction, given the wide range of physical and mechanical properties of MOF materials and their structural flexibility.

Results

In situ crystallization of zeolitic imidazolate framework-8 (ZIF-8) on the polydopamine (PDA)-modified membrane significantly raised surface energy, wettability, roughness, and stiffness of the substrate. This modulation led to an almost twofold increment in the primary attachment of dental pulp stem cells (DPSCs) compare to conventional plastic culture dishes. The findings indicate that polypropylene (PP) membrane modified by PDA/ZIF-8 coating effectively supports the growth and proliferation of DPSCs at a substantial rate. Further analysis also displayed the exaggerated multilineage differentiation of DPSCs with amplified level of autocrine cell fate determination signals, like BSP1, BMP2, PPARG, FABP4, ACAN, and COL2A. Notably, osteogenic markers were dramatically overexpressed (more than 100-folds rather than tissue culture plate) in response to biomechanical characteristics of the ZIF-8 layer.

Conclusion

Hence, surface modification of cell culture platforms with MOF nanostructures proposed as a powerful nanomedical approach for selectively guiding stem cells for tissue regeneration. In particular, PP/PDA/ZIF-8 membrane presented ideal characteristics for using as a barrier membrane for guided bone regeneration (GBR) in periodontal tissue engineering.

Gao, L, Shan, X, Xu, X, Liu, Y, Liu, B, Li, S, Wen, S, Ma, C, Jin, D & Wang, F 2020, 'Correction: Video-rate upconversion display from optimized lanthanide ion doped upconversion nanoparticles', Nanoscale, vol. 12, no. 36, pp. 18987-18987.
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Correction for ‘Video-rate upconversion display from optimized lanthanide ion doped upconversion nanoparticles’ by Laixu Gao et al., Nanoscale, 2020, DOI: 10.1039/d0nr03076g.

Gao, L, Shan, X, Xu, X, Liu, Y, Liu, B, Li, S, Wen, S, Ma, C, Jin, D & Wang, F 2020, 'Video-rate upconversion display from optimized lanthanide ion doped upconversion nanoparticles', Nanoscale, vol. 12, no. 36, pp. 18595-18599.
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A method for video-rate display with optimized single UCNP brightness by integrating the full emission intensity over excitation time and lifetime.

Garcia, A, Deplazes, E, Aili, S, Padula, MP, Touchard, A, Murphy, C, Mirissa Lankage, U, Nicholson, GM, Cornell, B & Cranfield, CG 2020, 'Label-Free, Real-Time Phospholipase-A Isoform Assay', ACS Biomaterials Science & Engineering, vol. 6, no. 8, pp. 4714-4721.
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© 2020 American Chemical Society. Phospholipase-A (PLA) enzymes catalyze the hydrolysis of ester bonds in select glycerophospholipids. Sensors for rapidly measuring the PLA activity in biological samples have relevance in the study of venom compositions and in medical diagnostics for the diagnosis of diseases such as acute pancreatitis. Current PLA sensor technologies are often restricted by the time it takes to prepare an assay, the necessity of using fluorescent labels, or the fact they might require strict pH control of the buffer vehicles used. Here we present a tethered bilayer lipid membrane (tBLM) impedance sensor array for the rapid and real-time detection of PLA, which includes the ability to selectively detect phospholipase-A2 (PLA2) from phospholipase-A1 (PLA1) isoforms. Comparing the activity of PLA1 and PLA2 in an array of tBLMs composed of ether phospholipids, ester phospholipids or ether-ester phospholipids allows for the rapid and reliable distinction between the isoforms, as measured using swept-frequency electrical impedance spectroscopy. After testing the assay using pure enzymes, we demonstrate the capacity of the sensor to identify specific PLA2-type, calcium-dependent activity from the venom of the South American bullet ant, Paraponera clavata, at a concentration of 1 μg/mL. The specificity of the phospholipase activity was corroborated using matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry. As further validation, we tested the activities of a PLA1 isoform in the presence of different buffers commonly used in biology and biochemistry experiments. Sensitivity testing shows that PLA1 can be detected at an activity as low as 0.06 U/mL. The rapid and reliable detection of phospholipases presented in this study has potential applications in the study of animal venoms as well as in lipase bioreactors and point-of-care devices.

Ghorbani, F, Fathi, F, Aghebati-Maleki, L, Abolhasan, R, Rikhtegar, R, Dolatabadi, JEN, Babaloo, Z, Khalilzadeh, B, Ebrahimi-Warkiani, M, Sharifzadeh, Z, Rashidi, M-R & Yousefi, M 2020, 'Kinetic and thermodynamic study of c-Met interaction with single chain fragment variable (scFv) antibodies using phage based surface plasmon resonance', European Journal of Pharmaceutical Sciences, vol. 150, pp. 105362-105362.
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Mesenchymal epithelial transition factor (c-Met) has been recently regarded as an attractive target for the treatment of cancer. Our previous study showed that c-Met-specific single chain fragment variables (scFvs) can be considered as a promising therapy for cancer, however, their molecular interaction with c-Met protein have not been assessed. Accordingly, in the current study we aim to evaluate the kinetic and thermodynamic properties of c-Met interaction with these scFvs as anticancer agents by means of surface plasmon resonance (SPR) technique. Phage-scFvs were immobilized on the 11-mercaptoundecanoic acid gold chips after carboxylic groups activation by N-ethyl-N-(3-diethylaminopropyl) carbodiimide/N-hydroxysuccinimide and, then the c-Met binding to each scFvs (ES1, ES2, and ES3) at different concentrations (ranging from 20 to 665 μM) was explored. Kinetic studies revealed that ES1 has the highest affinity (KD = 3.36 × 10-8) toward its target at 25°C. Calculation of thermodynamic parameters also showed positive values for enthalpy and entropy changes, which was representative of hydrophobic forces between c-Met and ES1. Furthermore, the positive value of Gibbs free energy indicated that c-Met binding to ES1 was enthalpy-driven. Taken together, we concluded that produced ES1 can be applied as promising scFv-based therapy for diagnosis or targeting of c-Met in various cancers.

Hagihghi, R, Razmjou, A, Orooji, Y, Warkiani, ME & Asadnia, M 2020, 'A miniaturized piezoresistive flow sensor for real‐time monitoring of intravenous infusion', Journal of Biomedical Materials Research Part B: Applied Biomaterials, vol. 108, no. 2, pp. 568-576.
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AbstractDrug overdose (DO) is considered one of the current issues of intravenous (IV) infusion particularly resulting in serious injuries and deaths. Malfunction of infusion pumps is reported as the main cause of the drug overdose. Live monitoring and flow rate calculation by health professionals have been practicing to avoid DO. However, human errors and miscalculations are inevitable. A secondary measurement tool is required to avoid the risk of OD when infusion pump malfunctions cannot be detected immediately. Here, inspired by nature, we developed a real‐time monitoring device through which an administrator can review, evaluate, and modify the IV infusion process. Our flow sensor possesses an erected polymer hair cell on a multi‐layered silicon base forming from a patterned gold strained gauge layer on a piezoresistive liquid crystal polymer (LCP) membrane. Gold strain gauges on an LCP membrane have been used instead of a piezoresistive silicon membrane as the sensing element. The combination of gold strain gauges and LCP membrane provides better sensitivity than a piezoresistive silicon membrane of the same dimensions and thickness. We also miniaturized our biocompatible sensor such that it can be possible to install it inside the IV tube in contact with the liquid providing an in‐suite online flow monitoring. The proposed LCP membrane sensor is compared with two commercially available IV sensors to validate its flow sensing ability. The experimental results demonstrate that the proposed sensor provides a low threshold detection limit of 5 mL/hr, which betters the performance of other commercial sensors at low flow rates.

Hao, H, Niu, J, Xue, B, Su, QP, Liu, M, Yang, J, Qin, J, Zhao, S, Wu, C & Sun, Y 2020, 'Golgi‐associated microtubules are fast cargo tracks and required for persistent cell migration', EMBO reports, vol. 21, no. 3.
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Microtubules derived from the Golgi (Golgi MTs) have been implicated to play critical roles in persistent cell migration, but the underlying mechanisms remain elusive, partially due to the lack of direct observation of Golgi MT-dependent vesicular trafficking. Here, using super-resolution stochastic optical reconstruction microscopy (STORM), we discovered that post-Golgi cargos are more enriched on Golgi MTs and also surprisingly move much faster than on non-Golgi MTs. We found that, compared to non-Golgi MTs, Golgi MTs are morphologically more polarized toward the cell leading edge with significantly fewer inter-MT intersections. In addition, Golgi MTs are more stable and contain fewer lattice repair sites than non-Golgi MTs. Our STORM/live-cell imaging demonstrates that cargos frequently pause at the sites of both MT intersections and MT defects. Furthermore, by optogenetic maneuvering of cell direction, we demonstrate that Golgi MTs are essential for persistent cell migration but not for cells to change direction. Together, our study unveils the role of Golgi MTs in serving as a group of 'fast tracks' for anterograde trafficking of post-Golgi cargos.

Hassanzadeh-Barforoushi, A, Warkiani, ME, Gallego-Ortega, D, Liu, G & Barber, T 2020, 'Capillary-assisted microfluidic biosensing platform captures single cell secretion dynamics in nanoliter compartments', Biosensors and Bioelectronics, vol. 155, pp. 112113-112113.
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Cancer cells continuously secrete inflammatory biomolecules which play significant roles in disease progression and tumor metastasis toward secondary sites. Despite recent efforts to capture cancer cells' intercellular secretion heterogeneity using microfluidics, the challenges in operation of these systems as well as the complexity of designing a biosensing assay for long-term and real-time measurement of single cell secretions have become grand research barriers. Here, we present a new capillary-based microfluidic biosensing approach to easily and reliably capture ~500 single cells inside isolated dead-end nanoliter compartments using simple pipette injection, and quantify their individual secretion dynamics at the single cell resolution over a long period of culture (~16 h). We first present a detailed investigation of the fluid mechanics underlying the formation of nanoliter compartments in the microfluidic system. Based on the measurement of single cell capture efficiency, we employ a one-step FRET-based biosensor which monitors the single cancer cells' protease activity. The sensor reports the fluorescent signal as a product of amino acid chain cleavage and reduction in its quenching capability. Using the single cell protease secretion data, we identified modes of cell secretion dynamics in our cell sample. While most of the cells had low secretion levels, two other smaller and more aggressive secretion dynamics were cells with secretion modes that include sharp spikes or slow but progressive trend. The method presented here overcomes the difficulties associated with performing single cell secretion assays, enabling a feasible and reliable technique for high throughput measurement of metabolic activities in cancer cells.

Herath, S, Razavi Bazaz, S, Monkman, J, Ebrahimi Warkiani, M, Richard, D, O’Byrne, K & Kulasinghe, A 2020, 'Circulating tumor cell clusters: Insights into tumour dissemination and metastasis', Expert Review of Molecular Diagnostics, vol. 20, no. 11, pp. 1139-1147.
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INTRODUCTION:Metastasis results in more than 90% of cancer related deaths globally. The process is thought to be facilitated by metastatic precursor cells, commonly termed circulating tumour cells (CTCs). CTCs can exist as single cells or cell clusters and travel through the lymphovasculature to distant organs where they can form overt metastasis. Areas covered: Studies have highlighted that CTC clusters, which may be homotypic or heterotypic in composition, have a higher metastatic potential compared to single CTCs. The characterisation of CTC clusters is becoming important as heterotypic clusters can provide a mechanism for immune evasion. This review summarises the latest advances in CTC cluster mediated metastasis and clinical significance. Expert Opinion: Comprehensive characterisation of CTC clusters is needed to understand the cell types and interactions within clusters, in order to identify ways in which to reduce CTC cluster mediated metastasis. The role of CTC clusters in prognosticating disease progression needs to be determined by documenting CTC clusters from the time of diagnosis over the course of therapy.

Huang, G, Lin, G, Zhu, Y, Duan, W & Jin, D 2020, 'Emerging technologies for profiling extracellular vesicle heterogeneity', Lab on a Chip, vol. 20, no. 14, pp. 2423-2437.
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Approaches, challenges and promising opportunities towards decoding the complexity of extracellular vesicle heterogeneity are discussed.

Januszewski, AS, Watson, CJ, O’Neill, V, McDonald, K, Ledwidge, M, Robson, T, Jenkins, AJ, Keech, AC & McClements, L 2020, 'FKBPL is associated with metabolic parameters and is a novel determinant of cardiovascular disease', Scientific Reports, vol. 10, no. 1.
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AbstractType 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD). As disturbed angiogenesis and endothelial dysfunction are strongly implicated in T2D and CVD, we aimed to investigate the association between a novel anti-angiogenic protein, FK506-binding protein like (FKBPL), and these diseases. Plasma FKBPL was quantified by ELISA cross-sectionally in 353 adults, consisting of 234 T2D and 119 non–diabetic subjects with/without CVD, matched for age, BMI and gender. FKBPL levels were higher in T2D (adjusted mean: 2.03 ng/ml ± 0.90 SD) vs. non-diabetic subjects (adjusted mean: 1.79 ng/ml ± 0.89 SD, p = 0.02), but only after adjustment for CVD status. In T2D, FKBPL was negatively correlated with fasting blood glucose, HbA1c and diastolic blood pressure (DBP), and positively correlated with age, known diabetes duration, waist/hip ratio, urinary albumin/creatinine ratio (ACR) and fasting C-peptide. FKBPL plasma concentrations were increased in the presence of CVD, but only in the non-diabetic group (CVD: 2.02 ng/ml ± 0.75 SD vs. no CVD: 1.68 ng/ml ± 0.79 SD, p = 0.02). In non-diabetic subjects, FKBPL was positively correlated with an established biomarker for CVD, B-type Natriuretic Peptide (BNP), and echocardiographic parameters of diastolic dysfunction. FKBPL was a determinant of CVD in the non-diabetic group in addition to age, gender, total-cholesterol and systolic blood pressure (SBP). FKBPL may be a useful anti-angiogenic biomarker in CVD in the absence of diabetes and could represent a novel CVD mechanism.

Jiang, S, Guan, M, Wu, J, Fang, G, Xu, X, Jin, D, Liu, Z, Shi, K, Bai, F, Wang, S & Xi, P 2020, 'Frequency-domain diagonal extension imaging', Advanced Photonics, vol. 2, no. 03, pp. 1-1.
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Jin, D, Wen, S, Liu, Y, Wang, F, Lin, G, zhou, J, Shi, B & Suh, YD 2020, 'Nanobarcodes with multidimensional optical information beyond diffraction limit'.
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Abstract Precise design and fabrication of heterogeneous nanostructures will enable nanoscale devices to integrate multiple desirable functionalities. But due to the diffraction limit (~200 nm), the optical uniformity and diversity within the heterogeneous functional nanostructures are hardly controlled and characterized. Here we report a set of nanobarcodes, each optically active section has its unique nonlinear responses to donut illumination patterns, so that one can discern each unit with super resolution. To achieve this, we first realized an approach of highly controlled epitaxial growth and produced a range of one-dimensional heterogeneous structures. Each section along the nanorod structure display tunable upconversion emissions, in four optically orthogonal dimensions, including colour, lifetime, excitation wavelength, and power dependency. Moreover, we demonstrated a 210 nm single nanorod as the smallest polychromatic light source for the on-demand generation of RGB photonic emissions. Remarkably, within a space of 50 nm, only 1/20th of the excitation wavelength, multiple codes can be successfully coded and decoded in 4 optical dimensions. This precision control enables the fabrication of super capacity geometrical barcodes with theoretical coding capacity up to (24-1)4. This work benchmarks our new ability towards the full control of sub-diffraction-limit optical diversities of single heterogeneous nanoparticles.

Jing, N, Xu, Z, Guipeng, L, Pixi, Y, Qing, Y, Qionghai, D, Dayong, J, Xiaohua, S, Jichang, W, Michael Q., Z & Juntao, G 2020, 'Tn5-FISH, a novel cytogenetic method to image chromatin interactions with sub-kilobase resolution', Journal of Genetics and Genomics, vol. 47, no. 12, pp. 727-734.
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Kapeleris, J, Kulasinghe, A, Warkiani, ME, Oleary, C, Vela, I, Leo, P, Sternes, P, O’Byrne, K & Punyadeera, C 2020, 'Ex vivo culture of circulating tumour cells derived from non-small cell lung cancer', Translational Lung Cancer Research, vol. 9, no. 5, pp. 1795-1809.
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Background

Tumour tissue-based information is limited. Liquid biopsy can provide valuable real-time information through circulating tumour cells (CTCs). Profiling and expanding CTCs may provide avenues to study transient metastatic disease.

Methods

Seventy non-small cell lung cancer (NSCLC) patients were recruited. CTCs were enriched using the spiral microfluidic chip and a RosetteSep™ using bloods from NSCLC patients. CTC cultures were carried out using the Clevers media under hypoxic conditions. CTCs were characterized using immunofluorescence and mutation-specific antibodies for samples with known mutation profiles. Exome sequencing was used to characterized CTC cultures.

Results

CTCs (>2 cells) were detected in 38/70 (54.3%) of patients ranging from 0 to 385 CTCs per 7.5 mL blood. In 4/5 patients where primary tumours harboured an EGFR exon 19 deletion, this EGFR mutation was also captured in CTCs. ALK translocation was confirmed on CTCs from a patient harbouring an ALK-rearrangement in the primary tumour. Short term CTC cultures were successfully generated in 9/70 NSCLC patients. Whole exome sequencing (WES) confirmed the presence of somatic mutations in the CTC cultures with mutational signatures consistent with NSCLC.

Conclusions

We were able to detect CTCs in >50% of NSCLC patients. NSCLC patients with >2 CTCs had a poor prognosis. The short-term CTC culture success rate was 12.9%. Further optimization of this culture methodology may provide a means by which to expand CTCs derived from NSCLC patient's bloods. CTC cultures allow for expansion of cells to a critical mass, allowing for functional characterization of CTCs with the goal of drug sensitivity testing and the creation of CTC cell lines.

Khan, JU, Sayyar, S, Paull, B & Innis, PC 2020, 'Novel Approach toward Electrofluidic Substrates Utilizing Textile-Based Braided Structure', ACS Applied Materials & Interfaces, vol. 12, no. 40, pp. 45618-45628.
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Khan, MA, Zhu, Y, Yao, Y, Zhang, P, Agrawal, A & Reece, PJ 2020, 'Impact of metal crystallinity-related morphologies on the sensing performance of plasmonic nanohole arrays', Nanoscale, vol. 12, no. 14, pp. 7577-7585.
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Low surface roughness and large metal grain sizes improve the sensitivity of a plasmonic nanohole array sensor.

Kulasinghe, A, Lim, Y, Kapeleris, J, Warkiani, M, O’Byrne, K & Punyadeera, C 2020, 'The Use of Three-Dimensional DNA Fluorescent In Situ Hybridization (3D DNA FISH) for the Detection of Anaplastic Lymphoma Kinase (ALK) in Non-Small Cell Lung Cancer (NSCLC) Circulating Tumor Cells', Cells, vol. 9, no. 6, pp. 1465-1465.
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Tumor tissue biopsy is often limited for non-small cell lung cancer (NSCLC) patients and alternative sources of tumoral information are desirable to determine molecular alterations such as anaplastic lymphoma kinase (ALK) rearrangements. Circulating tumor cells (CTCs) are an appealing component of liquid biopsies, which can be sampled serially over the course of treatment. In this study, we enrolled a cohort of ALK-positive (n = 8) and ALK-negative (n = 12) NSCLC patients, enriched for CTCs using spiral microfluidic technology and performed DNA fluorescent in situ hybridization (FISH) for ALK. CTCs were identified in 12/20 NSCLC patients ranging from 1 to 26 CTCs/7.5 mL blood. Our study revealed that 3D imaging of CTCs for ALK translocations captured a well-defined separation of 3′ and 5′ signals indicative of ALK translocations and overlapping 3′/5′ signal was easily resolved by imaging through the nuclear volume. This study provides proof-of-principle for the use of 3D DNA FISH in the determination of CTC ALK translocations in NSCLC.

Lazar, S, Rayner, B, Lopez Campos, G, McGrath, K & McClements, L 2020, 'Mechanisms of heart failure with preserved ejection fraction in the presence of diabetes mellitus', Translational Metabolic Syndrome Research, vol. 3, pp. 1-5.
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Cardiovascular disease (CVD) is the leading cause of death globally. People living with type 2 diabetes mellitus (T2DM) have a three times higher risk of developing CVD, particularly heart failure with preserved ejection fraction (HFpEF), for which there is no treatment. The need for tangible interventions has led to investigations into a number of biomarkers associated with metabolic and vascular dysfunction that could be utilised for diagnostic and treatment purposes. This review discusses the importance and mechanisms of inflammatory and angiogenic biomarkers, which have shown the most potential in the pathogenesis and diagnosis of HFpEF in the presence of diabetes. In depth “in silico” analysis was also carried out to identify pathogenic pathways associated with HFpEF, both in the presence and absence of diabetes. The results identified mostly inflammatory pathways associated with HFpEF in the presence of diabetes, and a number of pathways related to angiogenesis, remodelling and metabolism. In addition, the results also identified inflammation, in the absence of diabetes. The shared and unique pathways identified in HFpEF in the presence and absence of diabetes, should be explored further in order to improve management and outcomes of people living with HFpEF.

Li, D, Wen, S, Kong, M, Liu, Y, Hu, W, Shi, B, Shi, X & Jin, D 2020, 'Highly Doped Upconversion Nanoparticles for In Vivo Applications Under Mild Excitation Power', Analytical Chemistry, vol. 92, no. 16, pp. 10913-10919.
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One of the major challenges in using upconversion nanoparticles (UCNPs) is to improve their brightness. This is particularly true for in vivo studies, as the low power excitation is required to prevent the potential photo toxicity to live cells and tissues. Here, we report that the typical NaYF4:Yb0.2,Er0.02 nanoparticles can be highly doped, and the formula of NaYF4:Yb0.8,Er0.06 can gain orders of magnitude more brightness, which is applicable to a range of mild 980 nm excitation power densities, from 0.005 W/cm2 to 0.5 W/cm2. Our results reveal that the concentration of Yb3+ sensitizer ions plays an essential role, while increasing the doping concentration of Er3+ activator ions to 6 mol % only has incremental effect. We further demonstrated a type of bright UCNPs 12 nm in total diameter for in vivo tumor imaging at a power density as low as 0.0027 W/cm2, bringing down the excitation power requirement by 42 times. This work redefines the doping concentrations to fight for the issue of concentration quenching, so that ultrasmall and bright nanoparticles can be used to further improve the performance of upconversion nanotechnology in photodynamic therapy, light-triggered drug release, optogenetics, and night vision enhancement.

Li, G, Du, P, Qiang, X, Jin, D, Liu, H, Li, B & Guo, J 2020, 'RETRACTED: Low-expressed GAS5 injure myocardial cells and progression of chronic heart failure via regulation of miR-223-3P', Experimental and Molecular Pathology, vol. 117, pp. 104529-104529.
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Li, M, Li, Y, Liu, W, Lal, A, Jiang, S, Jin, D, Yang, H, Wang, S, Zhanghao, K & Xi, P 2020, 'Structured illumination microscopy using digital micro-mirror device and coherent light source', Applied Physics Letters, vol. 116, no. 23, pp. 233702-233702.
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Structured illumination microscopy (SIM) achieves doubled spatial resolution through exciting the specimen with high-contrast, high-frequency sinusoidal patterns. Such an illumination pattern can be generated by laser interference or incoherent structured patterns. Opto-electronic devices, such as a Spatial Light Modulator (SLM) or a Digital Micro-mirror Device (DMD), can provide rapid switch of illumination patterns for SIM. Although the DMD is much more cost-effective than the SLM, it was previously restricted in association with incoherent light sources, as its diffractive orders are related to the incident angle and the wavelength of coherent incidence. To extend its application with coherent illumination, here, we model the DMD as a blazed grating and simulate the effect with DMD pattern changes in the SIM. With careful analysis of the illumination contrast along different angles and phases, we report a fast, high-resolution, and cost-efficient SIM with DMD modulation. Our home-built laser interference-based DMD-SIM (LiDMD-SIM) reveals the nuclear pore complex and microtubule in mammalian cells with doubled spatial resolution. We further proposed the multi-color LiDMD-SIM concept by jointly employing the DMD ON/OFF states with different incident angles for different wavelengths, with high contrast and maximum resolution enhancement.

Liao, J, Jin, D, Chen, C, Li, Y & Zhou, J 2020, 'Helix Shape Power-Dependent Properties of Single Upconversion Nanoparticles', The Journal of Physical Chemistry Letters, vol. 11, no. 8, pp. 2883-2890.
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Nonblinking, nonbleaching, and superbright single upconversion nanoparticles have been recently discovered with nonlinear power-dependent properties and can be switchable under dual-beam excitations, which are ideal for super-resolution microscopy, single-molecule tracking, and digital assays. Here, we report that the brightness of Nd3+-Yb3+-Er3+-doped nanoparticles displays a pair of unusual double helix shapes as the function of power densities of 976 and 808 nm excitations. We systemically analyze the power-dependent emission spectra, lifetimes, and power-intensity double-log slopes of single upconversion nanoparticles, which reveal that the dynamic roles of Nd3+ ions in the tridoped nanosystem with underlining electron population pathways are power dependent. That is, at high power 808 nm excitation, Nd3+ ions can directly emit upconverted luminescence, with their conventional role of sensitization saturated in the Nd3 → Yb3+ → Er3+ energy transfer systems. Moreover, we confirm that the universal helix shape phenomena commonly exist in a set of eight batches of core-shell nanoparticles regardless of the doping concentrations of Nd3+, Yb3+, and Er3+ ions in the sensitization shell, migration shell, and active core, though the crossing nodes occur at different excitation power ranges. This study emphasizes the important role of power-dependent properties in both improving the upconversion emission efficiency and the design of nonlinear responsive probes for imaging and sensing.

Liu, B, Chen, C, Di, X, Liao, J, Wen, S, Su, QP, Shan, X, Xu, Z-Q, Ju, LA, Mi, C, Wang, F & Jin, D 2020, 'Upconversion Nonlinear Structured Illumination Microscopy', Nano Letters, vol. 20, no. 7, pp. 4775-4781.
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Video-rate super-resolution imaging through biological tissue can visualize and track biomolecule interplays and transportations inside cellular organisms. Structured illumination microscopy allows for wide-field super resolution observation of biological samples but is limited by the strong extinction of light by biological tissues, which restricts the imaging depth and degrades its imaging resolution. Here we report a photon upconversion scheme using lanthanide-doped nanoparticles for wide-field super-resolution imaging through the biological transparent window, featured by near-infrared and low-irradiance nonlinear structured illumination. We demonstrate that the 976 nm excitation and 800 nm upconverted emission can mitigate the aberration. We found that the nonlinear response of upconversion emissions from single nanoparticles can effectively generate the required high spatial frequency components in the Fourier domain. These strategies lead to a new modality in microscopy with a resolution below 131 nm, 1/7th of the excitation wavelength, and an imaging rate of 1 Hz.

Liu, Y, Cai, C, Aquino, A, Al‐Mousawi, S, Zhang, X, Choong, SKS, He, X, Fan, X, Chen, B, Feng, J, Zhu, X, Al‐Naimi, A, Mao, H, Tang, H, Jin, D, Li, X, Cao, F, Jiang, H, Long, Y, Zhang, W, Wang, G, Xu, Z, Zhang, X, Yin, S & Zeng, G 2020, 'Management of large renal stones with super‐mini percutaneous nephrolithotomy: an international multicentre comparative study', BJU International, vol. 126, no. 1, pp. 168-176.
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ObjectivesTo comparatively evaluate the clinical outcomes of super‐mini percutaneous nephrolithotomy (SMP) and mini‐percutaneous nephrolithotomy (Miniperc) for treating urinary tract calculi of >2 cm.Patients and MethodsAn international multicentre, retrospective cohort study was conducted at 20 tertiary care hospitals across five countries (China, the Philippines, Qatar, UK, and Kuwait) between April 2016 and May 2019. SMP and Miniperc were performed in 3525 patients with renal calculi with diameters of >2 cm. The primary endpoint was the stone‐free rate (SFR). The secondary outcomes included: blood loss, operating time, postoperative pain scores, auxiliary procedures, complications, tubeless rate, and hospital stay. Propensity score matching analysis was used to balance the selection bias between the two groups.ResultsIn all, 2012 and 1513 patients underwent SMP and Miniperc, respectively. After matching, 1380 patients from each group were included for further analysis. Overall, there was no significant difference in the mean operating time or SFR between the two groups. However, the hospital stay and postoperative pain score were significantly in favour of SMP (both P < 0.001). The tubeless rate was significantly higher in the SMP group (72.6% vs 57.8%, P < 0.001). Postoperative fever was much more common in the Miniperc group (12.0% vs 8.4%, P = 0.002). When the patients were further classified into three subgroups based on stones diameters (2–3, 3–4, and >4 cm). The advantages of SMP were most obvious in the 2–3 cm stone group and diminished as the size of the stone increased, with longer operating time in the latter two subgroups. Compared with Miniperc, the SFR of SMP was comparable for...

Liu, Y, Lin, G, Chen, Y, Mönch, I, Makarov, D, Walsh, BJ & Jin, D 2020, 'Coding and decoding stray magnetic fields for multiplexing kinetic bioassay platform', Lab on a Chip, vol. 20, no. 24, pp. 4561-4571.
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The stray magnetic fields of hierarchically-assembled magnetic beads are utilised to code and decode information for multiplexed kinetic assays.

Liu, Y, Wang, F, Lu, H, Fang, G, Wen, S, Chen, C, Shan, X, Xu, X, Zhang, L, Stenzel, M & Jin, D 2020, 'Cancer Spheroids: Super‐Resolution Mapping of Single Nanoparticles inside Tumor Spheroids (Small 6/2020)', Small, vol. 16, no. 6, pp. 2070030-2070030.
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Liu, Y, Wang, F, Lu, H, Fang, G, Wen, S, Chen, C, Shan, X, Xu, X, Zhang, L, Stenzel, M & Jin, D 2020, 'Super‐Resolution Mapping of Single Nanoparticles inside Tumor Spheroids', Small, vol. 16, no. 6, pp. 1905572-1905572.
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AbstractCancer spheroids have structural, functional, and physiological similarities to the tumor, and have become a low‐cost in vitro model to study the physiological responses of single cells and therapeutic efficacy of drugs. However, the tiny spheroid, made of a cluster of high‐density cells, is highly scattering and absorptive, which prevents light microscopy techniques to reach the depth inside spheroids with high resolution. Here, a method is reported for super‐resolution mapping of single nanoparticles inside a spheroid. It first takes advantage of the self‐healing property of a “nondiffractive” doughnut‐shaped Bessel beam from a 980 nm diode laser as the excitation, and further employs the nonlinear response of the 800 nm emission from upconversion nanoparticles, so that both excitation and emission at the near‐infrared can experience minimal loss through the spheroid. These strategies lead to the development of a new nanoscopy modality with a resolution of 37 nm, 1/26th of the excitation wavelength. This method enables mapping of single nanoparticles located 55 µm inside a spheroid, with a resolution of 98 nm. It suggests a solution to track single nanoparticles and monitor their release of drugs in 3D multicellar environments.

Mahmoudi, T, Pirpour Tazehkand, A, Pourhassan-Moghaddam, M, Alizadeh-Ghodsi, M, Ding, L, Baradaran, B, Razavi Bazaz, S, Jin, D & Ebrahimi Warkiani, M 2020, 'PCR-free paper-based nanobiosensing platform for visual detection of telomerase activity via gold enhancement', Microchemical Journal, vol. 154, pp. 104594-104594.
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© 2020 Elsevier B.V. Telomerase activity has been demonstrated in a wide variety of most solid tumors and considered as a well-known cancer biomarker. The commonly utilized method for its detection is polymerase chain reaction (PCR)-based telomeric repeat amplification protocol (TRAP). However, the TRAP technique suffers from false-negative results caused by the failure of PCR step. Moreover, it requires advanced equipment with a tedious and time-consuming procedure. Herein, we presented a portable nitrocellulose paper-based nanobiosensing platform for ultrafast and equipment-free detection of telomerase activity based on a simple colorimetric assay that enabled naked-eye visualization of the color change in response to enzyme activity. In this platform, hybridization was initially performed between telomere complementary oligonucleotide immobilized on gold nanoparticles (GNPs) and telomerase elongated biotinylated probe. Thereafter, the assembly was attached on activated paper strip via avidin-biotin interaction. The signal amplification was carried out by enlargement of the attached GNPs on the paper strip, forming tightly compact rod-shaped submicron structures of gold representing a visual color formation. Thanks to significant sensitivity enhancement, the color change was occurred for down to 6 cells, which can be easily observed by the naked eye. Due to the desired aspects of the developed assay including PCR-free, low cost, simple, and high sensitivity, it can be used for evaluation of telomerase activity in cell extracts for future clinical applications. Furthermore, this design has the ability to be easily integrated into lab-on-chip devices for point-of-care telomerase sensing.

Mahmoudi, Z, Mohammadnejad, J, Razavi Bazaz, S, Abouei Mehrizi, A, Saidijam, M, Dinarvand, R, Ebrahimi Warkiani, M & Soleimani, M 2020, 'Promoted chondrogenesis of hMCSs with controlled release of TGF-β3 via microfluidics synthesized alginate nanogels', Carbohydrate Polymers, vol. 229, pp. 115551-115551.
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The field of cartilage tissue engineering has been evolved in the last decade and a myriad of scaffolding biomaterials and bioactive agents have been proposed. Controlled release of growth factors encapsulated in the polymeric nanomaterials has been of interest notably for the repair of damaged articular cartilage. Here, we proposed an on-chip hydrodynamic flow focusing microfluidic approach for synthesis of alginate nanogels loaded with the transforming growth factor beta 3 (TGF-β3) through an ionic gelation method in order to achieve precise release profile of these bioactive agents during chondrogenic differentiation of mesenchymal stem cells (MSCs). Alginate nanogels with adjustable sizes were synthesized by fine-tuning the flow rate ratio (FRR) in the microfluidic device consisting of cross-junction microchannels. The result of present study showed that the proposed approach can be a promising tool to synthesize bioactive -loaded polymeric nanogels for applications in drug delivery and tissue engineering.

Martin, AD, Wojciechowski, JP, Du, EY, Rawal, A, Stefen, H, Au, CG, Hou, L, Cranfield, CG, Fath, T, Ittner, LM & Thordarson, P 2020, 'Decoupling the effects of hydrophilic and hydrophobic moieties at the neuron–nanofibre interface', Chemical Science, vol. 11, no. 5, pp. 1375-1382.
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The mobility of hydrophobic moieties at a peptide nanofibre surface determines its suitability as a scaffold for sensitive primary cells.

Mihandoust, A, Razavi Bazaz, S, Maleki-Jirsaraei, N, Alizadeh, M, A. Taylor, R & Ebrahimi Warkiani, M 2020, 'High-Throughput Particle Concentration Using Complex Cross-Section Microchannels', Micromachines, vol. 11, no. 4, pp. 440-440.
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High throughput particle/cell concentration is crucial for a wide variety of biomedical, clinical, and environmental applications. In this work, we have proposed a passive spiral microfluidic concentrator with a complex cross-sectional shape, i.e., a combination of rectangle and trapezoid, for high separation efficiency and a confinement ratio less than 0.07. Particle focusing in our microfluidic system was observed in a single, tight focusing line, in which higher particle concentration is possible, as compared with simple rectangular or trapezoidal cross-sections with similar flow area. The sharper focusing stems from the confinement of Dean vortices in the trapezoidal region of the complex cross-section. To quantify this effect, we introduce a new parameter, complex focusing number or CFN, which is indicative of the enhancement of inertial focusing of particles in these channels. Three spiral microchannels with various widths of 400 µm, 500 µm, and 600 µm, with the corresponding CFNs of 4.3, 4.5, and 6, respectively, were used. The device with the total width of 600 µm was shown to have a separation efficiency of ~98%, and by recirculating, the output concentration of the sample was 500 times higher than the initial input. Finally, the investigation of results showed that the magnitude of CFN relies entirely on the microchannel geometry, and it is independent of the overall width of the channel cross-section. We envision that this concept of particle focusing through complex cross-sections will prove useful in paving the way towards more efficient inertial microfluidic devices.

Mirzaaghaian, A, Ramiar, A, Ranjbar, AA & Warkiani, ME 2020, 'Application of level-set method in simulation of normal and cancer cells deformability within a microfluidic device', Journal of Biomechanics, vol. 112, pp. 110066-110066.
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Application of microfluidic systems for the study of cellular behaviors has been a flourishing area of research in the past decade. In the process of probing cell biomechanics the passage of a cell through a narrow microchannel or a small pore has attracted much attention during the recent years. And the study of cellular deformability and transportability using these systems with enhanced resolution and accuracy has opened a new paradigm for high-throughput characterization of both healthy and diseased cell populations.Here we use the level-set method to explore the relationship between the transit time and mechanical properties of normal white blood cells (WBCs) and breast cancer epithelial cells (MCF7) under different microenvironmental parameters (i.e., pressure difference, cell size, effective cell surface tension, constriction size and taper angle) in a 2-D computational domain by considering the cell as a viscous drop. The novel biomechanical relations are obtained for each cell type by the Response Surface Method (RSM), relating microenvironmental parameters to the dimensionless entry time of the normal and cancer cells. Our results revealed that MCF7 cells show asignificantly different behavior (a bifurcating behavior when the pressure difference of inlet/outlet increases) in regards to the dimensionless entry time as a function of microchannel taper angle in comparison with the WBC. These results suggest that the microenvironmental parameters have a significant effect on the transportability of the cells and different cells have different behaviors in response to a specific microenvironmental parameter. Finally, it can be claimed that this method can be also utilized to distinguish between benign and cancerous cells or even to probe tumor heterogeneity toward high throughput cell cytometry.

Monkman, J, Taheri, T, Ebrahimi Warkiani, M, O’Leary, C, Ladwa, R, Richard, D, O’Byrne, K & Kulasinghe, A 2020, 'High-Plex and High-Throughput Digital Spatial Profiling of Non-Small-Cell Lung Cancer (NSCLC)', Cancers, vol. 12, no. 12, pp. 3551-3551.
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Profiling the tumour microenvironment (TME) has been informative in understanding the underlying tumour–immune interactions. Multiplex immunohistochemistry (mIHC) coupled with molecular barcoding technologies have revealed greater insights into the TME. In this study, we utilised the Nanostring GeoMX Digital Spatial Profiler (DSP) platform to profile a non-small-cell lung cancer (NSCLC) tissue microarray for protein markers across immune cell profiling, immuno-oncology (IO) drug targets, immune activation status, immune cell typing, and pan-tumour protein modules. Regions of interest (ROIs) were selected that described tumour, TME, and normal adjacent tissue (NAT) compartments. Our data revealed that paired analysis (n = 18) of matched patient compartments indicate that the TME was significantly enriched in CD27, CD3, CD4, CD44, CD45, CD45RO, CD68, CD163, and VISTA relative to the tumour. Unmatched analysis indicated that the NAT (n = 19) was significantly enriched in CD34, fibronectin, IDO1, LAG3, ARG1, and PTEN when compared to the TME (n = 32). Univariate Cox proportional hazards indicated that the presence of cells expressing CD3 (hazard ratio (HR): 0.5, p = 0.018), CD34 (HR: 0.53, p = 0.004), and ICOS (HR: 0.6, p = 0.047) in tumour compartments were significantly associated with improved overall survival (OS). We implemented both high-plex and high-throughput methodologies to the discovery of protein biomarkers and molecular phenotypes within biopsy samples, and demonstrate the power of such tools for a new generation of pathology research.

Moore, G, Annett, S, McClements, L & Robson, T 2020, 'Top Notch Targeting Strategies in Cancer: A Detailed Overview of Recent Insights and Current Perspectives', Cells, vol. 9, no. 6, pp. 1503-1503.
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Evolutionarily conserved Notch plays a critical role in embryonic development and cellular self-renewal. It has both tumour suppressor and oncogenic activity, the latter of which is widely described. Notch-activating mutations are associated with haematological malignancies and several solid tumours including breast, lung and adenoid cystic carcinoma. Moreover, upregulation of Notch receptors and ligands and aberrant Notch signalling is frequently observed in cancer. It is involved in cancer hallmarks including proliferation, survival, migration, angiogenesis, cancer stem cell renewal, metastasis and drug resistance. It is a key component of cell-to-cell interactions between cancer cells and cells of the tumour microenvironment, such as endothelial cells, immune cells and fibroblasts. Notch displays diverse crosstalk with many other oncogenic signalling pathways, and may drive acquired resistance to targeted therapies as well as resistance to standard chemo/radiation therapy. The past 10 years have seen the emergence of different classes of drugs therapeutically targeting Notch including receptor/ligand antibodies, gamma secretase inhibitors (GSI) and most recently, the development of Notch transcription complex inhibitors. It is an exciting time for Notch research with over 70 cancer clinical trials registered and the first-ever Phase III trial of a Notch GSI, nirogacestat, currently at the recruitment stage.

Murphy, C, Deplazes, E, Cranfield, CG & Garcia, A 2020, 'The Role of Structure and Biophysical Properties in the Pleiotropic Effects of Statins', International Journal of Molecular Sciences, vol. 21, no. 22, pp. 8745-8745.
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Statins are a class of drugs used to lower low-density lipoprotein cholesterol and are amongst the most prescribed medications worldwide. Most statins work as a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGR), but statin intolerance from pleiotropic effects have been proposed to arise from non-specific binding due to poor enzyme-ligand sensitivity. Yet, research into the physicochemical properties of statins, and their interactions with off-target sites, has not progressed much over the past few decades. Here, we present a concise perspective on the role of statins in lowering serum cholesterol levels, and how their reported interactions with phospholipid membranes offer a crucial insight into the mechanism of some of the more commonly observed pleiotropic effects of statin administration. Lipophilicity, which governs hepatoselectivity, is directly related to the molecular structure of statins, which dictates interaction with and transport through membranes. The structure of statins is therefore a clinically important consideration in the treatment of hypercholesterolaemia. This review integrates the recent biophysical studies of statins with the literature on the physiological effects and provides new insights into the mechanistic cause of statin pleiotropy, and prospective means of understanding the cholesterol-independent effects of statins.

Pang, B, Zhu, Y, Ni, J, Ruan, J, Thompson, J, Malouf, D, Bucci, J, Graham, P & Li, Y 2020, '<p>Quality Assessment and Comparison of Plasma-Derived Extracellular Vesicles Separated by Three Commercial Kits for Prostate Cancer Diagnosis</p>', International Journal of Nanomedicine, vol. Volume 15, pp. 10241-10256.
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Introduction

Current standard biomarkers in clinic are not specific enough for prostate cancer (PCa) diagnosis. Extracellular vesicles (EVs) are nano-scale vesicles released by most mammalian cells. EVs are promising biomarker source for PCa liquid biopsy due to its minimal invasive approach, rich information and improved accuracy compared to the clinical standard prostate-specific antigen (PSA). However, current EV separation methods cannot separate pure EVs and the quality characteristics from these methods remain largely unknown. In this study, we evaluated the quality characteristics of human plasma-derived EVs by comparing three clinical suitable separation kits.

Methods

We combined EV separation by commercial kits with magnetic beads capture and flow cytometry analysis, and compared three kits including ExoQuick Ultra based on precipitation and qEV35 and qEV70 based on size exclusion chromatography (SEC).

Results

Our results indicated that two SEC kits provided higher EV purity and lower protein contamination compared to ExoQuick Ultra precipitation and that qEV35 demonstrated a higher EV yield but lower EV purity compared to qEV70. Particle number correlated very well particularly with CD9/81/63 positive EVs for all three kits, which confirms that particle number can be used as the estimate for EV amount. At last, we found that several EV metrics including total EVs and PSA-specific EVs could not differentiate PCa patients from health controls.

Conclusion

We provided a systematic workflow for the comparison of three separation kits as well as a general analysis process in clinical laboratories for EV-based cancer diagnosis. Better EV-associated cancer biomarkers need to be explored in the future study with a larger cohort.

Pang, B, Zhu, Y, Ni, J, Thompson, J, Malouf, D, Bucci, J, Graham, P & Li, Y 2020, 'Extracellular vesicles: the next generation of biomarkers for liquid biopsy-based prostate cancer diagnosis', Theranostics, vol. 10, no. 5, pp. 2309-2326.
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Prostate cancer (PCa) is a leading cause of cancer death for males in western countries. The current gold standard for PCa diagnosis - template needle biopsies - often does not convey a true representation of the molecular profile given sampling error and complex tumour heterogeneity. Presently available biomarker blood tests have limited accuracy. There is a growing demand for novel diagnostic approaches to reduce both the number of men with an abnormal PSA/ DRE who undergo invasive biopsy and the number of cores collected per biopsy. 'Liquid biopsy' is a minimally invasive biofluid-based approach that has the potential to provide information and improve the accuracy of diagnosis for patients' treatment selection, prognostic counselling and development of risk-adjusted follow-up protocols. Extracellular vesicles (EVs) are lipid bilayer-delimited particles released by tumour cells which may provide a real-time snapshot of the entire tumour in a non-invasive way. EVs can regulate physiological processes and mediate systemic dissemination of various types of cancers. Emerging evidence suggests that EVs have crucial roles in PCa development and metastasis. Most importantly, EVs are directly derived from their parent cells with their information. EVs contain components including proteins, mRNAs, DNA fragments, non-coding RNAs and lipids, and play a critical role in intercellular communication. Therefore, EVs hold promise for the discovery of liquid biopsy-based biomarkers for PCa diagnosis. Here, we review the current approaches for EV isolation and analysis, summarise the recent advances in EV protein biomarkers in PCa and focus on liquid biopsy-based EV biomarkers in PCa diagnosis for personalised medicine.

Poon, C, Chou, J, Cortie, M & Kabakova, I 2020, 'Brillouin imaging for studies of micromechanics in biology and biomedicine: from current state-of-the-art to future clinical translation', Journal of Physics: Photonics, vol. 3, no. 1, pp. 1-25.
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Brillouin imaging is increasingly recognized to be a powerful technique thatenables non-invasive measurement of the mechanical properties of cells andtissues on a microscopic scale. This provides an unprecedented tool forinvestigating cell mechanobiology, cell-matrix interactions, tissuebiomechanics in healthy and disease conditions and other fundamental biologicalquestions. Recent advances in optical hardware have particularly acceleratedthe development of the technique, with increasingly finer spectral resolutionand more powerful system capabilities. We envision that further developmentswill enable translation of Brillouin imaging to assess clinical specimens andsamples for disease screening and monitoring. The purpose of this review is tosummarize the state-of-the-art in Brillouin microscopy and imaging with aspecific focus on biological tissue and cell measurements. Key system andoperational requirements will be discussed to facilitate wider application ofBrillouin imaging along with current challenges for translation of thetechnology for clinical and medical applications.

Qin, J, Guo, Y, Xue, B, Shi, P, Chen, Y, Su, QP, Hao, H, Zhao, S, Wu, C, Yu, L, Li, D & Sun, Y 2020, 'ER-mitochondria contacts promote mtDNA nucleoids active transportation via mitochondrial dynamic tubulation', Nature Communications, vol. 11, no. 1, p. 4471.
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AbstractA human cell contains hundreds to thousands of mitochondrial DNA (mtDNA) packaged into nucleoids. Currently, the segregation and allocation of nucleoids are thought to be passively determined by mitochondrial fusion and division. Here we provide evidence, using live-cell super-resolution imaging, that nucleoids can be actively transported via KIF5B-driven mitochondrial dynamic tubulation (MDT) activities that predominantly occur at the ER-mitochondria contact sites (EMCS). We further demonstrate that a mitochondrial inner membrane protein complex MICOS links nucleoids to Miro1, a KIF5B receptor on mitochondria, at the EMCS. We show that such active transportation is a mechanism essential for the proper distribution of nucleoids in the peripheral zone of the cell. Together, our work identifies an active transportation mechanism of nucleoids, with EMCS serving as a key platform for the interplay of nucleoids, MICOS, Miro1, and KIF5B to coordinate nucleoids segregation and transportation.

Quan, D, Ji, D, Wen, Q, Du, L, Wang, L, Jia, P, Liu, D, Ding, L, Dong, H, Lu, D, Jiang, L & Guo, W 2020, 'Laterally Heterogeneous 2D Layered Materials as an Artificial Light‐Harvesting Proton Pump', Advanced Functional Materials, vol. 30, no. 34.
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AbstractHeterogeneous structures in nacre‐mimetic 2D layered materials generate novel transport phenomena in angstrom range, and thus provide new possibilities for innovative applications for sustainable energy, a clean environment, and human healthcare. In the two orthogonal transport directions, either vertical or horizontal, heterostructures in horizontal direction have never been reported before. Here, a 2D‐material‐based laterally heterogeneous membrane is fabricated via an unconventional dual‐flow filtration method. Negatively and positively charged graphene oxide multilayers are laterally patterned and interconnected in a planar configuration. Upon visible light illumination on the bipolar nanofluidic heterojunction, protons are able to move uphill against their concentration gradient, functioning as a light‐harvesting proton pump. A maximum proton concentration gradient of about 5.4 pH units mm−2 membrane area can be established at a transport rate up to 14.8 mol h−1 m−2. The transport mechanism can be understood as a light‐triggered asymmetric polarization in surface potential and the consequent change in proton capacity in separate parts. The implementation of photonic–ionic conversion with abiotic materials provides a full‐solid‐state solution for bionic vision and artificial photosynthesis. There is plenty of room to expect the laterally heterogeneous membranes for new functions and better performance in the abundant family of liquid processable colloidal 2D materials.

Raoufi, MA, Razavi Bazaz, S, Niazmand, H, Rouhi, O, Asadnia, M, Razmjou, A & Ebrahimi Warkiani, M 2020, 'Fabrication of unconventional inertial microfluidic channels using wax 3D printing', Soft Matter, vol. 16, no. 10, pp. 2448-2459.
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A novel workflow for the fabrication of inertial microfluidic devices based on the wax 3D printing method.

Rawling, T, MacDermott-Opeskin, H, Roseblade, A, Pazderka, C, Clarke, C, Bourget, K, Wu, X, Lewis, W, Noble, B, Gale, PA, O'Mara, ML, Cranfield, C & Murray, M 2020, 'Aryl urea substituted fatty acids: a new class of protonophoric mitochondrial uncoupler that utilises a synthetic anion transporter', Chemical Science, vol. 11, no. 47, pp. 12677-12685.
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A new mitochondrial uncoupler that forms membrane permeable dimers through interactions of remote acidic and anion receptor groups.

Razavi Bazaz, S, Amiri, HA, Vasilescu, S, Abouei Mehrizi, A, Jin, D, Miansari, M & Ebrahimi Warkiani, M 2020, 'Obstacle-free planar hybrid micromixer with low pressure drop', Microfluidics and Nanofluidics, vol. 24, no. 8.
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© 2020, Springer-Verlag GmbH Germany, part of Springer Nature. Planar micromixers with repetitive units have received substantial research interest since they allow low cost, lab-on-a-chip (LOC), and point-of-care (POC) systems to achieve a proper level of mixing for any given process. This paper presents an efficient planar micromixer that combines four types of mixing units, including convergent–divergent, circular, rhombic, and G-shaped micromixers. Their combinations and resulting effects on the mixing efficiency are numerically and experimentally investigated. A comprehensive Taguchi design of experiment method was used to reduce the number of the combinations from 1024 to only 16, among which a micromixer made of rhombic and G-shaped units readily showed a mixing efficiency beyond 80% over a wide range of inlet Reynolds numbers 0.001–0.3 and 35–65; meanwhile, a pressure drop as low as 12 kPa was reported. The velocity and concentration fields and their gradients within the nominated micromixer were analyzed, providing a better understanding of the mixing mechanism. These results offer design insights for further development of planar micromixers with repetitive unites for low-cost LOC and POC devices.

Razavi Bazaz, S, Hazeri, AH, Rouhi, O, Mehrizi, AA, Jin, D & Warkiani, ME 2020, 'Volume-preserving strategies to improve the mixing efficiency of serpentine micromixers', Journal of Micromechanics and Microengineering, vol. 30, no. 11, pp. 115022-115022.
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Abstract In this study, we have proposed volume-preserving strategies to boost chaoticadvection and improve the mixing efficiency of serpentine micromixers. The proposed strategies revolve around the point that the volume of the micromixer is kept constant during the manipulation. The first strategy involves the utilization of a nozzle-diffuser (ND) shaped microchannel. Using this, the velocity of the fluids fluctuates in an alternating pattern, leading to additional chaotic advection, a decrease in the mixing path, and an increase in the mixing index. The second strategy uses non-aligned inlets to generate swirl inducing effects at the microchannel entrance, where the collision of two fluids generates angular momentum in the flow, providing more chaotic advection. These strategies proved to be effective in boosting the mixing efficiency over wide ranges of Re in which 60% enhancement (from 20.53% to 80.31%) was achieved for Re of 30 by applying an ND shaped microchannel, and 20% enhancement (from 12.71% to 32.21%) was achieved for a critical Re of 15 by applying both of the strategies simultaneously.

Razavi Bazaz, S, Mashhadian, A, Ehsani, A, Saha, SC, Krüger, T & Ebrahimi Warkiani, M 2020, 'Computational inertial microfluidics: a review', Lab on a Chip, vol. 20, no. 6, pp. 1023-1048.
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Schematic illustration of various kinds of geometries used for inertial microfluidics.

Razavi Bazaz, S, Rouhi, O, Raoufi, MA, Ejeian, F, Asadnia, M, Jin, D & Ebrahimi Warkiani, M 2020, '3D Printing of Inertial Microfluidic Devices', Scientific Reports, vol. 10, no. 1, p. 5929.
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AbstractInertial microfluidics has been broadly investigated, resulting in the development of various applications, mainly for particle or cell separation. Lateral migrations of these particles within a microchannel strictly depend on the channel design and its cross-section. Nonetheless, the fabrication of these microchannels is a continuous challenging issue for the microfluidic community, where the most studied channel cross-sections are limited to only rectangular and more recently trapezoidal microchannels. As a result, a huge amount of potential remains intact for other geometries with cross-sections difficult to fabricate with standard microfabrication techniques. In this study, by leveraging on benefits of additive manufacturing, we have proposed a new method for the fabrication of inertial microfluidic devices. In our proposed workflow, parts are first printed via a high-resolution DLP/SLA 3D printer and then bonded to a transparent PMMA sheet using a double-coated pressure-sensitive adhesive tape. Using this method, we have fabricated and tested a plethora of existing inertial microfluidic devices, whether in a single or multiplexed manner, such as straight, spiral, serpentine, curvilinear, and contraction-expansion arrays. Our characterizations using both particles and cells revealed that the produced chips could withstand a pressure up to 150 psi with minimum interference of the tape to the total functionality of the device and viability of cells. As a showcase of the versatility of our method, we have proposed a new spiral microchannel with right-angled triangular cross-section which is technically impossible to fabricate using the standard lithography. We are of the opinion that the method proposed in this study will open the door for more complex geometries with the bespoke passive internal flow. Furthermore, the proposed fabrication workflow can be adopted at the production level, enabling large-scale man...

Ren, W, Lin, G, Clarke, C, Zhou, J & Jin, D 2020, 'Anticounterfeiting Systems: Optical Nanomaterials and Enabling Technologies for High‐Security‐Level Anticounterfeiting (Adv. Mater. 18/2020)', Advanced Materials, vol. 32, no. 18, pp. 2070141-2070141.
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Ren, W, Lin, G, Clarke, C, Zhou, J & Jin, D 2020, 'Optical Nanomaterials and Enabling Technologies for High‐Security‐Level Anticounterfeiting', Advanced Materials, vol. 32, no. 18, pp. 1901430-1901430.
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AbstractOptical nanomaterials have been widely used in anticounterfeiting applications. There have been significant developments powered by recent advances in material science, printing technologies, and the availability of smartphone‐based decoding technology. Recent progress in this field is surveyed, including the availability of optical reflection, absorption, scattering, and luminescent nanoparticles. It is demonstrated that advances in the design and synthesis of lanthanide‐doped upconversion nanoparticles will lead to the next generation of anticounterfeiting technologies. Their tunable optical properties and optical responses to a range of external stimuli allow high‐security level information encoding. Challenges in the scale‐up synthesis of nanomaterials, engineering of assessorial devices for smart‐phone‐based decryption, and alignment to the potential markets which will lead to new directions for research, are discussed.

Rezaei, M, Razavi Bazaz, S, Zhand, S, Sayyadi, N, Jin, D, Stewart, MP & Ebrahimi Warkiani, M 2020, 'Point of Care Diagnostics in the Age of COVID-19', Diagnostics, vol. 11, no. 1, pp. 9-9.
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The recent outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated serious respiratory disease, coronavirus disease 2019 (COVID-19), poses a major threat to global public health. Owing to the lack of vaccine and effective treatments, many countries have been overwhelmed with an exponential spread of the virus and surge in the number of confirmed COVID-19 cases. Current standard diagnostic methods are inadequate for widespread testing as they suffer from prolonged turn-around times (>12 h) and mostly rely on high-biosafety-level laboratories and well-trained technicians. Point-of-care (POC) tests have the potential to vastly improve healthcare in several ways, ranging from enabling earlier detection and easier monitoring of disease to reaching remote populations. In recent years, the field of POC diagnostics has improved markedly with the advent of micro- and nanotechnologies. Due to the COVID-19 pandemic, POC technologies have been rapidly innovated to address key limitations faced in existing standard diagnostic methods. This review summarizes and compares the latest available POC immunoassay, nucleic acid-based and clustered regularly interspaced short palindromic repeats- (CRISPR)-mediated tests for SARS-CoV-2 detection that we anticipate aiding healthcare facilities to control virus infection and prevent subsequent spread.

Rzhevskiy, AS, Razavi Bazaz, S, Ding, L, Kapitannikova, A, Sayyadi, N, Campbell, D, Walsh, B, Gillatt, D, Ebrahimi Warkiani, M & Zvyagin, AV 2020, 'Rapid and Label-Free Isolation of Tumour Cells from the Urine of Patients with Localised Prostate Cancer Using Inertial Microfluidics', Cancers, vol. 12, no. 1, pp. 81-81.
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During the last decade, isolation of circulating tumour cells via blood liquid biopsy of prostate cancer (PCa) has attracted significant attention as an alternative, or substitute, to conventional diagnostic tests. However, it was previously determined that localised forms of PCa shed a small number of cancer cells into the bloodstream, and a large volume of blood is required just for a single test, which is impractical. To address this issue, urine has been used as an alternative to blood for liquid biopsy as a truly non-invasive, patient-friendly test. To this end, we developed a spiral microfluidic chip capable of isolating PCa cells from the urine of PCa patients. Potential clinical utility of the chip was demonstrated using anti-Glypican-1 (GPC-1) antibody as a model of the primary antibody in immunofluorescent assay for identification and detection of the collected tumour cells. The microchannel device was first evaluated using DU-145 cells in a diluted Dulbecco’s phosphate-buffered saline sample, where it demonstrated >85 (±6) % efficiency. The microchannel proved to be functional in at least 79% of cases for capturing GPC1+ putative tumour cells from the urine of patients with localised PCa. More importantly, a correlation was found between the amount of the captured GPC1+ cells and crucial diagnostic and prognostic parameter of localised PCa—Gleason score. Thus, the technique demonstrated promise for further assessment of its diagnostic value in PCa detection, diagnosis, and prognosis.

Sadeghi Rad, H, Bazaz, SR, Monkman, J, Ebrahimi Warkiani, M, Rezaei, N, O'Byrne, K & Kulasinghe, A 2020, 'The evolving landscape of predictive biomarkers in immuno‐oncology with a focus on spatial technologies', Clinical & Translational Immunology, vol. 9, no. 11.
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AbstractImmunotherapies have shown long‐lasting and unparalleled responses for cancer patients compared to conventional therapy. However, they seem to only be effective in a subset of patients. Therefore, it has become evident that a greater understanding of the tumor microenvironment (TME) is required to understand the nuances which may be at play for a favorable outcome to therapy. The immune contexture of the TME is an important factor in dictating how well a tumor may respond to immune checkpoint inhibitors. While traditional immunohistochemistry techniques allow for the profiling of cells in the tumor, this is often lost when tumors are analysed using bulk tissue genomic approaches. Moreover, the actual cellular proportions, cellular heterogeneity and deeper spatial distribution are lacking in characterisation. Advances in tissue interrogation technologies have given rise to spatially resolved characterisation of the TME. This review aims to provide an overview of the current methodologies that are used to profile the TME, which may provide insights into the immunopathology associated with a favorable outcome to immunotherapy.

Shamshirian, A, Aref, AR, Yip, GW, Ebrahimi Warkiani, M, Heydari, K, Razavi Bazaz, S, Hamzehgardeshi, Z, Shamshirian, D, Moosazadeh, M & Alizadeh-Navaei, R 2020, 'Diagnostic value of serum HER2 levels in breast cancer: a systematic review and meta-analysis', BMC Cancer, vol. 20, no. 1, p. 1049.
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Abstract Background Measurement of serum human epidermal growth factor receptor-2 (HER-2/neu) levels might play an essential role as a diagnostic/screening marker for the early selection of therapeutic approaches and predict prognosis in breast cancer patients. We aimed to undertake a systematic review and meta-analysis focusing on the diagnostic/screening value of serum HER-2 levels in comparison to routine methods. Methods We performed a systematic search via PubMed, Scopus, Cochrane-Library, and Web of Science databases for human diagnostic studies reporting the levels of serum HER-2 in breast cancer patients, which was confirmed using the histopathological examination. Meta-analyses were carried out for sensitivity, specificity, accuracy, area under the ROC curve (AUC), positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (PLR), and negative likelihood ratio (NLR). Results Fourteen studies entered into this investigation. The meta-analysis indicated the low sensitivity for serum HER2 levels (Sensitivity: 53.05, 95%CI 40.82–65.28), but reasonable specificity of 79.27 (95%CI 73.02–85.51), accuracy of 72.06 (95%CI 67.04–77.08) and AUC of 0.79 (95%CI 0.66–0.92). We also found a significant differences for PPV (PPV: 56.18, 95%CI 44.16–68.20), NPV (NPV: 76.93, 95%CI 69.56–84.31), PLR (PLR: 2.10, 95%CI 1.69–2.50) and NLR (NLR: 0.58, 95%CI 0.44–0.71). Conclusion Our findings revealed that although serum HER-2 le...

Shang, Y, Zhou, J, Cai, Y, Wang, F, Fernandez-Bravo, A, Yang, C, Jiang, L & Jin, D 2020, 'Low threshold lasing emissions from a single upconversion nanocrystal', Nature Communications, vol. 11, no. 1.
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AbstractCross-relaxation among neighboring emitters normally causes self-quenching and limits the brightness of luminescence. However, in nanomaterials, cross-relaxation could be well-controlled and employed for increasing the luminescence efficiency at specific wavelengths. Here we report that cross-relaxation can modulate both the brightness of single upconversion nanoparticles and the threshold to reach population inversion, and both are critical factors in producing the ultra-low threshold lasing emissions in a micro cavity laser. By homogenously coating a 5-μm cavity with a single layer of nanoparticles, we demonstrate that doping Tm3+ ions at 2% can facilitate the electron accumulation at the intermediate state of 3H4 level and efficiently decrease the lasing threshold by more than one order of magnitude. As a result, we demonstrate up-converted lasing emissions with an ultralow threshold of continuous-wave excitation of ~150 W/cm2 achieved at room temperature. A single nanoparticle can lase with a full width at half-maximum as narrow as ~0.45 nm.

Shrestha, J, Razavi Bazaz, S, Aboulkheyr Es, H, Yaghobian Azari, D, Thierry, B, Ebrahimi Warkiani, M & Ghadiri, M 2020, 'Lung-on-a-chip: the future of respiratory disease models and pharmacological studies', Critical Reviews in Biotechnology, vol. 40, no. 2, pp. 213-230.
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© 2020, © 2020 Informa UK Limited, trading as Taylor & Francis Group. Recently, organ-on-a-chip models, which are microfluidic devices that mimic the cellular architecture and physiological environment of an organ, have been developed and extensively investigated. The chips can be tailored to accommodate the disease conditions pertaining to many organs; and in the case of this review, the lung. Lung-on-a-chip models result in a more accurate reflection compared to conventional in vitro models. Pharmaceutical drug testing methods traditionally use animal models in order to evaluate pharmacological and toxicological responses to a new agent. However, these responses do not directly reflect human physiological responses. In this review, current and future applications of the lung-on-a-chip in the respiratory system will be discussed. Furthermore, the limitations of current conventional in vitro models used for respiratory disease modeling and drug development will be addressed. Highlights of additional translational aspects of the lung-on-a-chip will be discussed in order to demonstrate the importance of this subject for medical research.

Smyth, L, McClements, L & Murphy, P 2020, 'Engaging hard-to-reach populations in research on health in pregnancy: the value of Boal’s simultaneous dramaturgy', Arts & Health, vol. 12, no. 1, pp. 71-79.
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© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group. Background: Migrant populations are among the hardest to reach for research purposes. Methods: An interdisciplinary research team piloted a modified version of Boal's simultaneous dramaturgy with Roma mothers in Belfast. Results: The technique, based on scripted performances, translations, and discussions, proved effective for engaging with this hard-to-reach population, despite low levels of literacy, high language barriers, and cultural separateness. The approach uncovered attitudes to pregnancy which reinforce health inequalities, and present significant challenges for improving the health of marginalized populations. Conclusions: This pilot underlines the importance of building trust through holistic approaches to working with hard-to-reach populations through the creative arts.

Su, QP, Zhao, ZW, Meng, L, Ding, M, Zhang, W, Li, Y, Liu, M, Li, R, Gao, Y-Q, Xie, XS & Sun, Y 2020, 'Superresolution imaging reveals spatiotemporal propagation of human replication foci mediated by CTCF-organized chromatin structures', Proceedings of the National Academy of Sciences, vol. 117, no. 26, pp. 15036-15046.
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Mammalian DNA replication is initiated at numerous replication origins, which are clustered into thousands of replication domains (RDs) across the genome. However, it remains unclear whether the replication origins within each RD are activated stochastically or preferentially near certain chromatin features. To understand how DNA replication in single human cells is regulated at the sub-RD level, we directly visualized and quantitatively characterized the spatiotemporal organization, morphology, and in situ epigenetic signatures of individual replication foci (RFi) across S-phase at superresolution using stochastic optical reconstruction microscopy. Importantly, we revealed a hierarchical radial pattern of RFi propagation dynamics that reverses directionality from early to late S-phase and is diminished upon caffeine treatment or CTCF knockdown. Together with simulation and bioinformatic analyses, our findings point to a “CTCF-organized REplication Propagation” (CoREP) model, which suggests a nonrandom selection mechanism for replication activation at the sub-RD level during early S-phase, mediated by CTCF-organized chromatin structures. Collectively, these findings offer critical insights into the key involvement of local epigenetic environment in coordinating DNA replication across the genome and have broad implications for our conceptualization of the role of multiscale chromatin architecture in regulating diverse cell nuclear dynamics in space and time.

Suvakov, S, Bonner, E, Nikolic, V, Jerotic, D, Simic, TP, Garovic, VD, Lopez-Campos, G & McClements, L 2020, 'Overlapping pathogenic signalling pathways and biomarkers in preeclampsia and cardiovascular disease', Pregnancy Hypertension, vol. 20, pp. 131-136.
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Suvakov, S, Richards, C, Nikolic, V, Simic, T, McGrath, K, Krasnodembskaya, A & McClements, L 2020, 'Emerging Therapeutic Potential of Mesenchymal Stem/Stromal Cells in Preeclampsia', Current Hypertension Reports, vol. 22, no. 5, pp. 37-37.
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Purpose of Review Preeclampsia is a dangerous pregnancy condition affecting both the mother and offspring. It is a multifactorial disease with poorly understood pathogenesis, lacking effective treatments. Maternal immune response, inflammation and oxidative stress leading to endothelial dysfunction are the most prominent pathogenic processes implicated in preeclampsia development. Here, we give a detailed overview of the therapeutic applications and mechanisms of mesenchymal stem/stromal cells (MSCs) as a potential new treatment for preeclampsia. Recent Findings MSCs have gained growing attention due to low immunogenicity, easy cultivation and expansion in vitro. Accumulating evidence now suggests that MSCs act primarily through their secretomes facilitating paracrine signalling that leads to potent immunomodulatory, pro-angiogenic and regenerative therapeutic effects. Summary MSCs have been studied in different animal models of preeclampsia demonstrating promising result, which support further investigations into the therapeutic effects and mechanisms of MSC-based therapies in preeclampsia, steering these therapies into clinical trials.

Syed, MS, Mirakhorli, F, Marquis, C, Taylor, RA & Warkiani, ME 2020, 'Particle movement and fluid behavior visualization using an optically transparent 3D-printed micro-hydrocyclone', Biomicrofluidics, vol. 14, no. 6, pp. 064106-064106.
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A hydrocyclone is a macroscale separation device employed in various industries, with many advantages, including high-throughput and low operational costs. Translating these advantages to microscale has been a challenge due to the microscale fabrication limitations that can be surmounted using 3D printing technology. Additionally, it is difficult to simulate the performance of real 3D-printed micro-hydrocyclones because of turbulent eddies and the deviations from the design due to printing resolution. To address these issues, we propose a new experimental method for the direct observation of particle motion in 3D printed micro-hydrocyclones. To do so, wax 3D printing and soft lithography were used in combination to construct a transparent micro-hydrocyclone in a single block of polydimethylsiloxane. A high-speed camera and fluorescent particles were employed to obtain clear in situ images and to confirm the presence of the vortex core. To showcase the use of this method, we demonstrate that a well-designed device can achieve a 95% separation efficiency for a sample containing a mixture of (desired) stem cells and (undesired) microcarriers. Overall, we hope that the proposed method for the direct visualization of particle trajectories in micro-hydrocyclones will serve as a tool, which can be leveraged to accelerate the development of micro-hydrocyclones for biomedical applications.

Tang, Z, Liu, Y, Ni, D, Zhou, J, Zhang, M, Zhao, P, Lv, B, Wang, H, Jin, D & Bu, W 2020, 'Biodegradable Nanoprodrugs: “Delivering” ROS to Cancer Cells for Molecular Dynamic Therapy', Advanced Materials, vol. 32, no. 4, pp. 1904011-1904011.
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AbstractBiodegradable nanoprodrugs, inheriting the antitumor effects of chemotherapy drugs and overcoming the inevitable drawback of side effects on normal tissues, hold promise as next‐generation cancer therapy candidates. Biodegradable nanoprodrugs of transferrin‐modified MgO2 nanosheets are developed to selectively deliver reactive oxygen species to cancer cells for molecular dynamic therapy strategy. The nanosheets favor the acidic and low catalase activity tumor microenvironment to react with proton and release nontoxic Mg2+. This reaction simultaneously produces abundant H2O2 to induce cell death and damage the structure of transferrin to release Fe3+, which will react with H2O2 to produce highly toxic ·OH to kill tumor cells.

Tripathi, A, Kruk, S, Shang, Y, Zhou, J, Kravchenko, I, Jin, D & Kivshar, Y 2020, 'Topological nanophotonics for photoluminescence control', Nanophotonics, vol. 10, no. 1, pp. 435-441.
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AbstractObjectivesRare-earth-doped nanocrystals are emerging light sources that can produce tunable emissions in colours and lifetimes, which has been typically achieved in chemistry and material science. However, one important optical challenge – polarization of photoluminescence – remains largely out of control by chemistry methods. Control over photoluminescence polarization can be gained via coupling of emitters to resonant nanostructures such as optical antennas and metasurfaces. However, the resulting polarization is typically sensitive to position disorder of emitters, which is difficult to mitigate.MethodsRecently, new classes of disorder-immune optical systems have been explored within the framework of topological photonics. Here we explore disorder-robust topological arrays of Mie-resonant nanoparticles for polarization control of photoluminescence of nanocrystals.ResultsWe demonstrate polarized emission from rare-earth-doped nanocrystals governed by photonic topological edge states supported by zigzag arrays of dielectric resonators. We verify the topological origin of polarized photoluminescence by comparing emission from nanoparticles coupled to topologically trivial and nontrivial arrays of nanoresonators.ConclusionsWe expect that our results may open a new direction in the study of topology-enable emission properties of topological edge states in many photonic systems.

Vasilescu, SA, Bazaz, SR, Jin, D, Shimoni, O & Warkiani, ME 2020, '3D printing enables the rapid prototyping of modular microfluidic devices for particle conjugation', Applied Materials Today, vol. 20, pp. 100726-100726.
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© 2020 Elsevier Ltd Antibody micro/nano-particle conjugates have proven to be essential tools in many diagnostic and nanomedicine applications. However, their production with homogenous coating and in a continuous fashion remains a tedious, labor-intensive, and costly process. In this regard, 3D micromixer-based microfluidic devices offer significant advantages over existing methods, where manipulating the flow in three dimensions increases fluid contact area and surface disruption, facilitating efficient mixing. While conventional softlithography is capable of fabricating simple 2D micromixers, complications arise when processing 3D structures. In this paper, we report the direct fabrication of a 3D complex microchannel design using additive manufacturing for the continuous conjugation of antibodies onto particle surfaces. This method benefits from a reduction in cost and time (from days to hours), simplified fabrication process, and limited post-processing. The flexibility of direct 3D printing allows quick and easy tailoring of design features to facilitate the production of micro and nanoparticles conjugated with functional antibodies in a continuous mixing process. We demonstrate that the produced antibody-functionalized particles retain their functionality by a firm and specific interaction with antigen presenting cells. By connecting 3D printed micromixers across the conjugation process, we illustrate the role of 3D printed microchannels as modularized components. The 3D printing method we report enables a broad spectrum of researchers to produce complex microfluidic geometries within a short time frame.

Wang, M, Chang, M, Chen, Q, Wang, D, Li, C, Hou, Z, Lin, J, Jin, D & Xing, B 2020, 'Au2Pt-PEG-Ce6 nanoformulation with dual nanozyme activities for synergistic chemodynamic therapy / phototherapy', Biomaterials, vol. 252, pp. 120093-120093.
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Although synergistic therapy for tumors has displayed significant promise for effective treatment of cancer, developing a simple and effective strategy to build a multi-functional nanoplatform is still a huge challenge. By virtue of the characteristics of tumor microenvironment, such as hypoxia, slight acidity and H2O2 overexpression, Au2Pt-PEG-Ce6 nanoformulation is constructed for collaborative chemodynamic/phototherapy of tumors. Specifically, the Au2Pt nanozymes with multiple functions are synthesized in one step at room temperature. The photosensitizer chlorin e6 (Ce6) is covalently linked to Au2Pt nanozymes for photodynamic therapy (PDT). Interestingly, the Au2Pt nanozymes possess catalase- and peroxidase-like activities simultaneously, which not only can generate O2 for relaxation of tumor hypoxia and enhancement of PDT efficiency but also can produce ∙OH for chemodynamic therapy (CDT). In addition, the high photothermal conversion efficiency (η = 31.5%) of Au2Pt-PEG-Ce6 nanoformulation provides the possibility for photoacoustic (PA) and photothermal (PT) imaging guided photothermal therapy (PTT). Moreover, the presence of high-Z elements (Au and Pt) in Au2Pt-PEG-Ce6 nanoformulation endows it with the ability to act as an X-ray computed tomography (CT) imaging contrast agent. All in all, the Au2Pt-PEG-Ce6 exhibits great potential in multimodal imaging-guided synergistic PTT/PDT/CDT with remarkably tumor specificity and enhanced therapy.

Weilin, M, Xu, H, Yang, L, Wenqi, C, Huanyu, W, Wentao, Z, Dayong, J, Wenchuan, W, Dansong, W, Tiantao, K, Lei, Z, Wenhui, L & Xuefeng, X 2020, 'Propensity score-matched analysis of clinical outcome after enucleation versus regular pancreatectomy in patients with small non-functional pancreatic neuroendocrine tumors', Pancreatology, vol. 20, no. 2, pp. 169-176.
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Wen, Q, Jia, P, Cao, L, Li, J, Quan, D, Wang, L, Zhang, Y, Lu, D, Jiang, L & Guo, W 2020, 'Electric‐Field‐Induced Ionic Sieving at Planar Graphene Oxide Heterojunctions for Miniaturized Water Desalination', Advanced Materials, vol. 32, no. 16, p. e1903954.
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AbstractLayered graphene oxide membranes (GOMs) offer a unique platform for precise sieving of small ions and molecules due to controlled sub‐nanometer‐wide interlayer distance and versatile surface chemistry. Pristine and chemically modified GOMs effectively block organic dyes and nanoparticles, but fail to exclude smaller ions with hydrated diameters less than 9 Å. Toward sieving of small inorganic salt ions, a number of strategies are proposed by reducing the interlayer spacing down to merely several angstroms. However, one critical challenge for such compressed GOMs is the extremely low water flux (<0.1 Lm−2 h−1 bar−1) that prevents these innovative nanomaterials from being used in real‐world applications. Here, a planar heterogeneous graphene oxide membrane (PHGOM) with both nearly perfect salt rejection and high water flux is reported. Horizontal ion transport through oppositely charged GO multilayer lateral heterojunction exhibits bi‐unipolar transport behavior, blocking the conduction of both cations and anions. Assisted by a forward electric field, salt concentration is depleted in the near‐neutral transition area of the PHGOM. In this situation, deionized water can be extracted from the depletion zone. Following this mechanism, a high rejection rate of 97.0% for NaCl and water flux of 1529 Lm−2 h−1 bar−1 at the outlet via an inverted T‐shaped water extraction mode are achieved.

Wen, S, Liu, Y, Wang, F, Lin, G, Zhou, J, Shi, B, Suh, YD & Jin, D 2020, 'Nanorods with multidimensional optical information beyond the diffraction limit', Nature Communications, vol. 11, no. 1.
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AbstractPrecise design and fabrication of heterogeneous nanostructures will enable nanoscale devices to integrate multiple desirable functionalities. But due to the diffraction limit (~200 nm), the optical uniformity and diversity within the heterogeneous functional nanostructures are hardly controlled and characterized. Here, we report a set of heterogeneous nanorods; each optically active section has its unique nonlinear response to donut-shaped illumination, so that one can discern each section with super-resolution. To achieve this, we first realize an approach of highly controlled epitaxial growth and produce a range of heterogeneous structures. Each section along the nanorod structure displays tunable upconversion emissions, in four optical dimensions, including color, lifetime, excitation wavelength, and power dependency. Moreover, we demonstrate a 210 nm single nanorod as an extremely small polychromatic light source for the on-demand generation of RGB photonic emissions. This work benchmarks our ability toward the full control of sub-diffraction-limit optical diversities of single heterogeneous nanoparticles.

Xiang, Y, Basirun, C, Chou, J, Warkiani, ME, Török, P, Wang, Y, Gao, S & Kabakova, IV 2020, 'Background-free fibre optic Brillouin probe for remote mapping of micromechanics', Biomedical Optics Express, vol. 11, no. 11, pp. 6687-6687.
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Brillouin spectroscopy is a century-old technique that has recently receivedrenewed interest, as modern instrumentation has transformed it into a powerfulcontactless and label-free probe of micromechanical properties for biomedicalapplications. In particular, to fully harness the non-contact andnon-destructive nature of Brillouin imaging, there is strong motivation todevelop a fibre-integrated device and extend the technology into the domain ofin vivo and in situ operation, such as for medical diagnostics. This workpresents the first demonstration of a fibre optic Brillouin probe that iscapable of mapping the mechanical properties of a tissue-mimicking phantom.This is achieved through combination of miniaturised optical design, advancedhollow-core fibre fabrication and high-resolution 3D printing. The protypeprobe is compact, background-free and possesses the highest collectionefficiency to date, thus provides the foundation of a fibre-based Brillouindevice for remote in situ measurements in challenging and otherwisedifficult-to-reach environments, for biomedical, material science andindustrial applications.

Xu, J, Zhou, J, Chen, Y, Yang, P & Lin, J 2020, 'Lanthanide-activated nanoconstructs for optical multiplexing', Coordination Chemistry Reviews, vol. 415, pp. 213328-213328.
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© 2020 Elsevier B.V. Lanthanide-activated nanoconstructs (LANCs) have attracted a great attention in optical multiplexing. This review, is the integrated conclusion of reported LANCs being applied as signal codes in optical multiplexing during the past decade. An introduction of the basic concepts and theories about optical multiplexing technique is provided initially. On top of that, the optical advantages of LANCs is comprehensively summarized to illuminate the superiority of LANCs over conventional materials in optical multiplexing. It particularly focuses on the near-infrared (NIR) light excited upconversion (UC) and downshifting (DS) nanomaterials, concerning their diverse and narrow excitation and emission wavelengths, tunable emission lifetime (μs-ms range) and intensity. Subsequently, the exploitation of UC- or DS-emitting LANCs as encoding tools in multiplexing based on various optical parameters is described in detail, including emission wavelength, intensity (ratiometric), temporal lifetime (τ), phase angle and excitation power. Notably, these parameters can not only work by themselves to be encoders, but also ally with each other to remarkably enrich the encoding capability of LANCs. In addition, the attractive dual-modal DS and UC emission-based multiplexing is emphasized. Finally, a summary of the challenges faced by LANCs-based optical multiplexing and a discussion of their future development is given.

Xu, L, Li, J, Lu, K, Wen, S, Chen, H, Shahzad, MK, Zhao, E, Li, H, Ren, J, Zhang, J & Liu, L 2020, 'Sub-10 nm NaNdF₄ Nanoparticles as Near-Infrared Photothermal Probes with Self-Temperature Feedback', ACS Applied Nano Materials, vol. 3, no. 3, pp. 2517-2526.
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Xu, Y, WANG, D, Kuang, T, Wu, W, Xu, X, Jin, D, Zhang, H, Zhong, S, Wang, Y & Lou, W 2020, 'Nanomaterials augmented LDI-TOF-MS for pancreatic ductal adenocarcinoma diagnosis and classification.', Journal of Clinical Oncology, vol. 38, no. 15_suppl, pp. e16761-e16761.
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e16761 Background: Pancreatic ductal adenocarcinoma (PAAD) is one type of cancer with poor prognosis. Although CA 19-9 was the most common serological marker for cancer screening and surveillance after treatment, there are still unignorable limitations, including low sensitivity, possible false-negatives/positives owing to confounding conditions. Reliable non-invasive diagnostics is in urgent need. As PAAD is increasingly considered as a metabolic disorder, serum metabolite profiling is becoming critical to reveal important cancer-related bioinformation. This work proposes a novel LDI-TOF-MS technique for PAAD screening and diagnosis. Methods: An LDI-TOF-MS platform was established for cancer screening. All mass spectrum was collected within a mass range of 100 to 1,100 Da, while the spectra were manually examined using the FlexAnalysis 3.4 software (Bruker Daltonics, Bremen, Germany). In a typical process, 0.5 uL of serum samples were spotted on a polished steel target plate MTP 384 and air-dried followed by another 1 uL of GNS or SiNW nanomaterials. The spectra were then acquired in the reflection positive mode with smartbeam-II laser at 355 nm with laser frequency of 1,000 Hz. A random walk of 25 shots at raster spot and 20 different spots were measured for each individual sample, therefore, 500 satisfactory shots were obtained. Results: By taking advantage of 3D nanostructures and machine learning, we applied proposed approach to 94 patients with PAAD, as well as 203 healthy controls (Table). The results demonstrated an average sensitivity of 99% and a specificity over 98% in detecting cancers. 11 of 94 PAAD patients (11.70%) were CA 19-9 negative (CA19-9 < 37U/ml, stage I n = 2, stage II n = 7, stage III n = 1 and stage IV n = 1). LDI-TOF-MS recognized almost all CA 19-9-negative PAAD. The sensitivity and specificity were obviously superior to CA 19-9 in PAAD: only 1 of 94 PAAD (1.06%) were misclassified as healthy con...

Yang, L, Chen, X, Ma, P, Jin, D, Zhou, J, He, H, Cheng, Z & Lin, J 2020, 'Upconversion nanoparticles coated with molecularly imprinted polymers for specific sensing', Dalton Transactions, vol. 49, no. 47, pp. 17200-17206.
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The development of fluorescent sensors based on lanthanide-doped luminescent nanoparticles has increased their application in biomarker detection.

Yang, X, Yang, Z, Wu, Z, He, Y, Shan, C, Chai, P, Ma, C, Tian, M, Teng, J, Jin, D, Yan, W, Das, P, Qu, J & Xi, P 2020, 'Mitochondrial dynamics quantitatively revealed by STED nanoscopy with an enhanced squaraine variant probe', Nature Communications, vol. 11, no. 1.
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AbstractMitochondria play a critical role in generating energy to support the entire lifecycle of biological cells, yet it is still unclear how their morphological structures evolve to regulate their functionality. Conventional fluorescence microscopy can only provide ~300 nm resolution, which is insufficient to visualize mitochondrial cristae. Here, we developed an enhanced squaraine variant dye (MitoESq-635) to study the dynamic structures of mitochondrial cristae in live cells with a superresolution technique. The low saturation intensity and high photostability of MitoESq-635 make it ideal for long-term, high-resolution (stimulated emission depletion) STED nanoscopy. We performed time-lapse imaging of the mitochondrial inner membrane over 50 min (3.9 s per frame, with 71.5 s dark recovery) in living HeLa cells with a resolution of 35.2 nm. The forms of the cristae during mitochondrial fusion and fission can be clearly observed. Our study demonstrates the emerging capability of optical STED nanoscopy to investigate intracellular physiological processes with nanoscale resolution for an extended period of time.

Yu, TT, Kuppusamy, R, Yasir, M, Hassan, MM, Alghalayini, A, Gadde, S, Deplazes, E, Cranfield, C, Willcox, MDP, Black, DS & Kumar, N 2020, 'Design, Synthesis and Biological Evaluation of Biphenylglyoxamide-Based Small Molecular Antimicrobial Peptide Mimics as Antibacterial Agents', International Journal of Molecular Sciences, vol. 21, no. 18, pp. 6789-6789.
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There has been an increasing interest in the development of antimicrobial peptides (AMPs) and their synthetic mimics as a novel class of antibiotics to overcome the rapid emergence of antibiotic resistance. Recently, phenylglyoxamide-based small molecular AMP mimics have been identified as potential leads to treat bacterial infections. In this study, a new series of biphenylglyoxamide-based small molecular AMP mimics were synthesised from the ring-opening reaction of N-sulfonylisatin bearing a biphenyl backbone with a diamine, followed by the conversion into tertiary ammonium chloride, quaternary ammonium iodide and guanidinium hydrochloride salts. Structure–activity relationship studies of the analogues identified the octanesulfonyl group as being essential for both Gram-positive and Gram-negative antibacterial activity, while the biphenyl backbone was important for Gram-negative antibacterial activity. The most potent analogue was identified to be chloro-substituted quaternary ammonium iodide salt 15c, which possesses antibacterial activity against both Gram-positive (MIC against Staphylococcus aureus = 8 μM) and Gram-negative bacteria (MIC against Escherichia coli = 16 μM, Pseudomonas aeruginosa = 63 μM) and disrupted 35% of pre-established S. aureus biofilms at 32 μM. Cytoplasmic membrane permeability and tethered bilayer lipid membranes (tBLMs) studies suggested that 15c acts as a bacterial membrane disruptor. In addition, in vitro toxicity studies showed that the potent compounds are non-toxic against human cells at therapeutic dosages.

Zhand, S, Razmjou, A, Azadi, S, Bazaz, SR, Shrestha, J, Jahromi, MAF & Warkiani, ME 2020, 'Metal–Organic Framework-Enhanced ELISA Platform for Ultrasensitive Detection of PD-L1', ACS Applied Bio Materials, vol. 3, no. 7, pp. 4148-4158.
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© 2020 American Chemical Society. The programmed cell death ligand 1 (PD-L1) protein has emerged as a predictive cancer biomarker and sensitivity to immune checkpoint blockade-based cancer immunotherapies. Current technologies for the detection of protein-based biomarkers, including the enzyme-linked immunosorbent assay (ELISA), have limitations such as low sensitivity and limit of detection (LOD) in addition to degradation of antibodies in exposure to environmental changes such as temperature and pH. To address these issues, we have proposed a metal-organic framework (MOF)-based ELISA for the detection of the PD-L1. A protective coating based on Zeolitic Imidazolate Framework 8 (ZIF-8) MOF thin film and polydopamine-polyethylenimine (PDA-PEI) was introduced on an ELISA plate for the improvement of antibody immobilization. Sensitivity and LOD of the resulting platform were compared with a conventional ELISA kit, and the bioactivity of the antibody in the proposed immunoassay was investigated in response to various pH and temperature values. The LOD and sensitivity of the MOF-based PD-L1 ELISA were 225 and 15.12 times higher, respectively, compared with those of the commercial ELISA kit. The antibody@ZIF-8/PDA-PEI was stable up to 55 °C and the pH range 5-10. The proposed platform can provide sensitive detection for target proteins, in addition to being resistant to elevated temperature and pH. The proposed MOF-based ELISA has significant potential for the clinical and diagnostic studies.

Zhanghao, K, Liu, W, Li, M, Wu, Z, Wang, X, Chen, X, Shan, C, Wang, H, Chen, X, Dai, Q, Xi, P & Jin, D 2020, 'High-dimensional super-resolution imaging reveals heterogeneity and dynamics of subcellular lipid membranes', Nature Communications, vol. 11, no. 1.
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AbstractLipid membranes are found in most intracellular organelles, and their heterogeneities play an essential role in regulating the organelles’ biochemical functionalities. Here we report a Spectrum and Polarization Optical Tomography (SPOT) technique to study the subcellular lipidomics in live cells. Simply using one dye that universally stains the lipid membranes, SPOT can simultaneously resolve the membrane morphology, polarity, and phase from the three optical-dimensions of intensity, spectrum, and polarization, respectively. These high-throughput optical properties reveal lipid heterogeneities of ten subcellular compartments, at different developmental stages, and even within the same organelle. Furthermore, we obtain real-time monitoring of the multi-organelle interactive activities of cell division and successfully reveal their sophisticated lipid dynamics during the plasma membrane separation, tunneling nanotubules formation, and mitochondrial cristae dissociation. This work suggests research frontiers in correlating single-cell super-resolution lipidomics with multiplexed imaging of organelle interactome.

Zheng, P, Su, QP, Jin, D, Yu, Y & Huang, X-F 2020, 'Prevention of Neurite Spine Loss Induced by Dopamine D2 Receptor Overactivation in Striatal Neurons', Frontiers in Neuroscience, vol. 14.
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Psychosis has been considered a disorder of impaired neuronal connectivity. Evidence for excessive formation of dopamine D2 receptor (D2R) - disrupted in schizophrenia 1 (DISC1) complexes has led to a new perspective on molecular mechanisms involved in psychotic symptoms. Here, we investigated how excessive D2R-DISC1 complex formation induced by D2R agonist quinpirole affects neurite growth and dendritic spines in striatal neurons. Fluorescence resonance energy transfer (FRET), stochastic optical reconstruction microscopy (STORM), and cell penetrating-peptide delivery were used to study the cultured striatal neurons from mouse pups. Using these striatal neurons, our study showed that: (1) D2R interacted with DISC1 in dendritic spines, neurites and soma of cultured striatal neurons; (2) D2R and DISC1 complex accumulated in clusters in dendritic spines of striatal neurons and the number of the complex were reduced after application of TAT-D2pep; (3) uncoupling D2R-DISC1 complexes by TAT-D2pep protected neuronal morphology and dendritic spines; and (4) TAT-D2pep prevented neurite and dendritic spine loss, which was associated with restoration of expression levels of synaptophysin and PSD-95. In addition, we found that Neuropeptide Y (NPY) and GSK3β were involved in the protective effects of TAT-D2pep on the neurite spines of striatal spiny projection neurons. Thus, our results may offer a new strategy for precisely treating neurite spine deficits associated with schizophrenia.

Zhou, J, Chizhik, AI, Chu, S & Jin, D 2020, 'Single-particle spectroscopy for functional nanomaterials', Nature, vol. 579, no. 7797, pp. 41-50.
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Tremendous progress in nanotechnology has enabled advances in the use of luminescent nanomaterials in imaging, sensing and photonic devices. This translational process relies on controlling the photophysical properties of the building block, that is, single luminescent nanoparticles. In this Review, we highlight the importance of single-particle spectroscopy in revealing the diverse optical properties and functionalities of nanomaterials, and compare it with ensemble fluorescence spectroscopy. The information provided by this technique has guided materials science in tailoring the synthesis of nanomaterials to achieve optical uniformity and to develop novel applications. We discuss the opportunities and challenges that arise from pushing the resolution limit, integrating measurement and manipulation modalities, and establishing the relationship between the structure and functionality of single nanoparticles.

Zhou, J, del Rosal, B, Jaque, D, Uchiyama, S & Jin, D 2020, 'Advances and challenges for fluorescence nanothermometry', Nature Methods, vol. 17, no. 10, pp. 967-980.
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Fluorescent nanothermometers can probe changes in local temperature in living cells and in vivo and reveal fundamental insights into biological properties. This field has attracted global efforts in developing both temperature-responsive materials and detection procedures to achieve sub-degree temperature resolution in biosystems. Recent generations of nanothermometers show superior performance to earlier ones and also offer multifunctionality, enabling state-of-the-art functional imaging with improved spatial, temporal and temperature resolutions for monitoring the metabolism of intracellular organelles and internal organs. Although progress in this field has been rapid, it has not been without controversy, as recent studies have shown possible biased sensing during fluorescence-based detection. Here, we introduce the design principles and advances in fluorescence nanothermometry, highlight application achievements, discuss scenarios that may lead to biased sensing, analyze the challenges ahead in terms of both fundamental issues and practical implementations, and point to new directions for improving this interdisciplinary field.

Khan, J, Sayyar, S, Paull, B & Innis, P 1970, '3D textile structures as electrophoresis platforms for selective delivery and separation of complex matrices', International Conference on Nanoscience and Nanotechnology, Brisbane, Australia.

Kulasinghe, A, Kapeleris, J, Kenny, L, Hughes, B, Warkiani, M, Vela, I, Thiery, J-P, O'Byrne, K & Punyadeera, C 1970, 'Abstract 3384: Characterization of the tumor microenvironment and liquid biopsy in head and neck and non-small cell lung cancer', Cancer Research, American Association for Cancer Research (AACR), pp. 3384-3384.
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Abstract Metastasis in cancer patients is reflected by measurable levels of circulating tumor cells (CTCs) in the blood of cancer patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumor burden of an individual patient. Recent advancements have shown that PD-1/PD-L1 immune checkpoint therapies have durable responses in a number of solid tumor types. Our study was designed to use multiple CTC enrichment platforms for the capture of CTCs and novel culture formulations for the ex vivo expansion of CTCs. Head and Neck cancer (n=350) and lung cancer (n=150) patients were recruited to investigate the prognostic role of CTCs. In parallel, a subset of HNC tumors were profiled using the NanoString GeoMx Digital Spatial Profiling (DSP) technology using a 44-plex antibody cocktail. We evaluated multiple CTC isolation technologies (CellSearch, filtration, CD45 depletion, Spiral, Straight and novel microfluidic chip technology) using matched patient samples which showed that epitope-independent CTC isolation captured a greater proportion of CTCs. Molecular alterations present in the primary tissue were confirmed in the CTCs by 3D-DNA FISH (EGFR-amplification, ALK-translocations). In HNC, the presence of CTC clusters associated with the development of distant metastatic disease (P=0.0313). HNC CTC-positive patients had shorter progression free survival (Hazard ratio [HR]: 4.946; 95% [CI]:1.571-15.57; P=0.0063) and PD-L1-positive CTCs were found to be significantly associated with worse outcome ([HR]:5.159; 95% [CI]:1.011-26.33; P=0.0485). In a proof of principle study, we were able to demonstrate for the first time, short-term patient derived CTC cultures outside the patient's body and exome sequencing of CTCs cultures confirmed the presence of mutational signatures consistent with The Cancer Genome Atlas (T...

Kulasinghe, A, Kapeleris, J, Kenny, L, Warkiani, M, Vela, I, Thiery, JP, O'Byrne, K & Punyadeera, C 1970, 'Isolation, characterization, and expansion of circulating tumor cells in head and neck cancers', CLINICAL CANCER RESEARCH, AACR-AHNS Head and Neck Conference - Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research, AMER ASSOC CANCER RESEARCH, TX, Austin, pp. 31-31.

Kulasinghe, A, O’Leary, C, Ladwa, R, Warkiani, M & O’byrne, K 1970, '43 Highly multiplexed digital spatial profiling of the tumor microenvironment of non-small-cell lung cancer (NSCLC)', Regular and young investigator award abstracts, 35th Anniversary Annual Meeting (SITC 2020), BMJ Publishing Group Ltd.
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Li, M, Li, Y, Liu, W, Lal, A, Jiang, S, Jin, D, Yang, H, Wang, S, Zhanghao, K & Xi, P 1970, 'Structured illumination microscopy using digital micromirror device and coherent light source', Optics in Health Care and Biomedical Optics X, Optics in Health Care and Biomedical Optics X, SPIE.
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Liu, Y, Wang, F, Lu, H, Wen, S, Chen, C, Shan, X, Fang, G & Jin, D 1970, 'Deep tissue super-resolution microscopy mapping single nanoparticles inside multicellular spheroids', Enhanced Spectroscopies and Nanoimaging 2020, Enhanced Spectroscopies and Nanoimaging 2020, SPIE.
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Organoid, an in vitro model to study cell behaviours in a living organism, holds great potential for human cellular biology study, especially in disease pathology, drug delivery and drug efficacy trials. However, it remains challenging to track subcellular features inside organoid, as organoid are clusters of high-density cells that highly scatters and absorbs both excitation and emission light. Here we report a strategy on nanoscopy that applying “non-diffractive” beam and near-infrared imaging probe to minimize the light scattering and absorption inside scattering bio-tissue. Using a single Bessel-doughnut beam excitation from a 980nm diode laser and detecting at 800nm, we achieved a near-infrared, “non-diffractive” nanoscopy with high resolution under-diffractive limit in water solution. We further demonstrate that this method can image single upconversion nanoparticles inside spheroids, as deep as half-100µm, with resolution of 113nm. This method provides simple solution to inspect inter-and intra-cellular trafficking and drug release of single nanoparticles in 3D biological systems.

Mahmodi, H, Piloni, A, Utama, R & Kabakova, I 1970, '3D mechanical mapping of bioprinted hydrogel models by Brillouin microscopy', 14th Pacific Rim Conference on Lasers and Electro-Optics (CLEO PR 2020), Conference on Lasers and Electro-Optics/Pacific Rim, Optica Publishing Group.
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We apply Brillouin microscopy to characterize micromechanical properties of 3D bioprinted hydrogel constructs. Non-contact and label-free mapping of constructs’ mechanical properties in situ provides invaluable insight into spatial distribution and swelling behavior of hydrogels.

McClements, L, Rayner, B, Alqudah, A, Grieve, D & Robson, T 1970, 'FKBPL, a novel player in cardiac ischaemia and fibrosis', Journal of Molecular and Cellular Cardiology, International Society for Heart Research, Elsevier BV, Beijing, pp. 5-5.
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Background: FKBPL is a critical regulator of physiological and pathological angiogenesis. In an FKBPL knockdown mouse model, impaired cardiac and vascular function were previously observed. In this study, we investigated the role of FKBPL in ischaemic heart disease and fibrosis, which are the leading causes of mortality in people with cardiovascular disease, using relevant in vivo and in vitro experimental models. Methods: FKBPL mRNA expression was determined by qPCR in rat hearts 48 h after ischaemia/reperfusion (I/R) compared to sham control. In complementary experiments, the human cardiac fibroblast cell line, T0446, was exposed to acute hypoxia (2% O2) or TGF-β (10 ng/mL) for 24 h before RNA lysates were collected. In addition, FKBPL was overexpressed in human aortic endothelial cells (HAOECs), cells plated in Matrigel in the presence of hypoxia (1%) or normoxia for 24 h, and tubule network length quantified. Depending on the number of groups compared t-test, two-way or one-way ANOVA with Tukey’s posthoc test were performed. Results: Cardiac FKBPL mRNA expression was significantly downregulated in our rat I/R model versus sham (n=4, p≤0.05). Interestingly, following exposure of cardiac fibroblasts to either hypoxia (2%) or TGF-β for 24 h there was a significant increase in FKBPL mRNA expression versus normoxia (n=3, in triplicates, p≤0.01) or vehicle control (n=2, in triplicates, p≤0.01), respectively. Furthermore, whilst overexpression of FKBPL in HAOECs reduced length of the tubular network in normoxia (n=6, p<0.001), under hypoxic conditions FKBPL overexpression restored the tubule network so that it was comparable to that observed in normoxia with control vector (n=6, p≤0.01). Conclusion: FKBPL levels appears to be associated with cardiac ischaemia and fibrosis, activated by relevant in vitro stimuli, and to regulate cardiac angiogenic responses. Therefore, changes in FKBPL expression could be explored further in these conditions as a novel pathogenic ...

O'Byrne, KJ, Kapeleris, J, Kulasinghe, A, Warkiani, ME, O'Leary, CG, Ladwa, R, Vela, I, Leo, P, Sternes, P & Punyadeera, C 1970, 'Culture of circulating tumour cells derived from non-small cell lung cancer.', JOURNAL OF CLINICAL ONCOLOGY, Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), LIPPINCOTT WILLIAMS & WILKINS, ELECTR NETWORK.

Richard, C, Chhor, M, Glenn Ong, ZH, Bubb, K & McClements, L 1970, 'Cardiac health in the reduced uterine perfusion pressure rat model of preeclampsia', Journal of Paediatrics and Child Health, Wiley, Sydney.
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Background: Preeclampsia (PE) is a life-threatening disorder without treatment options except delivery of the baby and the placenta, often pre-term. PE increases the risk of subsequent cardiovascular complications in both mothers and offspring. In this study, our aim was to investigate the associated cardiac health in the reduced uterine perfusion pressure (RUPP) rat model of PE. Methods: The RUPP model was induced in pregnant rats (GD14) by applying silver clips around aorta and uterine arteries reducing the blood flow to the uterus by ~40%. On GD19, echocardiography was performed and blood pressure measured. At the end of the experiment, maternal organs were harvested and processed for downstream analyses. Results: Whilst RUPP rats had increased systolic pressure (sham 113 ± 1 vs RUPP 125 ± 2 mmHg, n=8, P<0.001), diastolic blood pressure was substantially augmented and in the hypertensive range (sham 88 ± 2 vs RUPP 102 ± 2 mmHg, n=8, P<0.0001). Left ventricular mass was greater in RUPP females (n=6-7, P=0.03), however wet heart weight to body weight ratio did not reach statistical significance (sham 0.30 ± 0.01 vs RUPP 0.33 ± 0.01, n=6, P=0.07). Left ventricular systolic function remained unaffected. Also increased expression of anti-angiogenic FKBPL mRNA (0.85 ± 0.15, n=6 vs 1.82 ± 0.27, n=6) was observed in the RUPP hearts. Conclusions: Despite no difference in cardiac systolic function in the RUPP model, early signs of restricted angiogenesis and greater augmentation of diastolic pressure suggest that diastolic dysfunction may be occurring, which will be investigated in future studies.

Sofela, S, Sahloul, S, Kwon, T, Han, J, Warkiani, ME & Song, YA 1970, 'Synchronization of C. Elegans through high-throughput separation of eggs in a spiral microfluidic chip', 21st International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2017, pp. 1100-1101.
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In this work, we report a high-throughput sorting of C. elegans embryos from a mixed-age worm population in a spiral microfluidic chip for synchronization. Using inertial forces in the spiral chip, C. elegans eggs could efficiently be focused along the inner channel wall and separated out with high sorting efficiency and purity.

Syed, MS, Rafeie, M, Vandamme, D, Henderson, R & Warkiani, ME 1970, 'Selective separation of microalgae cells using inertial microfluidics', 21st International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2017, pp. 1375-1376.
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Microalgae are considered to be the most promising new source of biomass to meet world's growing demands. However, microalgal cultures are often contaminated, by bacteria or invading diatoms. The invasion of diatoms in a cell culture results in an overall decrease of biomass productivity and quality. This work demonstrates the application of inertial microfluidics for the selective separation and sorting of green microalgae cells from diatoms to obtain monocultures, at optimum conditions.

Xu, Y, Wang, D, Kuang, T, Wu, W, Xu, X, Jin, D, Zhang, H, Zhong, S, Wang, Y & Lou, W 1970, 'Nanomaterials augmented LDI-TOF-MS for pancreatic ductal adenocarcinoma diagnosis and classification.', JOURNAL OF CLINICAL ONCOLOGY, Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), LIPPINCOTT WILLIAMS & WILKINS, ELECTR NETWORK.

Alqudah, A, Eastwood, K-A, Jerotic, D, Todd, N, Hoch, D, McNally, R, Obradovic, D, Dugalic, S, Hunter, AJ, Holmes, VA, McCance, DR, Young, IS, Watson, CJ, Robson, T, Desoye, G, Grieve, DJ & McClements, L 2020, 'FKBPL and SIRT-1, key angiogenesis proteins, are downregulated by diabetes in pregnancy', Cold Spring Harbor Laboratory.
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Chen, C, Liu, B, Liu, Y, Liao, J, Shan, X, Wang, F & Jin, D 2020, 'Heterochromatic nonlinear optical responses in upconversion nanoparticles for point spread function engineering'.

Chen, H, Chhor, M, Rayner, B, McGrath, K & McClements, L 2020, 'Diagnostics and prognostic potential of current biomarkers in heart failure with preserved ejection fraction: a systematic review and meta-analysis', Cold Spring Harbor Laboratory.
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Li, Y, Xue, B, Zhang, L, Su, QP, Zhang, M, Long, H, Wang, Y, Jin, Y, Hou, Y, Cao, Y, Li, G & Sun, Y 2020, 'Transcription-coupled structural dynamics of topologically associating domains regulate replication origin efficiency', Cold Spring Harbor Laboratory.
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Liu, B, Chen, C, Di, X, Liao, J, Wen, S, Su, QP, Shan, X, Xu, Z-Q, Ju, LA, Wang, F & Jin, D 2020, 'Upconversion nonlinear structured illumination microscopy', arXiv.
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Peng, H, Shi, X, Zuo, Y, Zhai, P, Shen, J, Yang, Y, Gao, Z, Liao, M, Wang, J, Xu, X, Tong, Q, Zhang, B, Sun, X, Zhang, L, Pei, Q, Jin, D & Chen, P 2020, 'Large-area display textiles integrated with functional systems', Research Square Platform LLC.
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Sadraeian, M, Bahou, C, da Cruz, EF, Janini, LMR, Sobhie Diaz, R, W. Boyle, R, Chudasama, V & Eduardo Gontijo Guimarães, F 2020, 'Photoimmunotherapy Using Cationic and Anionic Photosensitizer-Antibody Conjugates Against HIV Env-Expressing Cells', MDPI AG.
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Su, Q, Wei, H-L, Wang, S, Chen, C, Ming, G, Su, Y, Wang, H, Chen, Z & Jin, D 2020, 'Upconverted excitation energy lock-in for deep-ultraviolet enhancement', Research Square Platform LLC.
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Abstract Photon upconversion of near-infrared (NIR) irradiation into deep-ultraviolet (UV) emission offers many exciting opportunities for drug release in deep tissues, photodynamic therapy, solid-state lasing, energy storage, and photocatalysis. However, NIR-to-deep-UV upconversion remains a daunting challenge due to low quantum efficiency. Here, we report an unusual six-photon upconversion process in Gd3+/Tm3+-codoped nanoparticles comprising a heterogeneous, core-multishell nanostructure. This multishell design efficiently suppresses energy consumption induced by interior energy traps, maximizes cascade sensitizations of the NIR excitation, and promotes upconverted deep-UV emission from high-lying excited states. We released the intense six-photon-upconverted UV emissions at 253 nm under 808-nm excitation. This work provides new insight into mechanistic understanding of the upconversion process within the heterogeneous architecture, while offering exciting opportunities for developing nanoscale deep-UV emitters that can be remotely controlled in deep tissues upon NIR illumination.

Tripathi, A, Kruk, S, Shang, Y, Zhou, J, Kravchenko, I, Jin, D & Kivshar, Y 2020, 'Topological nanophotonics for photoluminescence control'.