Publications

Chen, C, Liao, J & Jin, D 2021, 'Lanthanide-Doped Upconversion Nanoparticles for Super-Resolution Imaging' in Phosphor Handbook, CRC Press, pp. 247-284.
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Du, W, Di, X & Su, QP 2021, 'Studying Mitochondrial Network Formation by In Vivo and In Vitro Reconstitution Assay' in Methods in Molecular Biology, Springer US, pp. 333-341.
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Tripathi, A, Kruk, S, Shang, Y, Zhou, J, Kravchenko, I, Jin, D & Kivshar, Y 2021, 'Topological nanophotonics for photoluminescence control' in Frontiers in Optics and Photonics, De Gruyter, pp. 447-454.
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Objectives: Rare-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. Methods: Recently, 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. Results: We 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. Conclusions: We 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.

Aboulkheyr Es, H, Bigdeli, B, Zhand, S, Aref, AR, Thiery, JP & Warkiani, ME 2021, 'Mesenchymal stem cells induce PD‐L1 expression through the secretion of CCL5 in breast cancer cells', Journal of Cellular Physiology, vol. 236, no. 5, pp. 3918-3928.
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AbstractVarious factors in the tumor microenvironment (TME) regulate the expression of PD‐L1 in cancer cells. In TME, mesenchymal stem cells (MSCs) play a crucial role in tumor progression, metastasis, and drug resistance. Emerging evidence suggests that MSCs can modulate the immune‐suppression capacity of TME through the stimulation of PD‐L1 expression in various cancers; nonetheless, their role in the induction of PD‐L1 in breast cancer remained elusive. Here, we assessed the potential of MSCs in the stimulation of PD‐L1 expression in a low PD‐L1 breast cancer cell line and explored its associated cytokine. We assessed the expression of MSCs‐related genes and their correlation with PD‐L1 across 1826 breast cancer patients from the METABRIC cohort. After culturing an ER+/differentiated/low PD‐L1 breast cancer cells with MSCs conditioned‐medium (MSC‐CM) in a microfluidic device, a variety of in‐vitro assays was carried out to determine the role of MSC‐CM in breast cancer cells' phenotype plasticity, invasion, and its effects on induction of PD‐L1 expression. In‐silico analysis showed a positive association between MSCs‐related genes and PD‐L1 expression in various types of breast cancer. Through functional assays, we revealed that MSC‐CM not only prompts a phenotype switch but also stimulates PD‐L1 expression at the protein level through secretion of various cytokines, especially CCL5. Treatment of MSCs with cytokine inhibitor pirfenidone showed a significant reduction in the secretion of CCL5 and consequently, expression of PD‐L1 in breast cancer cells. We concluded that MSCs‐derived CCL5 may act as a PD‐L1 stimulator in breast cancer.

Aghlmandi, A, Nikshad, A, Safaralizadeh, R, Warkiani, ME, Aghebati-Maleki, L & Yousefi, M 2021, 'Microfluidics as efficient technology for the isolation and characterization of stem cells.', EXCLI J, vol. 20, pp. 426-443.
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The recent years have been passed with significant progressions in the utilization of microfluidic technologies for cellular investigations. The aim of microfluidics is to mimic small-scale body environment with features like optical transparency. Microfluidics can screen and monitor different cell types during culture and study cell function in response to stimuli in a fully controlled environment. No matter how the microfluidic environment is similar to in vivo environment, it is not possible to fully investigate stem cells behavior in response to stimuli during cell proliferation and differentiation. Researchers have used stem cells in different fields from fundamental researches to clinical applications. Many cells in the body possess particular functions, but stem cells do not have a specific task and can turn into almost any type of cells. Stem cells are undifferentiated cells with the ability of changing into specific cells that can be essential for the body. Researchers and physicians are interested in stem cells to use them in testing the function of the body's systems and solving their complications. This review discusses the recent advances in utilizing microfluidic techniques for the analysis of stem cells, and mentions the advantages and disadvantages of using microfluidic technology for stem cell research.

Ahmadi, VE, Butun, I, Altay, R, Bazaz, SR, Alijani, H, Celik, S, Warkiani, ME & Koşar, A 2021, 'The effects of baffle configuration and number on inertial mixing in a curved serpentine micromixer: Experimental and numerical study', Chemical Engineering Research and Design, vol. 168, pp. 490-498.
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Recently, the application of micromixers in microfluidic systems including chemical and biological assays has been widely accomplished. Passive micromixers, benefitting from the low-cost and a less-complex fabrication process, rely solely on their geometry. In particular, Dean vortices generated in curved microchannels enhance the mixing performance through chaotic advection. To improve the mixing performance at relatively low Reynolds numbers (i.e. 1 ≤ Re ≤ 50), this study introduces baffles into the side walls of curved serpentine micromixers with curvature angles of 280°, which constantly agitate, stretch and fold the fluids streams. Six different baffle configurations were designed and the effects of geometry and the number of baffles were investigated both experimentally and numerically. According to the experimental results, while the maximum outlet mixing index of the micromixer with no baffles was 0.61, that of the micromixer with quasi-rectangular baffles was 0.98 at a low Reynolds number of 20, indicating the major contribution of the generated chaotic advection by baffles. Furthermore, numerical results, which were in good agreement with experimental results, shed more light onto the mechanisms involved in micromixing in terms of the flow behavior and mixing index.

Akar, S, Taheri, A, Bazaz, R, Warkiani, E & Shaegh, M 2021, 'Twisted architecture for enhancement of passive micromixing in a wide range of Reynolds numbers', Chemical Engineering and Processing - Process Intensification, vol. 160, pp. 108251-108251.
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Micromixers present essential roles in providing homogeneous mixtures in microfluidic systems. It is of critical importance to introduce strategies to increase the mixing efficiency of passive micromixers, capable of operating at high efficiency levels over a wide range of Reynolds (Re) numbers. To this end, a novel design of twisted microstructure for enhancing mixing performance in a wide range of Reynolds numbers was introduced. Incorporating this microstructure with straight and serpentine micromixers was numerically and experimentally investigated. Micromixers with twisted microstructures were fabricated in Poly(methyl methacrylate) (PMMA) using high-precision micromilling. The effects of Reynolds number, pitch number, and channel hydraulic diameter on mixing efficiency and pressure drop were analyzed. Results revealed that the twist architecture could increase mixing efficiency significantly with very low pressure drop of up to 0.89 kPa. The twisted serpentine micromixer could narrow the disparity of mixing efficiency from 87% (Re = 10) to 98% (Re = 400). High mixing efficiency could be achieved within a length of 4.8 mm in the twisted serpentine micromixer with a hydraulic diameter of 300 μm. Taken together, the twisted structure could be incorporated with various geometries to create compact and high efficiency micromixers for operation in a wide range of Re numbers.

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 2021, 'FKBPL and SIRT-1 Are Downregulated by Diabetes in Pregnancy Impacting on Angiogenesis and Endothelial Function', Frontiers in Endocrinology, vol. 12.
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Diabetes in pregnancy is associated with adverse pregnancy outcomes including preterm birth. Although the mechanisms leading to these pregnancy complications are still poorly understood, aberrant angiogenesis and endothelial dysfunction play a key role. FKBPL and SIRT-1 are critical regulators of angiogenesis, however, their roles in pregnancies affected by diabetes have not been examined before in detail. Hence, this study aimed to investigate the role of FKBPL and SIRT-1 in pre-gestational (type 1 diabetes mellitus, T1D) and gestational diabetes mellitus (GDM). Placental protein expression of important angiogenesis proteins, FKBPL, SIRT-1, PlGF and VEGF-R1, was determined from pregnant women with GDM or T1D, and in the first trimester trophoblast cells exposed to high glucose (25 mM) and varying oxygen concentrations [21%, 6.5%, 2.5% (ACH-3Ps)]. Endothelial cell function was assessed in high glucose conditions (30 mM) and following FKBPL overexpression. Placental FKBPL protein expression was downregulated in T1D (FKBPL; p<0.05) whereas PlGF/VEGF-R1 were upregulated (p<0.05); correlations adjusted for gestational age were also significant. In the presence of GDM, only SIRT-1 was significantly downregulated (p<0.05) even when adjusted for gestational age (r=-0.92, p=0.001). Both FKBPL and SIRT-1 protein expression was reduced in ACH-3P cells in high glucose conditions associated with 6.5%/2.5% oxygen concentrations compared to experimental normoxia (21%; p<0.05). FKBPL overexpression in endothelial cells (HUVECs) exacerbated reduction in tubule formation compared to empty vector control, in high glucose conditions (junctions; p<0.01, branches; p<0.05). In conclusion, FKBPL and/or SIRT-1 downregulation in response to diabetic pregnancies may have a key role in the development of vascular dysfunction and associated complications affected by impaired placental angiogenesis.

Alqudah, A, Wedyan, M, Qnais, E, Jawarneh, H & McClements, L 2021, 'Plasma Amino Acids Metabolomics' Important in Glucose Management in Type 2 Diabetes', Frontiers in Pharmacology, vol. 12, p. 695418.
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The perturbation in plasma free amino acid metabolome has been observed previously in diabetes mellitus, and is associated with insulin resistance as well as the onset of cardiovascular disease in this population. In this study, we investigated, for the first time, changes in the amino acid profile in a group of people with and without type 2 diabetes (T2D) with normal BMI, from Jordan, who were only managed on metformin. Twenty one amino acids were evaluated in plasma samples from 124 people with T2D and 67 healthy controls, matched for age, gender and BMI, using amino acids analyser. Total amino acids, essential amino acids, non-essential amino acids and semi-essential amino acids were similar in T2D compared to healthy controls. Plasma concentrations of four essential amino acids were increased in the presence of T2D (Leucine, p < 0.01, Lysine, p < 0.001, Phenylalanine, p < 0.01, Tryptophan, p < 0.05). On the other hand, in relation to non-essential amino acids, Alanine and Serine were reduced in T2D (p < 0.01, p < 0.001, respectively), whereas Aspartate and Glutamate were increased in T2D compared to healthy controls (p < 0.001, p < 0.01, respectively). A semi-essential amino acid, Cystine, was also increased in T2D compared to healthy controls (p < 0.01). Citrulline, a metabolic indicator amino acid, demonstrated lower plasma concentration in T2D compared to healthy controls (p < 0.01). These amino acids were also correlated with fasting blood glucose and HbA1c (p < 0.05). Glutamate, glycine and arginine were correlated with the duration of metformin treatment (

Augustine, R, Dan, P, Hasan, A, Khalaf, IM, Prasad, P, Ghosal, K, Gentile, C, McClements, L & Maureira, P 2021, 'Stem cell-based approaches in cardiac tissue engineering: controlling the microenvironment for autologous cells', Biomedicine & Pharmacotherapy, vol. 138, pp. 111425-111425.
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Augustine, R, Kalva, SN, Ahmad, R, Zahid, AA, Hasan, S, Nayeem, A, McClements, L & Hasan, A 2021, '3D Bioprinted cancer models: Revolutionizing personalized cancer therapy', Translational Oncology, vol. 14, no. 4, pp. 101015-101015.
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After cardiovascular disease, cancer is the leading cause of death worldwide with devastating health and economic consequences, particularly in developing countries. Inter-patient variations in anti-cancer drug responses further limit the success of therapeutic interventions. Therefore, personalized medicines approach is key for this patient group involving molecular and genetic screening and appropriate stratification of patients to treatment regimen that they will respond to. However, the knowledge related to adequate risk stratification methods identifying patients who will respond to specific anti-cancer agents is still lacking in many cancer types. Recent advancements in three-dimensional (3D) bioprinting technology, have been extensively used to generate representative bioengineered tumor in vitro models, which recapitulate the human tumor tissues and microenvironment for high-throughput drug screening. Bioprinting process involves the precise deposition of multiple layers of different cell types in combination with biomaterials capable of generating 3D bioengineered tissues based on a computer-aided design. Bioprinted cancer models containing patient-derived cancer and stromal cells together with genetic material, extracellular matrix proteins and growth factors, represent a promising approach for personalized cancer therapy screening. Both natural and synthetic biopolymers have been utilized to support the proliferation of cells and biological material within the personalized tumor models/implants. These models can provide a physiologically pertinent cell–cell and cell–matrix interactions by mimicking the 3D heterogeneity of real tumors. Here, we reviewed the potential applications of 3D bioprinted tumor constructs as personalized in vitro models in anticancer drug screening and in the establishment of precision treatment regimens.

Azadi, S, Tafazzoli Shadpour, M & Warkiani, ME 2021, 'Characterizing the effect of substrate stiffness on the extravasation potential of breast cancer cells using a 3D microfluidic model', Biotechnology and Bioengineering, vol. 118, no. 2, pp. 823-835.
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AbstractDifferent biochemical and biomechanical cues from tumor microenvironment affect the extravasation of cancer cells to distant organs; among them, the mechanical signals are poorly understood. Although the effect of substrate stiffness on the primary migration of cancer cells has been previously probed, its role in regulating the extravasation ability of cancer cells is still vague. Herein, we used a microfluidic device to mimic the extravasation of tumor cells in a 3D microenvironment containing cancer cells, endothelial cells, and the biological matrix. The microfluidic‐based extravasation model was utilized to probe the effect of substrate stiffness on the invasion ability of breast cancer cells. MCF7 and MDA‐MB‐231 cancer cells were cultured among substrates with different stiffness which followed by monitoring their extravasation capability through the microfluidic device. Our results demonstrated that acidic collagen at a concentration of 2.5 mg/ml promotes migration of cancer cells. Additionally, the substrate softening resulted in up to 46% reduction in the invasion of breast cancer cells. The substrate softening not only affected the number of extravasated cells but also reduced their migration distance up to 53%. We further investigated the secreted level of matrix metalloproteinase 9 (MMP9) and identified that there is a positive correlation between substrate stiffening, MMP9 concentration, and extravasation of cancer cells. These findings suggest that the substrate stiffness mediates the cancer cells extravasation in a microfluidic model. Changes in MMP9 level could be one of the possible underlying mechanisms which need more investigations to be addressed thoroughly.

Bai, X, Ni, J, Beretov, J, Wasinger, VC, Wang, S, Zhu, Y, Graham, P & Li, Y 2021, 'Activation of the eIF2α/ATF4 axis drives triple-negative breast cancer radioresistance by promoting glutathione biosynthesis', Redox Biology, vol. 43, pp. 101993-101993.
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Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Radiotherapy is an effective option for the treatment of TNBC; however, acquired radioresistance is a major challenge to the modality. In this study, we show that the integrated stress response (ISR) is the most activated signaling pathway in radioresistant TNBC cells. The constitutive phosphorylation of eIF2α in radioresistant TNBC cells promotes the activation of ATF4 and elicits the transcription of genes implicated in glutathione biosynthesis, including GCLC, SLC7A11, and CTH, which increases the intracellular level of reduced glutathione (GSH) and the scavenging of reactive oxygen species (ROS) after irradiation (IR), leading to a radioresistant phenotype. The cascade is significantly up-regulated in human TNBC tissues and is associated with unfavorable survival in patients. Dephosphorylation of eIF2α increases IR-induced ROS accumulation in radioresistant TNBC cells by disrupting ATF4-mediated GSH biosynthesis and sensitizes them to IR in vitro and in vivo. These findings reveal ISR as a vital mechanism underlying TNBC radioresistance and propose the eIF2α/ATF4 axis as a novel therapeutic target for TNBC treatment.

Bao, G, Wen, S, Lin, G, Yuan, J, Lin, J, Wong, K-L, Bünzli, J-CG & Jin, D 2021, 'Learning from lanthanide complexes: The development of dye-lanthanide nanoparticles and their biomedical applications', Coordination Chemistry Reviews, vol. 429, pp. 213642-213642.
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© 2020 Elsevier B.V. Coordination chemistry has been widely studied in lanthanide complexes, where organic ligands are used to chelate individual lanthanide ions, and the complexes are broadly used in analytical, biological, and clinical applications. Significant progress has recently been made to exploit the hybrid structure of lanthanide doped inorganic nanoparticles “coated” with organic dyes. This attributes to the fast developments of nanoscience and technology centred around well-controlled nanocrystal synthesis and engineering, with a variety of shape, size, composition and structures towards the desirable functions. There are a lot of similarities between the two forms of lanthanide materials, waiting for a systematic analysis to guide the emerging field of nanocrystal-dye hybrids. Therefore, we survey here the principles for the design of dye-lanthanide energy transfer systems and analyse the remarkable successes made in hybrid dye-lanthanide nanosystems.

Bao, G, Wen, S, Wang, W, Zhou, J, Zha, S, Liu, Y, Wong, K-L & Jin, D 2021, 'Enhancing Hybrid Upconversion Nanosystems via Synergistic Effects of Moiety Engineered NIR Dyes', Nano Letters, vol. 21, no. 23, pp. 9862-9868.
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Hybrid upconversion nanosystems have been reported to improve the low absorption efficiency of lanthanide-doped upconversion nanoparticles (UCNPs). However, the low quantum yield and poor photostability of NIR dyes pose challenges for practical uses. Here, we introduce a bulky moiety, 4-(1,2,2-triphenylvinyl)-1,1'-biphenyl (TPEO), to enhance its quantum yield by suppressing the bond rotation and improve the stability by deactivating the photoinduced oxidization. Compared with the conventional IR806, the formed NIR dye, TPEO-Cy, has been characterized to deliver three times higher quantum yield and seven times better photostability. Moreover, we take advantage of the strong affinity of sulfonate chains on the TPEO-Cy to bind to the surface of UCNPs. Taking together the synergistic effect, we have achieved a 242-fold upconversion emission enhancement over the benchmark of IR806-sensitized system and an ∼800 000-fold increase than the bare UCNPs. Our design of the NIR dyes suggests a new scope to search for more efficient upconversion nanohybrids.

Chai, H, Cheng, W, Jin, D & Miao, P 2021, 'Recent Progress in DNA Hybridization Chain Reaction Strategies for Amplified Biosensing', ACS Applied Materials & Interfaces, vol. 13, no. 33, pp. 38931-38946.
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With the continuous development of DNA nanotechnology, various spatial DNA structures and assembly techniques emerge. Hybridization chain reaction (HCR) is a typical example with exciting features and bright prospects in biosensing, which has been intensively investigated in the past decade. In this Spotlight on Applications, we summarize the assembly principles of conventional HCR and some novel forms of linear/nonlinear HCR. With advantages like great assembly kinetics, facile operation, and an enzyme-free and isothermal reaction, these strategies can be integrated with most mainstream reporters (e.g., fluorescence, electrochemistry, and colorimetry) for the ultrasensitive detection of abundant targets. Particularly, we select several representative studies to better illustrate the novel ideas and performances of HCR strategies. Theoretical and practical utilities are confirmed for a range of biosensing applications. In the end, a deep discussion is provided about the challenges and future tasks of this field.

Chai, M, Razavi Bazaz, S, Daiyan, R, Razmjou, A, Ebrahimi Warkiani, M, Amal, R & Chen, V 2021, 'Biocatalytic micromixer coated with enzyme-MOF thin film for CO2 conversion to formic acid', Chemical Engineering Journal, vol. 426, pp. 130856-130856.
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In this study, a novel micromixer with a 3D helical, threaded channel was fabricated via 3D printing. The micromixer can enhance the mass transfer of reactants and product in an enzymatic cascade reaction converting CO2 to formic acid. Two enzymes, including carbonic anhydrase (CA) and formate dehydrogenase (FDH), were biomineralised in a zeolitic imidazolate framework-8 composite thin film on the micromixer channel that has been modified with polydopamine/polyethyleneimine. The biocatalytic performance of the micromixer was evaluated by testing at various liquid flow rates, and an optimum liquid flow rate at 1 mL/min (Rel = 8, Del = 3) was observed as the two-phase flow pattern in the micromixer channel transitioned from slug flow to bubbly flow. A comparison of the micromixer performance with and without threaded channels revealed ~ 170% enhancement in formic acid yield, indicating improved mixing with the presence of threads. In addition, the formic acid production rate for the micromixer with threaded channel was three folds higher than a conventional bubble column, demonstrating the superior performance of the proposed micromixer. The ease of assembling multiple micromixer units in series also enabled the immobilisation of different enzymes in separate units to carry out sequential reactions in a modular system. As a proof of concept, the solution product collected from long term biocatalysis was also tested in a direct formic acid fuel cell, which showed a promising prospect of integrating these two systems for a closed-loop energy generation system.

Chan, Y, Mehta, M, Paudel, KR, Madheswaran, T, Panneerselvam, J, Gupta, G, Su, QP, Hansbro, PM, MacLoughlin, R, Dua, K & Chellappan, DK 2021, 'Versatility of liquid crystalline nanoparticles in inflammatory lung diseases', Nanomedicine, vol. 16, no. 18, pp. 1545-1548.
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Chen, C, Liu, B, Liu, Y, Liao, J, Shan, X, Wang, F & Jin, D 2021, 'Heterochromatic Nonlinear Optical Responses in Upconversion Nanoparticles for Super‐Resolution Nanoscopy', Advanced Materials, vol. 33, no. 23, pp. e2008847-2008847.
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AbstractPoint spread function (PSF) engineering by an emitter's response can code higher‐spatial‐frequency information of an image for microscopy to achieve super‐resolution. However, complexed excitation optics or repetitive scans are needed, which explains the issues of low speed, poor stability, and operational complexity associated with the current laser scanning microscopy approaches. Here, the diverse emission responses of upconversion nanoparticles (UCNPs) are reported for super‐resolution nanoscopy to improve the imaging quality and speed. The method only needs a doughnut‐shaped scanning excitation beam at an appropriate power density. By collecting the four‐photon emission of single UCNPs, the high‐frequency information of a super‐resolution image can be resolved through the doughnut‐emission PSF. Meanwhile, the two‐photon state of the same nanoparticle is oversaturated, so that the complementary lower‐frequency information of the super‐resolution image can be simultaneously collected by the Gaussian‐like emission PSF. This leads to a method of Fourier‐domain heterochromatic fusion, which allows the extended capability of the engineered PSFs to cover both low‐ and high‐frequency information to yield optimized image quality. This approach achieves a spatial resolution of 40 nm, 1/24th of the excitation wavelength. This work suggests a new scope for developing nonlinear multi‐color emitting probes in super‐resolution nanoscopy.

Chen, H, Chhor, M, Rayner, BS, McGrath, K & McClements, L 2021, 'Evaluation of the diagnostic accuracy of current biomarkers in heart failure with preserved ejection fraction: A systematic review and meta-analysis', Archives of Cardiovascular Diseases, vol. 114, no. 12, pp. 793-804.
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Background: A number of circulating biomarkers are currently utilized for the diagnosis of chronic heart failure with preserved ejection fraction (HFpEF). However, due to HFpEF heterogeneity, the accuracy of these biomarkers remains unclear. Aims: This study aimed to systematically determine the diagnostic accuracy of currently available biomarkers for chronic HFpEF. Methods: PubMed, Web of Science, MEDLINE and SCOPUS databases were searched systematically to identify studies assessing the diagnostic accuracy of biomarkers of chronic HFpEF with left ventricular ejection fraction (LVEF) ≥ 50%. All included studies were independently assessed for quality and relevant information was extracted. Random-effects models were used to estimate the pooled diagnostic accuracy of HFpEF biomarkers. Results: The search identified 6145 studies, of which 19 were included. Four biomarkers were available for meta-analysis. The pooled sensitivity of B-type natriuretic peptide (BNP) (0.787, 95% confidence interval [CI] 0.719–0.842) was higher than that of N-terminal pro-BNP (NT-proBNP) (0.696, 95% CI 0.599–0.779) in chronic HFpEF diagnosis. However, NT-proBNP showed improved specificity (0.882, 95% CI 0.778–0.941) compared to BNP (\0.796, 95% CI 0.672–0.882). Galectin-3 (Gal-3) exhibited a reliable diagnostic adequacy for HFpEF (sensitivity 0.760, 95% CI 0.631–0.855; specificity 0.803, 95% CI 0.667–0.893). However, suppression of tumorigenesis-2 (ST2) displayed limited diagnostic performance for chronic HFpEF diagnosis (sensitivity 0.636, 95% CI 0.465–0.779; specificity 0.595, 95% CI 0.427–0.743). Conclusion: NT-proBNP and BNP appear to be the most reliable biomarkers in chronic HFpEF with NT-proBNP showing higher specificity and BNP showing higher sensitivity. Although Gal-3 appears more reliable than ST2 in HFpEF diagnosis, the conclusions are limited as only three studies were included in this meta-analysis.

Chen, S-Y, Beretta, M, Alexopoulos, SJ, Shah, DP, Olzomer, EM, Hargett, SR, Childress, ES, Salamoun, JM, Aleksovska, I, Roseblade, A, Cranfield, C, Rawling, T, Quinlan, KGR, Morris, MJ, Tucker, SP, Santos, WL & Hoehn, KL 2021, 'Mitochondrial uncoupler SHC517 reverses obesity in mice without affecting food intake', Metabolism, vol. 117, pp. 154724-154724.
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Aims

Mitochondrial uncouplers decrease caloric efficiency and have potential therapeutic benefits for the treatment of obesity and related metabolic disorders. Herein we investigate the metabolic and physiologic effects of a recently identified small molecule mitochondrial uncoupler named SHC517 in a mouse model of diet-induced obesity.

Methods

SHC517 was administered as an admixture in food. The effect of SHC517 on in vivo energy expenditure and respiratory quotient was determined by indirect calorimetry. A dose-finding obesity prevention study was performed by starting SHC517 treatment concomitant with high fat diet for a period of 12 days. An obesity reversal study was performed by feeding mice western diet for 4 weeks prior to SHC517 treatment for 7 weeks. Biochemical assays were used to determine changes in glucose, insulin, triglycerides, and cholesterol. SHC517 concentrations were determined by mass spectrometry.

Results

SHC517 increased lipid oxidation without affecting body temperature. SHC517 prevented diet-induced obesity when administered at 0.05% and 0.1% w/w in high fat diet and reversed established obesity when tested at the 0.05% dose. In the obesity reversal model, SHC517 restored adiposity to levels similar to chow-fed control mice without affecting food intake or lean body mass. SHC517 improved glucose tolerance and fasting glucose levels when administered in both the obesity prevention and obesity reversal modes.

Conclusions

SHC517 is a mitochondrial uncoupler with potent anti-obesity and insulin sensitizing effects in mice. SHC517 reversed obesity without altering food intake or compromising lean mass, effects that are highly sought-after in anti-obesity therapeutics.

Chen, X, Yang, L, Liang, S, Dang, P, Jin, D, Cheng, Z & Lin, J 2021, 'Entropy-driven strand displacement reaction for ultrasensitive detection of circulating tumor DNA based on upconversion and Fe3O4 nanocrystals', Science China Materials, vol. 64, no. 10, pp. 2593-2600.
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Early detection of cancer biomarkers applied in real-time disease diagnosis and therapies can increase the survival rate of patients. Circulating tumor DNA (ctDNA) as a typical cancer biomarker plays a great role in the process of tumor disease monitoring, especially in early diagnosis. Unfortunately, most ctDNA detection systems have not been widely used due to their low sensitivity, poor specificity, and high cost. Herein, we developed an alternative ctDNA detection system to present the levels of ctDNA by recording the fluorescence signals of the system containing upconversion nanoparticles (UCNPs), Fe3O4, and entropy-driven strand displacement reaction. The method has a practical sensitivity with a wide linear range from 100 amol L−1 to 1 nmol L−1 and a low detection limit of 1.6 amol L−1. Furthermore, the system demonstrates a practical application in mouse blood serum samples and meets the requirements for rapid, sensitive, specific, and economical diagnosis of cancers. Thus, this ctDNA detection system may have great potential for ctDNA detection and clinical diagnosis.

Cranfield, C, Whelan, D, Cox, C, Shearwin, K, Ho, J, Allen, T, Shibuya, R, Hibino, E, Hayashi, K, dos Remedios, C & Li, A 2021, 'Announcing the call for the Special Issue on “The Australian Society for Biophysics (ASB) – 2021 Meeting”', Biophysical Reviews, vol. 13, no. 4, pp. 485-486.
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This Commentary describes a call for submissions for the upcoming Special Issue focused on the research topics presented at the Australian Society of Biophysics (ASB) in 2020 and 2021. Submissions from past and present ASB members who could not attend these meetings are also welcome as contributions to this special issue.

Deplazes, E, Tafalla, BD, Murphy, C, White, J, Cranfield, CG & Garcia, A 2021, 'Calcium Ion Binding at the Lipid–Water Interface Alters the Ion Permeability of Phospholipid Bilayers', Langmuir, vol. 37, no. 48, pp. 14026-14033.
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Di, X, Wang, D, Zhou, J, Zhang, L, Stenzel, MH, Su, QP & Jin, D 2021, 'Quantitatively Monitoring In Situ Mitochondrial Thermal Dynamics by Upconversion Nanoparticles', Nano Letters, vol. 21, no. 4, pp. 1651-1658.
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Temperature dynamics reflect the physiological conditions of cells and organisms. Mitochondria regulate the temperature dynamics in living cells as they oxidize the respiratory substrates and synthesize ATP, with heat being released as a byproduct of active metabolism. Here, we report an upconversion nanoparticle-based thermometer that allows the in situ thermal 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^-1 in 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 thermodynamic profiles under different stimulations, which highlight the potential applications of this thermometer to study in situ vital processes related to mitochondrial metabolism pathways and interactions between organelles.

Ding, L, Moloudi, R & Warkiani, ME 2021, 'Bioreactor-Based Adherent Cells Harvesting from Microcarriers with 3D Printed Inertial Microfluidics', pp. 257-266.
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Ding, L, Radfar, P, Rezaei, M & Warkiani, ME 2021, 'An easy-to-operate method for single-cell isolation and retrieval using a microfluidic static droplet array', Microchimica Acta, vol. 188, no. 8, pp. 1-11.
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In-depth study of cellular heterogeneity of rare cells (e.g. circulating tumour cells (CTCs) and circulating foetal cells (CFCs)) is greatly needed in disease management but has never been completely explored due to the current technological limitations. We have developed a retrieval method for single-cell detection using a static droplet array (SDA) device through liquid segmentation with almost no sample loss. We explored the potential of using SDA for low sample input and retrieving the cells of interest using everyday laboratory equipment for downstream molecular analysis. This single-cell isolation and retrieval method is low-cost, rapid and provides a solution to the remaining challenge for single rare cell detection. The entire process takes less than 15 min, is easy to fabricate and allows for on-chip analysis of cells in nanolitre droplets and retrieval of desired droplets. To validate the applicability of our device and method, we mimicked detection of single CTCs by isolating and retrieving single cells and perform real-time PCR on their mRNA contents.

Ding, L, Zhou, J, Fu, Q, Bao, G, Liu, Y & Jin, D 2021, 'Triplet Fusion Upconversion with Oxygen Resistance in Aqueous Media', Analytical Chemistry, vol. 93, no. 10, pp. 4641-4646.
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Triplet fusion upconversion (also called triplet-triplet annihilation, TTA) arouses much attention due to its potential in the fields of biological imaging, optogenetics, and light harvesting. However, oxygen quenching remains a challenge ahead, restricting its applications in aqueous media. Previous efforts to realize aqueous TTA with oxygen resistance have been focused on core-shell structures and self-assembly, but tedious processes and complicated chemical modification are required. Here, we report a direct and efficient strategy to realize aqueous TTA by controlling the ionic equilibrium of the TTA dyad. We find that the ionized organic dyad in physiological buffers and electrolyte-based media shows a natural aerotolerance without any complicated structure engineering. In particular, the upconversion intensity of this aqueous TTA in Tris buffer under an air-saturated condition is more than twice that under the deaerated condition. We further demonstrate the TTA system for potential applications in pH and temperature sensing with reversible and sensitive performance. We anticipate this facile approach will inspire the development of practical aqueous TTA and broad applications in biological science.

Dutt, S, Apel, P, Lizunov, N, Notthoff, C, Wen, Q, Trautmann, C, Mota-Santiago, P, Kirby, N & Kluth, P 2021, 'Shape of nanopores in track-etched polycarbonate membranes', Journal of Membrane Science, vol. 638, pp. 119681-119681.
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Elazezy, M, Schwentesius, S, Stegat, L, Wikman, H, Werner, S, Mansour, WY, Failla, AV, Peine, S, Müller, V, Thiery, JP, Ebrahimi Warkiani, M, Pantel, K & Joosse, SA 2021, 'Emerging Insights into Keratin 16 Expression during Metastatic Progression of Breast Cancer', Cancers, vol. 13, no. 15, pp. 3869-3869.
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Keratins are the main identification markers of circulating tumor cells (CTCs); however, whether their deregulation is associated with the metastatic process is largely unknown. Previously we have shown by in silico analysis that keratin 16 (KRT16) mRNA upregulation might be associated with more aggressive cancer. Therefore, in this study, we investigated the biological role and the clinical relevance of K16 in metastatic breast cancer. By performing RT-qPCR, western blot, and immunocytochemistry, we investigated the expression patterns of K16 in metastatic breast cancer cell lines and evaluated the clinical relevance of K16 expression in CTCs of 20 metastatic breast cancer patients. High K16 protein expression was associated with an intermediate mesenchymal phenotype. Functional studies showed that K16 has a regulatory effect on EMT and overexpression of K16 significantly enhanced cell motility (p < 0.001). In metastatic breast cancer patients, 64.7% of the detected CTCs expressed K16, which was associated with shorter relapse-free survival (p = 0.0042). Our findings imply that K16 is a metastasis-associated protein that promotes EMT and acts as a positive regulator of cellular motility. Furthermore, determining K16 status in CTCs provides prognostic information that helps to identify patients whose tumors are more prone to metastasize.

Es, HA, Cox, TR, Sarafraz-Yazdi, E, Thiery, JP & Warkiani, ME 2021, 'Pirfenidone Reduces Epithelial–Mesenchymal Transition and Spheroid Formation in Breast Carcinoma through Targeting Cancer-Associated Fibroblasts (CAFs)', Cancers, vol. 13, no. 20, pp. 5118-5118.
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The aim of this study was to assess the effects of pirfenidone (PFD) on promoting epithelial–mesenchymal-transition (EMT) and stemness features in breast carcinoma cells through targeting cancer-associated-fibroblasts (CAFs). Using The Cancer Genome Atlas (TCGA) database, we analyzed the association between stromal index, EMT, and stemness-related genes across 1084 breast cancer patients, identifying positive correlation between YAP1, EMT, and stemness genes in samples with a high-stromal index. We monitored carcinoma cell invasion and spheroid formation co-cultured with CAFs in a 3D microfluidic device, followed by exposing carcinoma cells, spheroids, and CAFs with PFD. We depicted a positive association between the high-stromal index and the expression of EMT and stemness genes. High YAP1 expression in samples correlated with more advanced EMT status and stromal index. Additionally, we found that CAFs promoted spheroid formation and induced the expression of YAP1, VIM, and CD44 in spheroids. Treatment with PFD reduced carcinoma cell migration and decreased the expression of these genes at the protein level. The cytokine profiling showed significant depletion of various EMT- and stemness-regulated cytokines, particularly IL8, CCL17, and TNF-beta. These data highlight the potential application of PFD on inhibiting EMT and stemness in carcinoma cells through the targeting of critical cytokines.

Eyni, H, Ghorbani, S, Nazari, H, Hajialyani, M, Razavi Bazaz, S, Mohaqiq, M, Ebrahimi Warkiani, M & Sutherland, DS 2021, 'Advanced bioengineering of male germ stem cells to preserve fertility', Journal of Tissue Engineering, vol. 12, pp. 204173142110605-204173142110605.
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In modern life, several factors such as genetics, exposure to toxins, and aging have resulted in significant levels of male infertility, estimated to be approximately 18% worldwide. In response, substantial progress has been made to improve in vitro fertilization treatments (e.g. microsurgical testicular sperm extraction (m-TESE), intra-cytoplasmic sperm injection (ICSI), and round spermatid injection (ROSI)). Mimicking the structure of testicular natural extracellular matrices (ECM) outside of the body is one clear route toward complete in vitro spermatogenesis and male fertility preservation. Here, a new wave of technological innovations is underway applying regenerative medicine strategies to cell-tissue culture on natural or synthetic scaffolds supplemented with bioactive factors. The emergence of advanced bioengineered systems suggests new hope for male fertility preservation through development of functional male germ cells. To date, few studies aimed at in vitro spermatogenesis have resulted in relevant numbers of mature gametes. However, a substantial body of knowledge on conditions that are required to maintain and mature male germ cells in vitro is now in place. This review focuses on advanced bioengineering methods such as microfluidic systems, bio-fabricated scaffolds, and 3D organ culture applied to the germline for fertility preservation through in vitro spermatogenesis.

Fang, G, Lu, H, Aboulkheyr Es, H, Wang, D, Liu, Y, Warkiani, ME, Lin, G & Jin, D 2021, 'Unidirectional intercellular communication on a microfluidic chip', Biosensors and Bioelectronics, vol. 175, pp. 112833-112833.
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Cell co-culture serves as a standard method to study intercellular communication. However, random diffusion of signal molecules during co-culture may arouse crosstalk among different types of cells and hide directive signal-target responses. Here, a microfluidic chip is proposed to study unidirectional intercellular communication by spatially controlling the flow of the signal molecules. The chip contains two separated chambers connected by two channels where the culture media flows oppositely. A zigzag signal-blocking channel is designed to study the function of a specific signal. The chip is applied to study the unidirectional communication between tumor cells and stromal cells. It shows that the expression of α-smooth muscle actin (a marker of cancer-associated fibroblast (CAF)) of both MRC-5 fibroblasts and mesenchymal stem cells can be up-regulated only by the secreta from invasive MDA-MB-231 cells, but not from non-invasive MCF-7 cells. The proliferation of the tumor cells can be improved by the stromal cells. Moreover, transforming growth factor beta 1 is found as one of the main factors for CAF transformation via the signal-blocking function. The chip achieves unidirectional cell communication along X-axis, signal concentration gradient along Y-axis and 3D cell culture along Z-axis, which provides a useful tool for cell communication studies.

Fang, G, Lu, H, Rodriguez de la Fuente, L, Law, AMK, Lin, G, Jin, D & Gallego‐Ortega, D 2021, 'Mammary Tumor Organoid Culture in Non‐Adhesive Alginate for Luminal Mechanics and High‐Throughput Drug Screening', Advanced Science, vol. 8, no. 21, pp. 1-13.
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AbstractMammary tumor organoids have become a promising in vitro model for drug screening and personalized medicine. However, the dependency on the basement membrane extract (BME) as the growth matrices limits their comprehensive application. In this work, mouse mammary tumor organoids are established by encapsulating tumor pieces in non‐adhesive alginate. High‐throughput generation of organoids in alginate microbeads is achieved utilizing microfluidic droplet technology. Tumor pieces within the alginate microbeads developed both luminal‐ and solid‐like structures and displayed a high similarity to the original fresh tumor in cellular phenotypes and lineages. The mechanical forces of the luminal organoids in the alginate capsules are analyzed with the theory of the thick‐wall pressure vessel (TWPV) model. The luminal pressure of the organoids increase with the lumen growth and can reach 2 kPa after two weeks’ culture. Finally, the mammary tumor organoids are treated with doxorubicin and latrunculin A to evaluate their application as a drug screening platform. It is found that the drug response is related to the luminal size and pressures of organoids. This high‐throughput culture for mammary tumor organoids may present a promising tool for preclinical drug target validation and personalized medicine.

Fardjahromi, MA, Ejeian, F, Razmjou, A, Vesey, G, Mukhopadhyay, SC, Derakhshan, A & Warkiani, ME 2021, 'Enhancing osteoregenerative potential of biphasic calcium phosphates by using bioinspired ZIF8 coating', Materials Science and Engineering: C, vol. 123, pp. 111972-111972.
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Biphasic calcium phosphate ceramics (BCPs) have been extensively used as a bone graft in dental clinics to reconstruct lost bone in the jaw and peri-implant hard tissue due to their good bone conduction and similar chemical structure to the teeth and bone. However, BCPs are not inherently osteoinductive and need additional modification and treatment to enhance their osteoinductivity. The present study aims to develop an innovative strategy to improve the osteoinductivity of BCPs using unique features of zeolitic imidazolate framework-8 (ZIF8). In this method, commercial BCPs (Osteon II) were pre-coated with a zeolitic imidazolate framework-8/polydopamine/polyethyleneimine (ZIF8/PDA/PEI) layer to form a uniform and compact thin film of ZIF8 on the surface of BCPs. The surface morphology and chemical structure of ZIF8 modified Osteon II (ZIF8-Osteon) were confirmed using various analytical techniques such as XRD, FTIR, SEM, and EDX. We evaluated the effect of ZIF8 coating on cell attachment, growth, and osteogenic differentiation of human adipose-derived mesenchymal stem cells (hADSCs). The results revealed that altering the surface chemistry and topography of Osteon II using ZIF8 can effectively promote cell attachment, proliferation, and bone regeneration in both in vitro and in vivo conditions. In conclusion, the method applied in this study is simple, low-cost, and time-efficient and can be used as a versatile approach for improving osteoinductivity and osteoconductivity of other types of alloplastic bone grafts.

Fisher, BM, Tang, KD, Warkiani, ME, Punyadeera, C & Batstone, MD 2021, 'A pilot study for presence of circulating tumour cells in adenoid cystic carcinoma', International Journal of Oral and Maxillofacial Surgery, vol. 50, no. 8, pp. 994-998.
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Adenoid cystic carcinoma (ACC) is a rare salivary gland neoplasm with a poor long-term prognosis due to multiple recurrences and distant metastatic spread. Circulating tumour cells (CTCs) are tumour cells shed from a primary, recurrent, or metastatic cancer that are detectable in the blood or lymphatics. There is no literature to date confirming the presence of CTCs in ACC. The aim of this study was to determine whether CTCs are detectable in ACC. Blood samples were collected from eight patients with histologically confirmed ACC. The TNM stage of the tumour was recorded, as well as any prior treatment. CTCs were isolated by spiral microfluidics and detected by immunofluorescence staining. Three of the eight patients recruited (32.5%) had staining consistent with the presence of CTCs. Of these three patients with detectable CTCs, one had confirmed pulmonary metastasis, one had suspected pulmonary metastasis and was awaiting confirmation, and one had local recurrence confirmed on re-resection. One patient with known isolated pulmonary metastasis had previously undergone a lung metastasectomy and did not have CTCs detected. CTCs are detectable in ACC. In this small patient sample, CTCs were found to be present in those patients with recurrent local disease and known distant metastatic disease. CTCs in ACC should be investigated further for their potential use as an adjunct in staging, prognosis, and the detection of recurrence.

Ghasemian, R, Shamshirian, A, Heydari, K, Malekan, M, Alizadeh‐Navaei, R, Ebrahimzadeh, MA, Ebrahimi Warkiani, M, Jafarpour, H, Razavi Bazaz, S, Rezaei Shahmirzadi, A, Khodabandeh, M, Seyfari, B, Motamedzadeh, A, Dadgostar, E, Aalinezhad, M, Sedaghat, M, Razzaghi, N, Zarandi, B, Asadi, A, Yaghoubi Naei, V, Beheshti, R, Hessami, A, Azizi, S, Mohseni, AR & Shamshirian, D 2021, 'The role of vitamin D in the age of COVID‐19: A systematic review and meta‐analysis', International Journal of Clinical Practice, vol. 75, no. 11, pp. 1-16.
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BackgroundEvidence recommends that vitamin D might be a crucial supportive agent for the immune system, mainly in cytokine response regulation against COVID-19. Hence, we carried out a systematic review and meta-analysis in order to maximise the use of everything that exists about the role of vitamin D in the COVID-19.MethodsA systematic search was performed in PubMed, Scopus, Embase and Web of Science up to December 18, 2020. Studies focused on the role of vitamin D in confirmed COVID-19 patients were entered into the systematic review.ResultsTwenty-three studies containing 11 901 participants entered into the meta-analysis. The meta-analysis indicated that 41% of COVID-19 patients were suffering from vitamin D deficiency (95% CI, 29%-55%), and in 42% of patients, levels of vitamin D were insufficient (95% CI, 24%-63%). The serum 25-hydroxyvitamin D concentration was 20.3 ng/mL among all COVID-19 patients (95% CI, 12.1-19.8). The odds of getting infected with SARS-CoV-2 are 3.3 times higher among individuals with vitamin D deficiency (95% CI, 2.5-4.3). The chance of developing severe COVID-19 is about five times higher in patients with vitamin D deficiency (OR: 5.1, 95% CI, 2.6-10.3). There is no significant association between vitamin D status and higher mortality rates (OR: 1.6, 95% CI, 0.5-4.4).ConclusionThis study found that most of the COVID-19 patients were suffering from vitamin D deficiency/insufficiency. Also, there is about three times higher chance of getting infected with SARS-CoV-2 among vitamin-D-deficient individuals and about five times higher probability of developing the severe disease in vitamin-D-deficient patients. Vitamin D deficiency showed no significant association with mortality rates in this population.

Gu, Y, Guo, Z, Yuan, W, Kong, M, Liu, Y, Liu, Y, Gao, Y, Feng, W, Wang, F, Zhou, J, Jin, D & Li, F 2021, 'Author Correction: High-sensitivity imaging of time-domain near-infrared light transducer', Nature Photonics, vol. 15, no. 9, pp. 712-712.
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Guan, M & Jin, D 2021, 'Dark bridge at the interface of hybrid nanosystem: Lanthanide-triplet NIR photosensitization', Chem, vol. 7, no. 6, pp. 1412-1414.
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“Dark” organic triplet states typically require visible light to activate via singlet-triplet intersystem crossing. In this issue of Chem, Deng and co-workers report a new near-infrared photosensitization strategy using lanthanide-doped nanoparticles to directly activate the dark triplet states of organic photosensitizers, significantly reducing the power requirement of irradiance.

Gupta, A, Ghosh, S, Thakur, MK, Zhou, J, (Ken) Ostrikov, K, Jin, D & Chattopadhyay, S 2021, 'Up-conversion hybrid nanomaterials for light- and heat-driven applications', Progress in Materials Science, vol. 121, pp. 100838-100838.
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Composites or hybrid materials offer diverse properties not achievable in pure materials. Here we critically review the interesting and controllable fluorescence and photothermal properties of diverse hybrid materials containing up-conversion nanoparticles (UCNPs). These hybrids couple plasmons, photonic crystals, bio-surfaces, and two dimensional (2D) materials to the UCNPs, offering optical non-linearity, and enable effective photo-electro-thermal control leading to new light and heat driven applications. Among the light driven applications, coupling of UCNPs with graphene and molybdenum disulfide (MoS2) enables photodetectors with better photoresponse, and broader spectral range not accessible to individual components. Irradiated MoS2 coupled-UCNPs is a new paradigm in resistive random access memory devices. Conjugation of graphene and perovskites, with the UCNPs, have led to novel optical limiting phenomenon and better solar cells. Examples of new opportunities offered by UCNPs in heat driven applications are photothermal water desalination using solar daylight and photothermal disintegration of fat droplets in obesity treatment. Phonons, manifesting as heat, can also be utilized to enhance fluorescence and translate to high sensitivity nanothermometers. This review covers fundamentals, and applications of the new UCNP-enabled class of hybrid materials in energy harnessing, light sources and detectors, memory devices, nanothermometers, desalination, intracellular pH sensing, and cancer theranostics.

Herath, S, Sadeghi Rad, H, Radfar, P, Ladwa, R, Warkiani, M, O’Byrne, K & Kulasinghe, A 2021, 'The Role of Circulating Biomarkers in Lung Cancer', Frontiers in Oncology, vol. 11, p. 801269.
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Lung cancer is the leading cause of cancer morbidity and mortality worldwide and early diagnosis is crucial for the management and treatment of this disease. Non-invasive means of determining tumour information is an appealing diagnostic approach for lung cancers as often accessing and removing tumour tissue can be a limiting factor. In recent years, liquid biopsies have been developed to explore potential circulating tumour biomarkers which are considered reliable surrogates for understanding tumour biology in a non-invasive manner. Most common components assessed in liquid biopsy include circulating tumour cells (CTCs), cell-free DNA (cfDNA), circulating tumour DNA (ctDNA), microRNA and exosomes. This review explores the clinical use of circulating tumour biomarkers found in liquid biopsy for screening, early diagnosis and prognostication of lung cancer patients.

Huang, H, Zhan, Y, Tao, Y, Ai, C, Ren, D & Jin, D 2021, 'Three-dimensional characterization of bonding features for asphalt pavement interface using a novel interlayer isolation film', Construction and Building Materials, vol. 311, pp. 125301-125301.
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Jerotić, Đ, Matić, M & McClements, L 2021, 'The importance of polymorphisms of regulatory and catalytic antioxidant proteins in chronic kidney disease', Medicinski podmladak, vol. 72, no. 1, pp. 25-33.
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Both excessive production of reactive oxygen species (ROS) and impaired antioxidant function are found in patients with chronic kidney disease (CKD). Therefore, individual susceptibility towards CKD can be induced by functional variations of genes encoding antioxidant regulatory (nuclear factor erythroid 2 - related factor 2 (Nrf2)) and catalytic (superoxide dismutase (SOD2) and glutathione peroxidase (GPX1)) proteins. Several types of single nucleotide polymorphisms (SNPs) have been found within the genes encoding these proteins, with Nrf2 (-617C/A), SOD2 (Ala16Val) and GPX1 (Pro198Leu) conferring impaired catalytic activity. The most unexplored gene polymorphism in CKD susceptibility, progression and survival, with only two original studies published, is the Nrf2 (-617C/A) polymorphism. The results of these studies showed that there was no individual impact of this polymorphism on the susceptibility towards end stage renal disease (ESRD) development, oxidative phenotype and mortality. However, Nrf2 had a significant role in ESRD risk and survival, when combined with other antioxidant genes. The results regarding the impact of SOD2 (Ala16Val) and GPX1 (Pro198Leu) polymorphisms on either CKD or ESRD are still inconclusive. Namely, some studies showed that patients having variant SOD2 (Val) or GPX1 (Leu) allele were at increased risk of CKD development and progression, while other studies reported only weak or no association between these polymorphisms and CKD. Surprisingly, the only study that reported an association of GPX1 polymorphism with overall/cardiovascular survival in ESRD patients showed a significant impact of low activity GPX1 (Leu/Leu) genotype on better survival. In this review, we comprehensively and critically appraise the literature on these polymorphisms related to oxidative stress in CKD patients, in order to identify gaps and provide recommendations for further clinical research and translation. New developments in the field ...

Jerotic, D, Suvakov, S, Matic, M, Alqudah, A, Grieve, DJ, Pljesa-Ercegovac, M, Savic-Radojevic, A, Damjanovic, T, Dimkovic, N, McClements, L & Simic, T 2021, 'GSTM1 Modulates Expression of Endothelial Adhesion Molecules in Uremic Milieu', Oxidative Medicine and Cellular Longevity, vol. 2021, pp. 1-12.
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Deletion polymorphism of glutathione S-transferase M1 (GSTM1), a phase II detoxification and antioxidant enzyme, increases susceptibility to end-stage renal disease (ESRD) as well as the development of cardiovascular diseases (CVD) among ESRD patients and leads to their shorter cardiovascular survival. The mechanisms by which GSTM1 downregulation contributes to oxidative stress and inflammation in endothelial cells in uremic conditions have not been investigated so far. Therefore, the aim of the present study was to elucidate the effects of GSTM1 knockdown on oxidative stress and expression of a panel of inflammatory markers in human umbilical vein endothelial cells (HUVECs) exposed to uremic serum. Additionally, we aimed to discern whether GSTM1-null genotype is associated with serum levels of adhesion molecules in ESRD patients. HUVECs treated with uremic serum exhibited impaired redox balance characterized by enhanced lipid peroxidation and decreased antioxidant enzyme activities, independently of the GSTM1 knockdown. In response to uremic injury, HUVECs exhibited alteration in the expression of a series of inflammatory cytokines including retinol-binding protein 4 (RBP4), regulated on activation, normal T cell expressed and secreted (RANTES), C-reactive protein (CRP), angiogenin, dickkopf-1 (Dkk-1), and platelet factor 4 (PF4). GSTM1 knockdown in HUVECs showed upregulation of monocyte chemoattractant protein-1 (MCP-1), a cytokine involved in the regulation of monocyte migration and adhesion. These cells also have shown upregulated intracellular and vascular cell adhesion molecules (ICAM-1 and VCAM-1). In accordance with these findings, the levels of serum ICAM-1 and VCAM-1 (sICAM-1 and sVCAM-1) were increased in ESRD patients lacking GSTM1, in comparison with patients with the GSTM1-active genotype. Based on these results, it may be concluded that incubation of endothelial cells in uremic serum induces redox imbalance accompanied with altere...

Jiang, Q, Zeng, H, Liu, X, Yan, J, Li, A & Zhou, J 2021, 'Superhydrophobic surface of glass powder derived from wet milling with aliphatic chemicals modification', Ceramics International, vol. 47, no. 20, pp. 29091-29098.
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Glass frit has emerged recently as a promising material for incorporation in adhesive of electronic components owing to its high sealing density, environmental stability and easy processing. This requires the glass surface to be hydrophobic to ensure high dispersity, grinding uniformity, and high-temperature sintering performance of the glass frit. However, the glass surface is usually hydrophilic. In this work, we developed a wet milling method to effectively produce hydrophobic glass powder by using aliphatic chemicals modification. We employed a series of aliphatic chemicals containing nucleophilic functional groups to prepare ultrafine lead aluminosilicate electronic glass powders. The nucleophilic substitution reaction of amino groups, carboxylic acid groups, hydroxyl groups and phosphoric acid groups reduces the hydroxyl content on the surface of the glass powder to 0.10 mg/m2, and generates steric hindrance and hydrophobicity (contact angle: 153.0°) through the long carbon chain. The obtained powder therefore shows a uniform particle size distribution, anti-agglomerated property, and maximum 25 °C lower hemispheric point temperature compared to powder prepared by conventional hydrophilic milling method. This work provides a versatile method to simultaneously control the structural and surface properties of glass powders at their formation stage.

Li, D, Wen, S, Kong, M, Liu, Y, Hu, W, Shi, B, Shi, X & Jin, D 2021, 'Correction to Highly Doped Upconversion Nanoparticles for In Vivo Applications Under Mild Excitation Power', Analytical Chemistry, vol. 93, no. 32, pp. 11346-11346.
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Li, G, Du, P, Qiang, X, Jin, D, Liu, H, Li, B & Guo, J 2021, 'Retraction notice to “Low-expressed GAS5 injure myocardial cells and progression of chronic heart failure via regulation of miR-223-3P” [Experimental and Molecular Pathology 117C (2020) 104529]', Experimental and Molecular Pathology, vol. 122, pp. 104683-104683.
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Li, H, Wu, Z, Yang, Z, Zhanghao, K, Xi, P & Jin, D 2021, 'Axially overlapped multi-focus light sheet with enlarged field of view', Applied Physics Letters, vol. 118, no. 22, pp. 1-6.
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Light sheet fluorescence microscopy provides optical sectioning and is widely used in volumetric imaging of large specimens. However, the axial resolution and the lateral Field of View (FoV) of the system, defined by the light sheet, typically limit each other due to the spatial band product of the excitation objective. Here, we develop a simple multi-focus scheme to extend the FoV, where a Gaussian light sheet can be focused at three or more consecutive positions. Axially overlapped multiple light sheets significantly enlarge the FoV with improved uniformity and negligible loss in axial resolution. By measuring the point spread function of fluorescent beads, we demonstrated that the obtained light sheet has a FoV of 450 μm and a maximum axial FWHM of 7.5 μm. Compared with the conventional single-focus one, the multi-focus Gaussian light sheet displays a significantly improved optical sectioning ability over the full FoV when imaging cells and zebrafish.

Li, J, Tong, H, Li, D, Jiang, Q, Zhang, Y, Tang, W, Jin, D, Chen, S, Qin, X, Zhang, S & Xue, R 2021, 'The long non-coding RNA DKFZp434J0226 regulates the alternative splicing process through phosphorylation of SF3B6 in PDAC', Molecular Medicine, vol. 27, no. 1.
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Abstract Background Long noncoding RNAs (lncRNAs), a type of pervasive genes that regulates various biological processes, are differentially expressed in different types of malignant tumors. The role of lncRNAs in the carcinogenesis of pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we investigated the role of the lncRNA DKFZp434J0226 in PDAC. Methods Aberrantly expressed mRNAs and lncRNAs among six PDAC and paired non-tumorous tissues were profiled using microarray analysis. Quantitative real-time polymerase chain reaction was used to evaluate DKFZp434J0226 expression in PDAC tissues. CCK-8 assay, wound-healing assay, soft agar colony formation assay, and transwell assay were performed to assess the invasiveness and proliferation of PDAC cells. Furthermore, RNA pull-down, immunofluorescence, RNA immunoprecipitation, and western blotting assays were performed to investigate the association between DKFZp434J0226 and SF3B6. Tumor xenografts in mice were used to test for tumor formation in vivo. Results In our study, 222 mRNAs and 128 lncRNAs were aberrantly expressed (≥ twofold change). Of these, 66 mRNAs and 53 lncRNAs were upregulated, while 75 lncRNAs and 156 mRNAs were downregulated. KEGG pathway analysis and the Gene ontology category indicated that these genes were associated with the regulation of mRNA alternative splicing and metabolic balance. Clinical analyses revealed that overexpression of DKFZp434J0226 was associated with worse tumor grading, frequent perineural invasion, advanced tumor-node-metastasis stage...

Li, X, Jin, D, Zhu, Y, Liu, L, Qiao, Y, Qian, Y, Tian, J, Jiang, B, Hou, C, Geng, J, Li, X, Gao, X, Ma, Y, Wang, S, Zong, J & Qin, Y 2021, 'Quantitative susceptibility mapping to evaluate brain iron deposition and its correlation with physiological parameters in hypertensive patients', Annals of Translational Medicine, vol. 9, no. 20, pp. 1582-1582.
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Li, Y, Xue, B, Zhang, M, Zhang, L, Hou, Y, Qin, Y, Long, H, Su, QP, Wang, Y, Guan, X, Jin, Y, Cao, Y, Li, G & Sun, Y 2021, 'Transcription-coupled structural dynamics of topologically associating domains regulate replication origin efficiency', Genome Biology, vol. 22, no. 1, pp. 1-29.
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Abstract Background Metazoan cells only utilize a small subset of the potential DNA replication origins to duplicate the whole genome in each cell cycle. Origin choice is linked to cell growth, differentiation, and replication stress. Although various genetic and epigenetic signatures have been linked to the replication efficiency of origins, there is no consensus on how the selection of origins is determined. Results We apply dual-color stochastic optical reconstruction microscopy (STORM) super-resolution imaging to map the spatial distribution of origins within individual topologically associating domains (TADs). We find that multiple replication origins initiate separately at the spatial boundary of a TAD at the beginning of the S phase. Intriguingly, while both high-efficiency and low-efficiency origins are distributed homogeneously in the TAD during the G1 phase, high-efficiency origins relocate to the TAD periphery before the S phase. Origin relocalization is dependent on both transcription and CTCF-mediated chromatin structure. Further, we observe that the replication machinery protein PCNA forms immobile clusters around TADs at the G1/S transition, explaining why origins at the TAD periphery are preferentially fired. Conclusion Our work reveals a new origin selection mechanism that the replication efficiency of origins is determined by their physical distribution in the chromatin domain, which undergoes a transcription-dependent structural re-organization process. Our model explains the complex links between replication origin efficiency and many genetic and epigenetic signatures that mark active transcription. The coordination bet...

Liao, J, Zhou, J, Song, Y, Liu, B, Chen, Y, Wang, F, Chen, C, Lin, J, Chen, X, Lu, J & Jin, D 2021, 'Preselectable Optical Fingerprints of Heterogeneous Upconversion Nanoparticles', Nano Letters, vol. 21, no. 18, pp. 7659-7668.
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The control in optical uniformity of single nanoparticles and tuning their diversity in multiple dimensions, dot to dot, holds the key to unlocking nanoscale applications. Here we report that the entire lifetime profile of the single upconversion nanoparticle (τ2 profile) can be resolved by confocal, wide-field, and super-resolution microscopy techniques. The advances in both spatial and temporal resolutions push the limit of optical multiplexing from microscale to nanoscale. We further demonstrate that the time-domain optical fingerprints can be created by utilizing nanophotonic upconversion schemes, including interfacial energy migration, concentration dependency, energy transfer, and isolation of surface quenchers. We exemplify that three multiple dimensions, including the excitation wavelength, emission color, and τ2 profile, can be built into the nanoscale derivative τ2-dots. Creating a vast library of individually preselectable nanotags opens up a new horizon for diverse applications, spanning from sub-diffraction-limit data storage to high-throughput single-molecule digital assays and super-resolution imaging.

Liao, J, Zhou, J, Song, Y, Liu, B, Lu, J & Jin, D 2021, 'Optical Fingerprint Classification of Single Upconversion Nanoparticles by Deep Learning', The Journal of Physical Chemistry Letters, vol. 12, no. 41, pp. 10242-10248.
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Highly controlled synthesis of upconversion nanoparticles (UCNPs) can be achieved in the heterogeneous design, so that a library of optical properties can be arbitrarily produced by depositing multiple lanthanide ions. Such a control offers the potential in creating nanoscale barcodes carrying high-capacity information. With the increasing creation of optical information, it poses more challenges in decoding them in an accurate, high-throughput, and speedy fashion. Here, we reported that the deep-learning approach can recognize the complexity of the optical fingerprints from different UCNPs. Under a wide-field microscope, the lifetime profiles of hundreds of single nanoparticles can be collected at once, which offers a sufficient amount of data to develop deep-learning algorithms. We demonstrated that high accuracies of over 90% can be achieved in classifying 14 kinds of UCNPs. This work suggests new opportunities in handling the diverse properties of nanoscale optical barcodes toward the establishment of vast luminescent information carriers.

Lin, G & Jin, D 2021, 'Responsive Sensors of Upconversion Nanoparticles', ACS Sensors, vol. 6, no. 12, pp. 4272-4282.
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Upconversion nanoparticles are a class of luminescent materials that convert longer-wavelength near-infrared photons into visible and ultraviolet emissions. They can respond to various external stimuli, which underpins many opportunities for developing the next generation of sensing technologies. In this perspective, the unique stimuli-responsive properties of upconverting nanoparticles are introduced, and their recent implementations in sensing are summarized. Promising material development strategies for enhancing the key sensing merits, including intrinsic sensitivity, biocompatibility and modality, are identified and discussed. The outlooks on future technological developments, novel sensing concepts, and applications of nanoscale upconversion sensors are provided.

Lin, G, Liu, Y, Huang, G, Chen, Y, Makarov, D, Lin, J, Quan, Z & Jin, D 2021, '3D Rotation‐Trackable and Differentiable Micromachines with Dimer‐Type Structures for Dynamic Bioanalysis', Advanced Intelligent Systems, vol. 3, no. 2, pp. 2170020-2170020.
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Lin, G, Liu, Y, Huang, G, Chen, Y, Makarov, D, Lin, J, Quan, Z & Jin, D 2021, '3D Rotation‐Trackable and Differentiable Micromachines with Dimer‐Type Structures for Dynamic Bioanalysis', Advanced Intelligent Systems, vol. 3, no. 2, pp. 2000205-2000205.
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Utilizing the magnetic interactions between microparticle building blocks allows creating long‐range ordered structures and constructing smart multifunctional systems at different scales. The elaborate control over the inter‐particle magnetic coupling interaction is entailed to unlock new magnetoactuation functionalities. Herein, dimer‐type microstructures consisting of a pair of magnetic emulsions with tailorable dimension and magnetic coupling strength are fabricated using a microfluidic emulsion‐templated assembly approach. The magnetite nanoparticles dispersed in vinylbenzene monomers are partitioned into a pair of emulsions with conserved volume, which are wrapped by an aqueous hydrogel shell and finally polymerized to form discrete structures. Tunable synchronous–asynchronous rotation over 60 dB is unlocked in magnetic dimers, which is shown to be dependent on the magnetic moments induced. This leads to a new class of magnetic actuators for the parallelized assay of distinctive virus DNAs and the dynamic optical evaluation of 3D cell cultures. The work suggests a new perspective to design smart multifunctional microstructures and devices by exploring their natural variance in magnetic coupling.

Liu Chung Ming, C, Sesperez, K, Ben-Sefer, E, Arpon, D, McGrath, K, McClements, L & Gentile, C 2021, 'Considerations to Model Heart Disease in Women with Preeclampsia and Cardiovascular Disease', Cells, vol. 10, no. 4, pp. 899-899.
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Preeclampsia is a multifactorial cardiovascular disorder diagnosed after 20 weeks of gestation, and is the leading cause of death for both mothers and babies in pregnancy. The pathophysiology remains poorly understood due to the variability and unpredictability of disease manifestation when studied in animal models. After preeclampsia, both mothers and offspring have a higher risk of cardiovascular disease (CVD), including myocardial infarction or heart attack and heart failure (HF). Myocardial infarction is an acute myocardial damage that can be treated through reperfusion; however, this therapeutic approach leads to ischemic/reperfusion injury (IRI), often leading to HF. In this review, we compared the current in vivo, in vitro and ex vivo model systems used to study preeclampsia, IRI and HF. Future studies aiming at evaluating CVD in preeclampsia patients could benefit from novel models that better mimic the complex scenario described in this article.

Liu, D, Jin, Y, Dong, X, Liu, L, Jin, D, Capobianco, JA & Shen, D 2021, 'Low-Temperature-Induced Controllable Transversal Shell Growth of NaLnF4 Nanocrystals', Nanomaterials, vol. 11, no. 3, pp. 654-654.
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Highly controllable anisotropic shell growth is essential for further engineering the function and properties of lanthanide-doped luminescence nanocrystals, especially in some of the advanced applications such as multi-mode bioimaging, security coding and three-dimensional (3D) display. However, the understanding of the transversal shell growth mechanism is still limited today, because the shell growth direction is impacted by multiple complex factors, such as the anisotropy of surface ligand-binding energy, anisotropic core–shell lattice mismatch, the size of cores and varied shell crystalline stability. Herein, we report a highly controlled transversal shell growth method for hexagonal sodium rare-earth tetrafluoride (β-NaLnF4) nanocrystals. Exploiting the relationship between reaction temperature and shell growth direction, we found that the shell growth direction could be tuned from longitudinal to transversal by decreasing the reaction temperature from 310 °C to 280 °C. In addition to the reaction temperature, we also discussed the roles of other factors in the transversal shell growth of nanocrystals. A suitable core size and a relative lower shell precursor concentration could promote transversal shell growth, although different shell hosts played a minor role in changing the shell growth direction.

Liu, D, Xu, X, Du, Y, Liao, J, Wen, S, Dong, X, Jin, Y, Liu, L, Jin, D, Capobianco, JA & Shen, D 2021, 'Reconstructing the Surface Structure of NaREF₄ Upconversion Nanocrystals with a Novel K⁺ Treatment', Chemistry of Materials, vol. 33, no. 7, pp. 2548-2556.
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Property of the nanocrystals' surface structure plays a key role in developing novel nanomaterials with high performance and new functionalities. Conventional methods of nanocrystal surface engineering are commonly based on tuning the synthesis reaction parameters or growing core-shell structures, which usually results in increasing the size of the nanoparticles. Here, we report an approach to tailoring the surface crystalline structure of β-NaYF4 nanocrystals by reheating the nanocrystals in a K+-rich environment of the oleic acid-1-octadecene (OA-ODE) system. We found that the crystal surface stability of nanocrystals was decreased in the K+-rich solution, which reconstructs the nanocrystals' surface into a porous surface structure. With a systematic design of experiments, the roles of the cations, such as K+, K+-Gd3+, and Na+-Y3+, are individually identified, which leads to a reformation of the surface structure of the hexagonal NaYF4 nanocrystal into different forms, e.g., a mesostructured, spherical, and diamond surface. The technique of tailoring the surface crystalline structures will provide new insight for the shape and surface-dependent property studies and luminescence enhancement without a size increase.

Liu, Y, Lin, G & Jin, D 2021, 'Off-axis gyration induces large-area circular motion of anisotropic microparticles in a dynamic magnetic trap', Applied Physics Letters, vol. 119, no. 3, pp. 034102-034102.
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Magnetic tweezers are crucial for single-molecule and atomic characterization and biomedical isolation of microparticle carriers. The trapping component of magnetic tweezing can be reliant on a magnetic potential well that can confine the relevant species to a localized region. Here, we report that magnetic microparticles with tailored anisotropy can transition from localized off-axis gyration to large-area locomotion in a rotating magnetic trap. The microparticles, consisting of assemblies of magnetic cores, are observed to either rotate about its structural geometric center or gyrate about one of the magnetic cores and the switching of which can be modulated by the external field. Raising the magnetic field strength above a threshold, the particles can go beyond the traditional synchronous-rotation and asynchronous-oscillation modes and into a scenario of large-area circular motion. This results in peculiar retrograde locomotion related to the magnetization maxima of the microparticle. Our finding suggests the important role of the microparticle's magnetic morphology in the controlled transport of microparticles and developing smart micro-actuators and micro-robot devices.

Liu, Y, Lin, G, Bao, G, Guan, M, Yang, L, Liu, Y, Wang, D, Zhang, X, Liao, J, Fang, G, Di, X, Huang, G, Zhou, J, Cheng, YY & Jin, D 2021, 'Stratified Disk Microrobots with Dynamic Maneuverability and Proton-Activatable Luminescence for in Vivo Imaging', ACS Nano, vol. 15, no. 12, pp. 19924-19937.
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Microrobots can expand our abilities to access remote, confined, and enclosed spaces. Their potential applications inside our body are obvious, e.g., to diagnose diseases, deliver medicine, and monitor treatment efficacy. However, critical requirements exist in relation to their operations in gastrointestinal environments, including resistance to strong gastric acid, responsivity to a narrow proton variation window, and locomotion in confined cavities with hierarchical terrains. Here, we report a proton-activatable microrobot to enable real-time, repeated, and site-selective pH sensing and monitoring in physiological relevant environments. This is achieved by stratifying a hydrogel disk to combine a range of functional nanomaterials, including proton-responsive molecular switches, upconversion nanoparticles, and near-infrared (NIR) emitters. By leveraging the 3D magnetic gradient fields and the anisotropic composition, the microrobot can be steered to locomote as a gyrating 'Euler's disk', i.e., aslant relative to the surface and along its low-friction outer circumference, exhibiting a high motility of up to 60 body lengths/s. The enhanced magnetomotility can boost the pH-sensing kinetics by 2-fold. The fluorescence of the molecular switch can respond to pH variations with over 600-fold enhancement when the pH decreases from 8 to 1, and the integration of upconversion nanoparticles further allows both the efficient sensitization of NIR light through deep tissue and energy transfer to activate the pH probes. Moreover, the embedded down-shifting NIR emitters provide sufficient contrast for imaging of a single microrobot inside a live mouse. This work suggests great potential in developing multifunctional microrobots to perform generic site-selective tasks in vivo.

Liu, Y, Zhou, Z, Wang, F, Kewes, G, Wen, S, Burger, S, Ebrahimi Wakiani, M, Xi, P, Yang, J, Yang, X, Benson, O & Jin, D 2021, 'Axial localization and tracking of self-interference nanoparticles by lateral point spread functions', Nature Communications, vol. 12, no. 1, pp. 1-9.
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AbstractSub-diffraction limited localization of fluorescent emitters is a key goal of microscopy imaging. Here, we report that single upconversion nanoparticles, containing multiple emission centres with random orientations, can generate a series of unique, bright and position-sensitive patterns in the spatial domain when placed on top of a mirror. Supported by our numerical simulation, we attribute this effect to the sum of each single emitter’s interference with its own mirror image. As a result, this configuration generates a series of sophisticated far-field point spread functions (PSFs), e.g. in Gaussian, doughnut and archery target shapes, strongly dependent on the phase difference between the emitter and its image. In this way, the axial locations of nanoparticles are transferred into far-field patterns. We demonstrate a real-time distance sensing technology with a localization accuracy of 2.8 nm, according to the atomic force microscope (AFM) characterization values, smaller than 1/350 of the excitation wavelength.

Maddahfar, M 2021, 'StableandHighlyEfficientAntibody−NanoparticlesConjugation', Bioconjugate Chemistry, vol. 32, no. 6, pp. 1146-1155.

Maddahfar, M, Wen, S, Hosseinpour Mashkani, SM, Zhang, L, Shimoni, O, Stenzel, M, Zhou, J, Fazekas de St Groth, B & Jin, D 2021, 'Stable and Highly Efficient Antibody–Nanoparticles Conjugation', Bioconjugate Chemistry, vol. 32, no. 6, pp. 1146-1155.
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Functional ligands and polymers have frequently been used to yield target-specific bio-nanoconjugates. Herein, we provide a systematic insight into the effect of the chain length of poly(oligo (ethylene glycol) methyl ether acrylate) (POEGMEA) containing polyethylene glycol on the colloidal stability and antibody-conjugation efficiency of nanoparticles. We employed Reversible Addition-Fragmentation Chain Transfer (RAFT) to design diblock copolymers composed of 7 monoacryloxyethyl phosphate (MAEP) units and 6, 13, 35, or 55 OEGMEA units. We find that when the POEGMEA chain is short, the polymer cannot effectively stabilize the nanoparticles, and when the POEGMEA chain is long, the nanoparticles cannot be efficiently conjugated to antibody. In other words, the majority of the carboxylic groups in larger POEGMEA chains are inaccessible to further chemical modification. We demonstrate that the polymer containing 13 OEGMEA units can effectively bind up to 64% of the antibody molecules, while the binding efficiency drops to 50% and 0% for the polymer containing 35 and 55 OEGMEA units. Moreover, flow cytometry assay statistically shows that about 9% of the coupled antibody retained its activity to recognize B220 biomarkers on the B cells. This work suggests a library of stabile, specific, and bioactive lanthanide-doped nanoconjugates for flow cytometry and mass cytometry application.

Mahmodi, H, Piloni, A, Utama, RH & Kabakova, I 2021, 'Mechanical mapping of bioprinted hydrogel models by brillouin microscopy', Bioprinting, vol. 23, pp. e00151-e00151.
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Three-dimensional (3D) bioprinting has revolutionised the field of biofabrication by delivering precise, cost-effective and a relatively simple way of engineering in vitro living systems in high volume for use in tissue regeneration, biological modelling, drug testing and cell-based diagnostics. The complexity of modern bioprinted systems requires quality control assessment to ensure the resulting product meets the desired criteria of structural design, micromechanical performance and long-term durability. Brillouin microscopy could be an excellent solution for micromechanical assessment of the bioprinted models during or post-fabrication since this technology is non-destructive, label-free and is capable of microscale 3D imaging. In this work, we demonstrate the application of Brillouin microscopy to 3D imaging of hydrogel microstructures created through drop-on-demand bioprinting. In addition, we show that this technology can resolve variations between mechanical properties of the gels with slightly different polymer fractions. This work confirms that Brillouin microscopy can be seen as a characterisation technology complementary to bioprinting, and in the future can be combined within the printer design to achieve simultaneous real-time fabrication and micromechanical characterisation of in vitro biological systems.

McNally, R, Alqudah, A, McErlean, EM, Rennie, C, Morshed, N, Short, A, McGrath, K, Shimoni, O, Robson, T, McCarthy, HO & McClements, L 2021, 'Non-viral gene delivery utilizing RALA modulates sFlt-1 secretion, important for preeclampsia', Nanomedicine, vol. 16, no. 22, pp. 1999-2012.
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Background: Overexpression of sFlt-1 or modulation of FKBPL, key antiangiogenic proteins, are important in the pathogenesis of preeclampsia. Methods: A newly developed nonviral gene-delivery system, RALA, capable of overexpressing sFlt-1 (e15a isoform) was delivered in vivo in transgenic haploinsufficient ( Fkbpl+/−) mice. RALA was also used in vitro to deliver human Flt1 (hFlt1) in trophoblast cells. Results: Serum stable and nontoxic RALA/DNA-based nanoparticles induced an increase in sFlt-1 protein levels in the blood and total protein in the urine; the effect was more pronounced in Fkbpl+/− mice. In vitro, RALA-hFlt nanoparticles significantly reduced secretion of sFlt-1 in trophoblast cells. Conclusion: The RALA-based genetic nanodelivery system can be safely and effectively applied to emulate preeclampsia-like features or reduce sFlt-1 levels in vitro.

Mehta, M, Paudel, KR, Shukla, SD, Allam, VSRR, Kannaujiya, VK, Panth, N, Das, A, Parihar, VK, Chakraborty, A, Ali, MK, Jha, NK, Xenaki, D, Su, QP, Wich, PR, Adams, J, Hansbro, PM, Chellappan, DK, Oliver, BGG & Dua, K 2021, 'Recent trends of NFκB decoy oligodeoxynucleotide-based nanotherapeutics in lung diseases', Journal of Controlled Release, vol. 337, pp. 629-644.
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Mei, S, Zhou, J, Sun, H, Cai, Y, Sun, L, Jin, D & Yan, C 2021, 'Networking State of Ytterbium Ions Probing the Origin of Luminescence Quenching and Activation in Nanocrystals', Advanced Science, vol. 8, no. 6, pp. 2003325-2003325.
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AbstractAt the organic–inorganic interface of nanocrystals, electron‐phonon coupling plays an important but intricate role in determining the diverse properties of nanomaterials. Here, it is reported that highly doping of Yb3+ ions within the nanocrystal host can form an energy‐migration network. The networking state Yb3+ shows both distinct Stark splitting peak ratios and lifetime dynamics, which allows quantitative investigations of quenching and thermal activation of luminescence, as the high‐dimensional spectroscopy signatures can be correlated to the attaching and de‐attaching status of surface molecules. By in‐situ surface characterizations, it is proved that the Yb‐O coordination associated with coordinated water molecules has significantly contributed to this reversible effect. Moreover, using this approach, the prime quencher OH can be switched to CH in the wet‐chemistry annealing process, resulting in the electron‐phonon coupling probability change. This study provides the molecular level insights and dynamics of the surface dark layer of luminescent nanocrystals.

Miao, MZ, Collins, JA, Bahnson, EM, Diekman, BO, Su, PQ, Chubinskaya, S & Loeser, RF 2021, 'Temporospatial production of reactive oxygen species in articular chondrocytes is induced by the endocytosis of fibronectin fragments, alpha 5 beta 1 integrin and NADPH oxidase 2', Osteoarthritis and Cartilage, vol. 29, pp. S114-S115.
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Mirzaie, M, Lakzian, E, Khan, A, Warkiani, ME, Mahian, O & Ahmadi, G 2021, 'COVID-19 spread in a classroom equipped with partition – A CFD approach', Journal of Hazardous Materials, vol. 420, pp. 126587-126587.
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In this study, the motion and distribution of droplets containing coronaviruses emitted by coughing of an infected person in front of a classroom (e.g., a teacher) were investigated using CFD. A 3D turbulence model was used to simulate the airflow in the classroom, and a Lagrangian particle trajectory analysis method was used to track the droplets. The numerical model was validated and was used to study the effects of ventilation airflow speeds of 3, 5, and 7 m/s on the dispersion of droplets of different sizes. In particular, the effect of installing transparent barriers in front of the seats on reducing the average droplet concentration was examined. The results showed that using the seat partitions for individuals can prevent the infection to a certain extent. An increase in the ventilation air velocity increased the droplets’ velocities in the airflow direction, simultaneously reducing the trapping time of the droplets by solid barriers. As expected, in the absence of partitions, the closest seats to the infected person had the highest average droplet concentration (3.80 × 10−8 kg/m3 for the case of 3 m/s).

Morshedi Rad, D, Alsadat Rad, M, Razavi Bazaz, S, Kashaninejad, N, Jin, D & Ebrahimi Warkiani, M 2021, 'A Comprehensive Review on Intracellular Delivery', Advanced Materials, vol. 33, no. 13, pp. e2005363-2005363.
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AbstractIntracellular delivery is considered an indispensable process for various studies, ranging from medical applications (cell‐based therapy) to fundamental (genome‐editing) and industrial (biomanufacture) approaches. Conventional macroscale delivery systems critically suffer from such issues as low cell viability, cytotoxicity, and inconsistent material delivery, which have opened up an interest in the development of more efficient intracellular delivery systems. In line with the advances in microfluidics and nanotechnology, intracellular delivery based on micro‐ and nanoengineered platforms has progressed rapidly and held great promises owing to their unique features. These approaches have been advanced to introduce a smorgasbord of diverse cargoes into various cell types with the maximum efficiency and the highest precision. This review differentiates macro‐, micro‐, and nanoengineered approaches for intracellular delivery. The macroengineered delivery platforms are first summarized and then each method is categorized based on whether it employs a carrier‐ or membrane‐disruption‐mediated mechanism to load cargoes inside the cells. Second, particular emphasis is placed on the micro‐ and nanoengineered advances in the delivery of biomolecules inside the cells. Furthermore, the applications and challenges of the established and emerging delivery approaches are summarized. The topic is concluded by evaluating the future perspective of intracellular delivery toward the micro‐ and nanoengineered approaches.

Müller Bark, J, Kulasinghe, A, Hartel, G, Leo, P, Warkiani, ME, Jeffree, RL, Chua, B, Day, BW & Punyadeera, C 2021, 'Isolation of Circulating Tumour Cells in Patients With Glioblastoma Using Spiral Microfluidic Technology – A Pilot Study', Frontiers in Oncology, vol. 11, p. 681130.
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Glioblastoma (GBM) is the most common and aggressive type of tumour arising from the central nervous system. GBM remains an incurable disease despite advancement in therapies, with overall survival of approximately 15 months. Recent literature has highlighted that GBM releases tumoural content which crosses the blood-brain barrier (BBB) and is detected in patients’ blood, such as circulating tumour cells (CTCs). CTCs carry tumour information and have shown promise as prognostic and predictive biomarkers in different cancer types. Currently, there is limited data for the clinical utility of CTCs in GBM. Here, we report the use of spiral microfluidic technology to isolate CTCs from whole blood of newly diagnosed GBM patients before and after surgery, followed by characterization for GFAP, cell-surface vimentin protein expression and EGFR amplification. CTCs were found in 13 out of 20 patients (9/20 before surgery and 11/19 after surgery). Patients with CTC counts equal to 0 after surgery had a significantly longer recurrence-free survival (p=0.0370). This is the first investigation using the spiral microfluidics technology for the enrichment of CTCs from GBM patients and these results support the use of this technology to better understand the clinical value of CTCs in the management of GBM in future studies.

Nikshad, A, Aghlmandi, A, Safaralizadeh, R, Aghebati-Maleki, L, Warkiani, ME, Khiavi, FM & Yousefi, M 2021, 'Advances of microfluidic technology in reproductive biology', Life Sciences, vol. 265, pp. 118767-118767.
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According to World Health Organization (WHO) reports about 70 million couples suffer from infertility all over the world. A lot of research groups are working on this issue and have made therapeutic approaches by integrating biology, medicine, genetics, chemistry, psychology, mechanic, and many other branches of science. However, these methods have their own pros and cons. Assisted Reproductive Technologies (ART) has appeared to solve infertility problems. In Vitro Fertilization (IVF), Intracytoplasmic Sperm Injection (ICSI), Intrauterine Insemination (IUI) are the most common and conventional technologies in this regard. There are at least two characteristics of microfluidics, mechanical and biochemical, which can be influential in the field of mammalian gamete and preimplantation embryo biology. These microfluidic characteristics can assist in basic biological studies on sperm, oocyte and preimplantation embryo structure, function and environment. Using microfluidics in sorting sperm, conducting different steps of oocyte selection and preparation, and transferring embryo by passing sub-microliter fluid through microchannels results in low cost and short time. The size and shape of microchannels and the volume of used fluid differs from non-human cells to human cells. The most progressions have been seen in animal models. Results suggest that microfluidic systems will lead to improved efficiencies in assisted reproduction.

Patel, D, Taudte, RV, Nizio, K, Herok, G, Cranfield, C & Shimmon, R 2021, 'Headspace analysis of E-cigarette fluids using comprehensive two dimensional GC×GC-TOF-MS reveals the presence of volatile and toxic compounds', Journal of Pharmaceutical and Biomedical Analysis, vol. 196, pp. 113930-113930.
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Polonchuk, L, Surija, L, Lee, MH, Sharma, P, Liu Chung Ming, C, Richter, F, Ben-Sefer, E, Rad, MA, Mahmodi Sheikh Sarmast, H, Shamery, WA, Tran, HA, Vettori, L, Haeusermann, F, Filipe, EC, Rnjak-Kovacina, J, Cox, T, Tipper, J, Kabakova, I & Gentile, C 2021, 'Towards engineering heart tissues from bioprinted cardiac spheroids', Biofabrication, vol. 13, no. 4, pp. 045009-045009.
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Abstract Current in vivo and in vitro models fail to accurately recapitulate the human heart microenvironment for biomedical applications. This study explores the use of cardiac spheroids (CSs) to biofabricate advanced in vitro models of the human heart. CSs were created from human cardiac myocytes, fibroblasts and endothelial cells (ECs), mixed within optimal alginate/gelatin hydrogels and then bioprinted on a microelectrode plate for drug testing. Bioprinted CSs maintained their structure and viability for at least 30 d after printing. Vascular endothelial growth factor (VEGF) promoted EC branching from CSs within hydrogels. Alginate/gelatin-based hydrogels enabled spheroids fusion, which was further facilitated by addition of VEGF. Bioprinted CSs contracted spontaneously and under stimulation, allowing to record contractile and electrical signals on the microelectrode plates for industrial applications. Taken together, our findings indicate that bioprinted CSs can be used to biofabricate human heart tissues for long term in vitro testing. This has the potential to be used to study biochemical, physiological and pharmacological features of human heart tissue.

Prates-Syed, WA, Chaves, LCS, Crema, KP, Vuitika, L, Lira, A, Côrtes, N, Kersten, V, Guimarães, FEG, Sadraeian, M, Barroso da Silva, FL, Cabral-Marques, O, Barbuto, JAM, Russo, M, Câmara, NOS & Cabral-Miranda, G 2021, 'VLP-Based COVID-19 Vaccines: An Adaptable Technology against the Threat of New Variants', Vaccines, vol. 9, no. 12, pp. 1409-1409.
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Virus-like particles (VLPs) are a versatile, safe, and highly immunogenic vaccine platform. Recently, there are developmental vaccines targeting SARS-CoV-2, the causative agent of COVID-19. The COVID-19 pandemic affected humanity worldwide, bringing out incomputable human and financial losses. The race for better, more efficacious vaccines is happening almost simultaneously as the virus increasingly produces variants of concern (VOCs). The VOCs Alpha, Beta, Gamma, and Delta share common mutations mainly in the spike receptor-binding domain (RBD), demonstrating convergent evolution, associated with increased transmissibility and immune evasion. Thus, the identification and understanding of these mutations is crucial for the production of new, optimized vaccines. The use of a very flexible vaccine platform in COVID-19 vaccine development is an important feature that cannot be ignored. Incorporating the spike protein and its variations into VLP vaccines is a desirable strategy as the morphology and size of VLPs allows for better presentation of several different antigens. Furthermore, VLPs elicit robust humoral and cellular immune responses, which are safe, and have been studied not only against SARS-CoV-2 but against other coronaviruses as well. Here, we describe the recent advances and improvements in vaccine development using VLP technology.

Rad, HS, Rad, HS, Shiravand, Y, Radfar, P, Arpon, D, Warkiani, ME, O'Byrne, K & Kulasinghe, A 2021, 'The Pandora’s box of novel technologies that may revolutionize lung cancer', Lung Cancer, vol. 159, pp. 34-41.
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Non-small cell lung cancer (NSCLC) is one of the most common cancers globally and has a 5-year survival rate ~20%. Immunotherapies have demonstrated long-term and durable responses in NSCLC patients, although they appear to be effective in only a subset of patients. A more comprehensive understanding of the underlying tumour biology may contribute to identifying those patients likely to achieve optimal outcomes. Profiling the tumour microenvironment (TME) has shown to be beneficial in addressing fundamental tumour-immune cell interactions. Advances in multiplexing immunohistochemistry and molecular barcoding has led to recent advances in profiling genes and proteins in NSCLC. Here, we review the recent advancements in spatial profiling technologies for the analysis of NSCLC tissue samples to gain new insights and therapeutic options for NSCLC. The combination of spatial transcriptomics combined with advanced imaging is likely to lead to deep insights into NSCLC tissue biology, which can be a powerful tool to predict likelihood of response to therapy.

Rad, HS, Röhl, J, Stylianou, N, Allenby, MC, Bazaz, SR, Warkiani, ME, Guimaraes, FSF, Clifton, VL & Kulasinghe, A 2021, 'The Effects of COVID-19 on the Placenta During Pregnancy', Frontiers in Immunology, vol. 12, p. 743022.
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Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. The virus primarily affects the lungs where it induces respiratory distress syndrome ranging from mild to acute, however, there is a growing body of evidence supporting its negative effects on other system organs that also carry the ACE2 receptor, such as the placenta. The majority of newborns delivered from SARS-CoV-2 positive mothers test negative following delivery, suggesting that there are protective mechanisms within the placenta. There appears to be a higher incidence of pregnancy-related complications in SARS-CoV-2 positive mothers, such as miscarriage, restricted fetal growth, or still-birth. In this review, we discuss the pathobiology of COVID-19 maternal infection and the potential adverse effects associated with viral infection, and the possibility of transplacental transmission.

Radfar, P, Bazaz, SR, Mirakhorli, F & Warkiani, ME 2021, 'The role of 3D printing in the fight against COVID-19 outbreak', Journal of 3D Printing in Medicine, vol. 5, no. 1, pp. 51-60.
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Along with the COVID-19 pandemic, urgent needs for medical and specialized products, especially personal protective equipment, has been overwhelming. The conventional production line of medical devices has been challenged by excessive global demand, and the need for an easy, low-cost and rapid fabrication method is felt more than ever. In a scramble to address this shortfall, manufacturers referred to additive manufacturing or 3D printing to fill the gap and increase the production line of medical devices. Various previously/conventionally fabricated designs have been modified and redesigned to suit the 3D printing requirement to fight against COVID-19. In this perspective, various designs accommodated for the current worldwide outbreak of COVID-19 are discussed and how 3D printing could help the global community against the current and future conditions has been explored.

Raoufi, MA, Joushani, HAN, Razavi Bazaz, S, Ding, L, Asadnia, M & Ebrahimi Warkiani, M 2021, 'Effects of sample rheology on the equilibrium position of particles and cells within a spiral microfluidic channel', Microfluidics and Nanofluidics, vol. 25, no. 9, pp. 1-13.
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Elasto-inertial migration in non-Newtonian fluids is a rapidly growing field with tremendous potentials for manipulating micron to submicron particles. Previous research attempts were mainly carried out in straight channels due to the complexity of particle migration, solution tuning, and data analysis in elasto-inertial microfluidics. Consequently, the combined effects of Dean drag force and solution rheology on coupled Dean drag elasto-inertial focusing phenomena have not been carefully analyzed. This study delved thoroughly into the combined effects of solution rheology and Dean drag force on elasto-inertial focusing of particles and cells within a spiral microchannel. Polyethylene oxide (PEO) of 1MDa, 2MDa, and 4MDa molecular weights were used to prepare 250, 500, and 1000 ppm non-Newtonian solutions to investigate the focusing behavior of particles and cells over a wide range of flow rates and solution rheologies. Dean coupled elasto-inertial effects were systematically investigated to demonstrate its potentials for position-adjustable and size-tunable particle and cell focusing phenomenon. Various cells and microbeads with diameters ranging from 1 to 17 μm were employed to carefully study the equilibrium position, focusing band, and migration behavior under different elastic, inertial, and Dean conditions. Following the focusing, cell viability, morphology, and growth rate were evaluated which showed cells remained undamaged from viscosity, shear rate, and chemical properties of PEO solutions. We are of the opinion that the current study can provide scientists with a better understanding of focusing phenomena in viscoelastic fluids within spiral microfluidic channels.

Rezaei, M, Radfar, P, Winter, M, McClements, L, Thierry, B & Warkiani, ME 2021, 'Simple-to-Operate Approach for Single Cell Analysis Using a Hydrophobic Surface and Nanosized Droplets', Analytical Chemistry, vol. 93, no. 10, pp. 4584-4592.
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Microfluidics-based technologies for single-cell analysis are becoming increasingly important tools in biological studies. With the increasing sophistication of microfluidics, cellular barcoding techniques, and next-generation sequencing, a more detailed picture of cellular subtype is emerging. Unfortunately, the majority of the methods developed for single-cell analysis are high-throughput and not suitable for rare cell analysis as they require a high input cell number. Here, we report a low-cost and reproducible method for rare single-cell analysis using a highly hydrophobic surface and nanosized static droplets. Our method allows rapid and efficient on-chip single-cell lysis and subsequent collection of genetic materials in nanoliter droplets using a micromanipulator or a laboratory pipette before subsequent genetic analysis. We show precise isolation of single cancer cells with high purity using two different strategies (i- cytospin and ii- static droplet array) for subsequent RNA analysis using droplet digital polymerase chain reaction (PCR) and real-time PCR. Our highly controlled isolation method opens a new avenue for the study of subcellular functional mechanisms, enabling the identification of rare cells of potential functional or pathogenic consequence.

Rezaei, M, Razavi Bazaz, S, Morshedi Rad, D, Shimoni, O, Jin, D, Rawlinson, W & Ebrahimi Warkiani, M 2021, 'A Portable RT-LAMP/CRISPR Machine for Rapid COVID-19 Screening', Biosensors, vol. 11, no. 10, pp. 369-369.
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The COVID-19 pandemic has changed people’s lives and has brought society to a sudden standstill, with lockdowns and social distancing as the preferred preventative measures. To lift these measurements and reduce society’s burden, developing an easy-to-use, rapid, and portable system to detect SARS-CoV-2 is mandatory. To this end, we developed a portable and semi-automated device for SARS-CoV-2 detection based on reverse transcription loop-mediated isothermal amplification followed by a CRISPR/Cas12a reaction. The device contains a heater element mounted on a printed circuit board, a cooler fan, a proportional integral derivative controller to control the temperature, and designated areas for 0.2 mL Eppendorf® PCR tubes. Our system has a limit of detection of 35 copies of the virus per microliter, which is significant and has the capability of being used in crisis centers, mobile laboratories, remote locations, or airports to diagnose individuals infected with SARS-CoV-2. We believe the current methodology that we have implemented in this article is beneficial for the early screening of infectious diseases, in which fast screening with high accuracy is necessary.

Richards, C, Sesperez, K, Chhor, M, Ghorbanpour, S, Rennie, C, Ming, CLC, Evenhuis, C, Nikolic, V, Orlic, NK, Mikovic, Z, Stefanovic, M, Cakic, Z, McGrath, K, Gentile, C, Bubb, K & McClements, L 2021, 'Characterisation of cardiac health in the reduced uterine perfusion pressure model and a 3D cardiac spheroid model, of preeclampsia', Biology of Sex Differences, vol. 12, no. 1.
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Abstract Background Preeclampsia is a dangerous cardiovascular disorder of pregnancy that leads to an increased risk of future cardiovascular and metabolic disorders. Much of the pathogenesis and mechanisms involved in cardiac health in preeclampsia are unknown. A novel anti-angiogenic protein, FKBPL, is emerging as having a potential role in both preeclampsia and cardiovascular disease (CVD). Therefore, in this study we aimed to characterise cardiac health and FKBPL regulation in the rat reduced uterine perfusion pressure (RUPP) and a 3D cardiac spheroid model of preeclampsia. Methods The RUPP model was induced in pregnant rats and histological analysis performed on the heart, kidney, liver and placenta (n ≥ 6). Picrosirius red staining was performed to quantify collagen I and III deposition in rat hearts, placentae and livers as an indicator of fibrosis. RT-qPCR was used to determine changes in Fkbpl, Icam1, Vcam1, Flt1 and Vegfa mRNA in hearts and/or placentae and ELISA to evaluate cardiac brain natriuretic peptide (BNP45) and FKBPL secretion. Immunofluorescent staining was also conducted to analyse the expression of cardiac FKBPL. Cardiac spheroids were generated using human cardiac fibroblasts and human coronary artery endothelial cells and treated with patient plasma from normotensive controls, early-onset preeclampsia (EOPE) and late-onset preeclampsia (LOPE); n = 3. FKBPL and CD31 expression was quantified by immunofluorescent labelling. Results The RUPP procedure induced ...

Rouhi, O, Razavi Bazaz, S, Niazmand, H, Mirakhorli, F, Mas-hafi, S, A. Amiri, H, Miansari, M & Ebrahimi Warkiani, M 2021, 'Numerical and Experimental Study of Cross-Sectional Effects on the Mixing Performance of the Spiral Microfluidics', Micromachines, vol. 12, no. 12, pp. 1470-1470.
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Mixing at the microscale is of great importance for various applications ranging from biological and chemical synthesis to drug delivery. Among the numerous types of micromixers that have been developed, planar passive spiral micromixers have gained considerable interest due to their ease of fabrication and integration into complex miniaturized systems. However, less attention has been paid to non-planar spiral micromixers with various cross-sections and the effects of these cross-sections on the total performance of the micromixer. Here, mixing performance in a spiral micromixer with different channel cross-sections is evaluated experimentally and numerically in the Re range of 0.001 to 50. The accuracy of the 3D-finite element model was first verified at different flow rates by tracking the mixing index across the loops, which were directly proportional to the spiral radius and were hence also proportional to the Dean flow. It is shown that higher flow rates induce stronger vortices compared to lower flow rates; thus, fewer loops are required for efficient mixing. The numerical study revealed that a large-angle outward trapezoidal cross-section provides the highest mixing performance, reaching efficiencies of up to 95%. Moreover, the velocity/vorticity along the channel length was analyzed and discussed to evaluate channel mixing performance. A relatively low pressure drop (<130 kPa) makes these passive spiral micromixers ideal candidates for various lab-on-chip applications.

Rozova, VS, Anwer, AG, Guller, AE, Es, HA, Khabir, Z, Sokolova, AI, Gavrilov, MU, Goldys, EM, Warkiani, ME, Thiery, JP & Zvyagin, AV 2021, 'Machine learning reveals mesenchymal breast carcinoma cell adaptation in response to matrix stiffness', PLOS Computational Biology, vol. 17, no. 7, pp. e1009193-e1009193.
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Epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition (MET), are believed to play key roles in facilitating the metastatic cascade. Metastatic lesions often exhibit a similar epithelial-like state to that of the primary tumour, in particular, by forming carcinoma cell clusters via E-cadherin-mediated junctional complexes. However, the factors enabling mesenchymal-like micrometastatic cells to resume growth and reacquire an epithelial phenotype in the target organ microenvironment remain elusive. In this study, we developed a workflow using image-based cell profiling and machine learning to examine morphological, contextual and molecular states of individual breast carcinoma cells (MDA-MB-231). MDA-MB-231 heterogeneous response to the host organ microenvironment was modelled by substrates with controllable stiffness varying from 0.2kPa (soft tissues) to 64kPa (bone tissues). We identified 3 distinct morphological cell types (morphs) varying from compact round-shaped to flattened irregular-shaped cells with lamellipodia, predominantly populating 2-kPa and >16kPa substrates, respectively. These observations were accompanied by significant changes in E-cadherin and vimentin expression. Furthermore, we demonstrate that the bone-mimicking substrate (64kPa) induced multicellular cluster formation accompanied by E-cadherin cell surface localisation. MDA-MB-231 cells responded to different substrate stiffness by morphological adaptation, changes in proliferation rate and cytoskeleton markers, and cluster formation on bone-mimicking substrate. Our results suggest that the stiffest microenvironment can induce MET.

Ryan, ST, Hosseini-Beheshti, E, Afrose, D, Ding, X, Xia, B, Grau, GE, Little, CB, McClements, L & Li, JJ 2021, 'Extracellular Vesicles from Mesenchymal Stromal Cells for the Treatment of Inflammation-Related Conditions', International Journal of Molecular Sciences, vol. 22, no. 6, pp. 3023-3023.
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Over the past two decades, mesenchymal stromal cells (MSCs) have demonstrated great potential in the treatment of inflammation-related conditions. Numerous early stage clinical trials have suggested that this treatment strategy has potential to lead to significant improvements in clinical outcomes. While promising, there remain substantial regulatory hurdles, safety concerns, and logistical issues that need to be addressed before cell-based treatments can have widespread clinical impact. These drawbacks, along with research aimed at elucidating the mechanisms by which MSCs exert their therapeutic effects, have inspired the development of extracellular vesicles (EVs) as anti-inflammatory therapeutic agents. The use of MSC-derived EVs for treating inflammation-related conditions has shown therapeutic potential in both in vitro and small animal studies. This review will explore the current research landscape pertaining to the use of MSC-derived EVs as anti-inflammatory and pro-regenerative agents in a range of inflammation-related conditions: osteoarthritis, rheumatoid arthritis, Alzheimer’s disease, cardiovascular disease, and preeclampsia. Along with this, the mechanisms by which MSC-derived EVs exert their beneficial effects on the damaged or degenerative tissues will be reviewed, giving insight into their therapeutic potential. Challenges and future perspectives on the use of MSC-derived EVs for the treatment of inflammation-related conditions will be discussed.

Rzhevskiy, A, Kapitannikova, A, Malinina, P, Volovetsky, A, Aboulkheyr Es, H, Kulasinghe, A, Thiery, JP, Maslennikova, A, Zvyagin, AV & Ebrahimi Warkiani, M 2021, 'Emerging role of circulating tumor cells in immunotherapy', Theranostics, vol. 11, no. 16, pp. 8057-8075.
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Over the last few years, immunotherapy, in particular, immune checkpoint inhibitor therapy, has revolutionized the treatment of several types of cancer. At the same time, the uptake in clinical oncology has been slow owing to the high cost of treatment, associated toxicity profiles and variability of the response to treatment between patients. In response, personalized approaches based on predictive biomarkers have emerged as new tools for patient stratification to achieve effective immunotherapy. Recently, the enumeration and molecular analysis of circulating tumor cells (CTCs) have been highlighted as prognostic biomarkers for the management of cancer patients during chemotherapy and for targeted therapy in a personalized manner. The expression of immune checkpoints on CTCs has been reported in a number of solid tumor types and has provided new insight into cancer immunotherapy management. In this review, we discuss recent advances in the identification of immune checkpoints using CTCs and shed light on the potential applications of CTCs towards the identification of predictive biomarkers for immunotherapy.

Sadeghi Rad, H, Monkman, J, Warkiani, ME, Ladwa, R, O'Byrne, K, Rezaei, N & Kulasinghe, A 2021, 'Understanding the tumor microenvironment for effective immunotherapy', Medicinal Research Reviews, vol. 41, no. 3, pp. 1474-1498.
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AbstractAdvances in immunotherapy have led to durable and long‐term benefits in a subset of patients across a number of solid tumor types. Understanding of the subsets of patients that respond to immune checkpoint inhibitors at the cellular level, and in the context of their tumor microenvironment (TME) is becoming increasingly important. The TME is composed of a heterogeneous milieu of tumor and immune cells. The immune landscape of the TME can inhibit or promote tumor initiation and progression; thus, a deeper understanding of tumor immunity is necessary to develop immunotherapeutic strategies. Recent developments have focused on characterizing the TME immune contexture (type, density, and function) to discover mechanisms and biomarkers that may predict treatment outcomes. This has, in part, been powered by advancements in spatial characterization technologies. In this review article, we address the role of specific immune cells within the TME at various stages of tumor progression and how the immune contexture determinants affecting tumor growth are used therapeutically.

Sadraeian, M, da Cruz, EF, Boyle, RW, Bahou, C, Chudasama, V, Janini, LMR, Diaz, RS & Guimarães, FEG 2021, 'Photoinduced Photosensitizer–Antibody Conjugates Kill HIV Env-Expressing Cells, Also Inactivating HIV', ACS Omega, vol. 6, no. 25, pp. 16524-16534.
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Sayyadi, N, Zhand, S, Razavi Bazaz, S & Warkiani, ME 2021, 'Affibody Functionalized Beads for the Highly Sensitive Detection of Cancer Cell-Derived Exosomes', International Journal of Molecular Sciences, vol. 22, no. 21, pp. 12014-12014.
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Exosomes belong to the class of extracellular vesicles of endocytic origin, which are regarded as a promising source of cancer biomarkers in liquid biopsy. As a result, an accurate, sensitive, and specific quantification of these nano-sized particles is of significant importance. Affinity-based approaches are recognized as the most valuable technique for exosome isolation and characterization. Indeed, Affibody biomolecules are a type of protein scaffold engineered with small size and enjoy the features of high thermal stability, affinity, and specificity. While the utilization of antibodies, aptamers, and other biologically active substances for exosome detection has been reported widely, there are no reports describing Affibody molecules’ usage for exosome detection. In this study, for the first time, we have proposed a novel strategy of using Affibody functionalized microbeads (AffiBeads) for exosome detection with a high degree of efficiency. As a proof-of-concept, anti-EGFR-AffiBeads were fabricated and applied to capture and detect human lung A549 cancer cell-derived EGFR-positive exosomes using flow cytometry and fluorescent microscopy. Moreover, the capture efficiency of the AffiBeads were compared with its counterpart antibody. Our results showed that the Affibody probe had a detection limit of 15.6 ng exosomes per mL (~12 exosomes per AffiBead). The approach proposed in the current study can be used for sensitive detection of low expression level markers on tumor-derived exosomes, providing a basis for early-stage cancer diagnosis.

Shan, X, Wang, F, Wang, D, Wen, S, Chen, C, Di, X, Nie, P, Liao, J, Liu, Y, Ding, L, Reece, PJ & Jin, D 2021, 'Optical tweezers beyond refractive index mismatch using highly doped upconversion nanoparticles', Nature Nanotechnology, vol. 16, no. 5, pp. 531-537.
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Optical tweezers are widely used in materials assembly1, characterization2, biomechanical force sensing3,4 and the in vivo manipulation of cells5 and organs6. The trapping force has primarily been generated through the refractive index mismatch between a trapped object and its surrounding medium. This poses a fundamental challenge for the optical trapping of low-refractive-index nanoscale objects, including nanoparticles and intracellular organelles. Here, we report a technology that employs a resonance effect to enhance the permittivity and polarizability of nanocrystals, leading to enhanced optical trapping forces by orders of magnitude. This effectively bypasses the requirement of refractive index mismatch at the nanoscale. We show that under resonance conditions, highly doping lanthanide ions in NaYF4 nanocrystals makes the real part of the Clausius-Mossotti factor approach its asymptotic limit, thereby achieving a maximum optical trap stiffness of 0.086 pN μm-1 mW-1 for 23.3-nm-radius low-refractive-index (1.46) nanoparticles, that is, more than 30 times stronger than the reported value for gold nanoparticles of the same size. Our results suggest a new potential of lanthanide doping for the optical control of the refractive index of nanomaterials, developing the optical force tag for the intracellular manipulation of organelles and integrating optical tweezers with temperature sensing and laser cooling7 capabilities.

Shi, X, Zuo, Y, Zhai, P, Shen, J, Yang, Y, Gao, Z, Liao, M, Wu, J, Wang, J, Xu, X, Tong, Q, Zhang, B, Wang, B, Sun, X, Zhang, L, Pei, Q, Jin, D, Chen, P & Peng, H 2021, 'Large-area display textiles integrated with functional systems', Nature, vol. 591, no. 7849, pp. 240-245.
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Displays are basic building blocks of modern electronics1,2. Integrating displays into textiles offers exciting opportunities for smart electronic textiles—the ultimate goal of wearable technology, poised to change the way in which we interact with electronic devices3,4,5,6. Display textiles serve to bridge human–machine interactions7,8,9, offering, for instance, a real-time communication tool for individuals with voice or speech difficulties. Electronic textiles capable of communicating10, sensing11,12 and supplying electricity13,14 have been reported previously. However, textiles with functional, large-area displays have not yet been achieved, because it is challenging to obtain small illuminating units that are both durable and easy to assemble over a wide area. Here we report a 6-metre-long, 25-centimetre-wide display textile containing 5 × 105 electroluminescent units spaced approximately 800 micrometres apart. Weaving conductive weft and luminescent warp fibres forms micrometre-scale electroluminescent units at the weft–warp contact points. The brightness between electroluminescent units deviates by less than 8 per cent and remains stable even when the textile is bent, stretched or pressed. Our display textile is flexible and breathable and withstands repeated machine-washing, making it suitable for practical applications. We show that an integrated textile system consisting of display, keyboard and power supply can serve as a communication tool, demonstrating the system’s potential within the ‘internet of things’ in various areas, including healthcare. Our approach unifies the fabrication and function of electronic devices with textiles, and we expect that woven-fibre materials will shape the next generation of electronics.

Shrestha, J, Ryan, ST, Mills, O, Zhand, S, Razavi Bazaz, S, Hansbro, PM, Ghadiri, M & Ebrahimi Warkiani, M 2021, 'A 3D-printed microfluidic platform for simulating the effects of CPAP on the nasal epithelium', Biofabrication, vol. 13, no. 3, pp. 035028-035028.
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Abstract Obstructive sleep apnea (OSA) is a chronic disorder that involves a decrease or complete cessation of airflow during sleep. It occurs when the muscles supporting the soft tissues in the throat relax during sleep, causing narrowing or closure of the upper airway. Sleep apnea is a serious medical condition with an increased risk of cardiovascular complications and impaired quality of life. Continuous positive airway pressure (CPAP) is the most effective treatment for moderate to severe cases of OSA and is effective in mild sleep apnea. However, CPAP therapy is associated with the development of several nasal side effects and is inconvenient for the user, leading to low compliance rates. The effects of CPAP treatment on the upper respiratory system, as well as the pathogenesis of side effects, are incompletely understood and not adequately researched. To better understand the effects of CPAP treatment on the upper respiratory system, we developed an in vitro 3D-printed microfluidic platform. A nasal epithelial cell line, RPMI 2650, was then exposed to certain conditions to mimic the in vivo environment. To create these conditions, the microfluidic device was utilized to expose nasal epithelial cells grown and differentiated at the air–liquid interface. The airflow was similar to what is experienced with CPAP, with pressure ranging between 0 and 20 cm of H2O. Cells exposed to pressure showed decreased barrier integrity, change in cellular shape, and increased cell death (lactate dehydrogenase release into media) compared to unstressed cells. Stressed cells also showed increased secretions of inflammatory markers IL-6 and IL-8 and had increased production of ATP. Our results suggest that stress induced by airflow leads to structural, metabolic, and inflammatory changes in the nasal epithelium, which may be responsible for develo...

Soleimanian, A, Khalilzadeh, B, Mahdipour, M, Aref, AR, Kalbasi, A, Bazaz, SR, Warkiani, ME, Rashidi, MR & Mahdavi, M 2021, 'An Efficient Graphene Quantum Dots-Based Electrochemical Cytosensor for the Sensitive Recognition of CD123 in Acute Myeloid Leukemia Cells', IEEE Sensors Journal, vol. 21, no. 15, pp. 16451-16463.
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Leukemia stem cells (LSCs) are suitable candidates to be deployed for the diagnosis and therapy of acute myeloid leukemia (AML) patients. In this study, a novel electrochemical cytosensor was designed for the sensitive detection and quantification of KG1a cells as a model of LSCs. The developed cytosensor was based on the overexpression of cell surface protein CD123 by leukemia KG1a cells. For this purpose, the glassy carbon electrode was modified by graphene quantum dots (GQDs), Au nanoparticles, streptavidin coated AuNPs, biotinylated CD123 antibody and target cells. The dense loading of CD123 antibody and electrical enhancement on the modified electrode were carried out using GQDs, this resulting in a sensitive detection of CD123 positive cells within KG1a cells. Step by step preparation of the nanomaterial-based cytosensor and its optimization steps were confirmed by different electrochemical techniques. The field emission scanning electron microscopy (FE-SEM) images also confirmed the proper attachment of the materials and the cells on the surface of the modified electrode. The linear detection range (LDR) and limit of detection (LOD) of the developed electrochemical biosensor were recorded as 1 cell/mL and 1-25 cells/mL, respectively, which is remarkable. Importantly, the present findings are precise and highly selective in the presence of other leukemia cells (NB4, HL60, and U937 cells). Further, the versatility and accuracy of the proposed cytosensor were evaluated using clinical samples. We believe that the cytosensor proposed in this study has the potential to serve as a next generation sensor for the early detection of leukemia stem cells.

Su, Q, Wei, H-L, Liu, Y, Chen, C, Guan, M, Wang, S, Su, Y, Wang, H, Chen, Z & Jin, D 2021, 'Six-photon upconverted excitation energy lock-in for ultraviolet-C enhancement', Nature Communications, vol. 12, no. 1, pp. 1-9.
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AbstractPhoton upconversion of near-infrared (NIR) irradiation into ultraviolet-C (UVC) emission offers many exciting opportunities for drug release in deep tissues, photodynamic therapy, solid-state lasing, energy storage, and photocatalysis. However, NIR-to-UVC upconversion remains a daunting challenge due to low quantum efficiency. Here, we report an unusual six-photon upconversion process in Gd3+/Tm3+-codoped nanoparticles following a heterogeneous core-multishell architecture. This design efficiently suppresses energy consumption induced by interior energy traps, maximizes cascade sensitizations of the NIR excitation, and promotes upconverted UVC emission from high-lying excited states. We realized the intense six-photon-upconverted UV emissions at 253 nm under 808 nm excitation. This work provides insight into mechanistic understanding of the upconversion process within the heterogeneous architecture, while offering exciting opportunities for developing nanoscale UVC emitters that can be remotely controlled through deep tissues upon NIR illumination.

Syed, MS, Marquis, C, Taylor, R & Warkiani, ME 2021, 'A two-step microengineered system for high-density cell retention from bioreactors', Separation and Purification Technology, vol. 254, pp. 117610-117610.
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Large-scale cell culture processes are required to produce biopharmaceuticals, cells for tissue engineering, and vaccine production while being effective in toxicity testing, gene therapy vector production for cancer research, and drug development. A growing trend in these industries, particularly for suspension cells, involves implementation of continuous cell perfusion processes, which require an aseptic, efficient, cost-effective, and reliable cell separation and retention scheme. Many cell separation techniques (membrane-based systems, lateral displacement devices, and acoustophoresis) have proven to be highly efficient, but suffer from issue of clogging and high cost, limiting their reliability, and thus, their overall feasibility. Some cell retention devices—those based on inertial microfluidics—offer high reliability (i.e., clog-free), but their efficiency reduces at higher cell concentrations. To overcome this apparent trade-off, we report the development of an integrated system consisting of two different membrane-less microfiltration techniques for cell separation from spent cell media. Although it could be adapted to numerous cell culture applications, this system was optimized and tested for suspension-adapted Chinese Hamster Ovary (CHO) cells. As the first step of the cell retention system, a miniaturised hydrocyclone was developed that could separate the cells with macroscopic volume processing rates (~200 mL/min). At this stage, up to 75% of the cells were isolated with minimal (<5%) change in the viability. The remaining cells passed through the overflow of the device and entered to a multiplexed spiral microchannel system, where more than 90% of the remaining cells were recovered, yielding an overall efficiency of up to 95%. The proposed integrated system is thus ideal for continuous and high throughput cell retention even at high cell concentrations (~80 million cells/mL), which is in range of current need in the bioprocessing industry.

Todd, N, McNally, R, Alqudah, A, Jerotic, D, Suvakov, S, Obradovic, D, Hoch, D, Hombrebueno, JR, Campos, GL, Watson, CJ, Gojnic-Dugalic, M, Simic, TP, Krasnodembskaya, A, Desoye, G, Eastwood, K-A, Hunter, AJ, Holmes, VA, McCance, DR, Young, IS, Grieve, DJ, Kenny, LC, Garovic, VD, Robson, T & McClements, L 2021, 'Role of A Novel Angiogenesis FKBPL-CD44 Pathway in Preeclampsia Risk Stratification and Mesenchymal Stem Cell Treatment', The Journal of Clinical Endocrinology & Metabolism, vol. 106, no. 1, pp. 26-41.
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Abstract Context Preeclampsia is a leading cardiovascular complication in pregnancy lacking effective diagnostic and treatment strategies. Objective To investigate the diagnostic and therapeutic target potential of the angiogenesis proteins, FK506-binding protein like (FKBPL) and CD44. Design and Intervention FKBPL and CD44 plasma concentration or placental expression were determined in women pre- or postdiagnosis of preeclampsia. Trophoblast and endothelial cell function was assessed following mesenchymal stem cell (MSC) treatment and in the context of FKBPL signaling. Settings and Participants Human samples prediagnosis (15 and 20 weeks of gestation; n ≥ 57), or postdiagnosis (n = 18 for plasma; n = 4 for placenta) of preeclampsia were used to determine FKBPL and CD44 levels, compared to healthy controls. Trophoblast or endothelial cells were exposed to low/high oxygen, and treated with MSC-conditioned media (MSC-CM) or a FKBPL overexpression plasmid. Main Outcome Measures Preeclampsia risk stratification and diagnostic potential of FKBPL and CD44 were investigated. MSC treatment effects and FKBPL-CD44 signaling in trophoblast and endothelial cells were assessed. Results The CD44/FKBPL ratio...

Vasilescu, SA, Khorsandi, S, Ding, L, Bazaz, SR, Nosrati, R, Gook, D & Warkiani, ME 2021, 'A microfluidic approach to rapid sperm recovery from heterogeneous cell suspensions', Scientific Reports, vol. 11, no. 1, pp. 1-11.
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AbstractThe isolation of sperm cells from background cell populations and debris is an essential step in all assisted reproductive technologies. Conventional techniques for sperm recovery from testicular sperm extractions stagnate at the sample processing stage, where it can take several hours to identify viable sperm from a background of collateral cells such as white bloods cells (WBCs), red blood cells (RBCs), epithelial cells (ECs) and in some cases cancer cells. Manual identification of sperm from contaminating cells and debris is a tedious and time-consuming operation that can be suitably addressed through inertial microfluidics. Microfluidics has proven an effective technology for high-quality sperm selection based on motility. However, motility-based selection methods cannot cater for viable, non-motile sperm often present in testicular or epididymal sperm extractions and aspirations. This study demonstrates the use of a 3D printed inertial microfluidic device for the separation of sperm cells from a mixed suspension of WBCs, RBCs, ECs, and leukemic cancer cells. This technology presents a 36-fold time improvement for the recovery of sperm cells (> 96%) by separating sperm, RBCS, WBCs, ECs and cancer cells into tight bands in less than 5 min. Furthermore, microfluidic processing of sperm has no impact on sperm parameters; vitality, motility, morphology, or DNA fragmentation of sperm. Applying inertial microfluidics for non-motile sperm recovery can greatly improve the current processing procedure of testicular sperm extractions, simplifying the fertility outcomes for severe forms of male infertility that warrant the surgery.

Wang, B, Chan, Y-L, Li, G, Ho, KF, Anwer, AG, Smith, BJ, Guo, H, Jalaludin, B, Herbert, C, Thomas, PS, Liao, J, Chapman, DG, Foster, PS, Saad, S, Chen, H & Oliver, BG 2021, 'Maternal Particulate Matter Exposure Impairs Lung Health and Is Associated with Mitochondrial Damage', Antioxidants, vol. 10, no. 7, pp. 1029-1029.
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Relatively little is known about the transgenerational effects of chronic maternal exposure to low-level traffic-related air pollution (TRAP) on the offspring lung health, nor are the effects of removing such exposure before pregnancy. Female BALB/c mice were exposed to PM2.5 (PM2.5, 5 µg/day) for 6 weeks before mating and during gestation and lactation; in a subgroup, PM was removed when mating started to model mothers moving to cleaner areas during pregnancy to protect their unborn child (Pre-exposure). Lung pathology was characterised in both dams and offspring. A subcohort of female offspring was also exposed to ovalbumin to model allergic airways disease. PM2.5 and Pre-exposure dams exhibited airways hyper-responsiveness (AHR) with mucus hypersecretion, increased mitochondrial reactive oxygen species (ROS) and mitochondrial dysfunction in the lungs. Female offspring from PM2.5 and Pre-exposure dams displayed AHR with increased lung inflammation and mitochondrial ROS production, while males only displayed increased lung inflammation. After the ovalbumin challenge, AHR was increased in female offspring from PM2.5 dams compared with those from control dams. Using an in vitro model, the mitochondria-targeted antioxidant MitoQ reversed mitochondrial dysfunction by PM stimulation, suggesting that the lung pathology in offspring is driven by dysfunctional mitochondria. In conclusion, chronic exposure to low doses of PM2.5 exerted transgenerational impairment on lung health.

Wang, B, Chen, H, Xenaki, D, Liao, J, Cowie, C & Oliver, BG 2021, 'Differential inflammatory and toxic effects in-vitro of wood smoke and traffic-related particulate matter from Sydney, Australia', Chemosphere, vol. 272, pp. 129616-129616.
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Background

It is well known that PM_2.5 generated by traffic or burning wood is pro-inflammatory and induces various adverse health outcomes in humans. In Sydney, New South Wales, Australia, the main anthropogenic contributors to particulate matter (PM) air pollution are wood combustion heaters, on-road vehicles, and coal-fired power stations. However, the relative toxicity of these local sources has not to date been investigated.

Method

PM_2.5 was collected on filters from the same sampling site in Liverpool, one suburb of Sydney. According to the positive matrix factorisation and collection season, filters were representative of either day with high traffic-related air pollution (TRAP), wood smoke, or both TRAP and woodsmoke (mixed air pollution). The elemental composition of the PM was assessed by accelerator-based ion beam analysis techniques (i.e. PIXE & PIGE) and size by Dynamic Light Scattering. Toxicity and inflammation were assessed in-vitro in human bronchial epithelial cells by measuring interleukin-6 (IL-6), interleukin-8 (IL-8) release, and MTT.

Results

Mixed air pollution (TRAP/wood smoke) PM had more nanometer (nm) sized PM than the other two groups. Using an in-vitro model of the lungs, the mixed air pollution PM was the most toxic, whereas the PM from woodsmoke induced greater IL-6 release than TRAP PM. There was no difference in the induction of IL-8 between the three sources of PM.

Conclusion

Marked differences occur in the cellular response to PM from different sources, with differences in both toxicity and inflammation.

Winston Zhao, Z, Peter Su, Q, Xie, XS & Sun, Y 2021, 'Super-Resolution Imaging Reveals Spatio-Temporal Propagation of Human Replication Foci Mediated by CTCF-Organized Chromatin Structures', Biophysical Journal, vol. 120, no. 3, pp. 278a-278a.
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Xue, B, Zhou, C, Qin, Y, Li, Y, Sun, Y, Chang, L, Shao, S, Li, Y, Zhang, M, Sun, C, He, R, Peter Su, Q & Sun, Y 2021, 'PN-ImTLSM facilitates high-throughput low background single-molecule localization microscopy deep in the cell', Biophysics Reports, vol. 7, no. 4, pp. 313-313.
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When imaging the nucleus structure of a cell, the out-of-focus fluorescence acts as background and hinders the detection of weak signals. Light-sheet fluorescence microscopy (LSFM) is a wide-field imaging approach which has the best of both background removal and imaging speed. However, the commonly adopted orthogonal excitation/detection scheme is hard to be applied to single-cell imaging due to steric hindrance. For LSFMs capable of high spatiotemporal single-cell imaging, the complex instrument design and operation largely limit their throughput of data collection. Here, we propose an approach for high-throughput background-free fluorescence imaging of single cells facilitated by the Immersion Tilted Light Sheet Microscopy (ImTLSM). ImTLSM is based on a light-sheet projected off the optical axis of a water immersion objective. With the illumination objective and the detection objective placed opposingly, ImTLSM can rapidly patrol and optically section multiple individual cells while maintaining single-molecule detection sensitivity and resolution. Further, the simplicity and robustness of ImTLSM in operation and maintenance enables high-throughput image collection to establish background removal datasets for deep learning. Using a deep learning model to train the mapping from epi-illumination images to ImTLSM illumination images, namely PN-ImTLSM, we demonstrated cross-modality fluorescence imaging, transforming the epi-illumination image to approach the background removal performance obtained with ImTLSM. We demonstrated that PN-ImTLSM can be generalized to large-field homogeneous illumination imaging, thereby further improving the imaging throughput. In addition, compared to commonly used background removal methods, PN-ImTLSM showed much better performance for areas where the background intensity changes sharply in space, facilitating high-density single-molecule localization microscopy. In summary, PN-ImTLSM paves the way for background-free fluor...

Yin, L, Au, WY, Yu, CC, Kwon, T, Lai, Z, Shang, M, Warkiani, ME, Rosche, R, Lim, CT & Han, J 2021, 'Miniature auto‐perfusion bioreactor system with spiral microfluidic cell retention device', Biotechnology and Bioengineering, vol. 118, no. 5, pp. 1951-1961.
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AbstractMedium perfusion is critical in maintaining high cell concentration in cultures. The conventional membrane filtration method for medium exchange has been challenged by the fouling and clogging of the membrane filters in long‐term cultures. In this study, we present a miniature auto‐perfusion system that can be operated inside a common‐size laboratory incubator. The system is equipped with a spiral microfluidic chip for cell retention to replace conventional membrane filters, which fundamentally overcomes the clogging and fouling problem. We showed that the system supported continuous perfusion culture of Chinese hamster ovary (CHO) cells in suspension up to 14 days without cell retention chip replacement. Compared to daily manual medium change, 25% higher CHO cell concentration can be maintained at an average auto‐perfusion rate of 196 ml/day in spinner flask at 70 ml working volume (2.8 VVD). The auto‐perfusion system also resulted in better cell quality at high concentrations, in terms of higher viability, more uniform and regular morphology, and fewer aggregates. We also demonstrated the potential application of the system for culturing mesenchymal stem cells on microcarriers. This miniature auto‐perfusion system provides an excellent solution to maintain cell‐favorable conditions and high cell concentration in small‐scale cultures for research and clinical uses.

Yu, L, Feng, Y, Zheng, S, Li, J, Liu, R & Jin, D 2021, 'Cloning and characterization of a novel DNase gene from Trichogramma pretiosum', Protein Expression and Purification, vol. 185, pp. 105896-105896.
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Zhand, S, Xiao, K, Razavi Bazaz, S, Zhu, Y, Bordhan, P, Jin, D & Warkiani, ME 2021, 'Improving capture efficiency of human cancer cell derived exosomes with nanostructured metal organic framework functionalized beads', Applied Materials Today, vol. 23, pp. 100994-100994.
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Extracellular vesicles (EVs) have emerged as an invaluable tool for analyzing the physiological processes and an alternative source of disease diagnostic and prognostic biomarkers in liquid biopsies. Exosomes are a subset of EVs offer a window into altered cellular or tissue states, and their detection potentially offers a multicomponent early-stage diagnostic readout. Immunocapture and flow cytometry analysis of exosomes using micron-sized beads has been reported to be a reproducible technique for analysis of exosome surface markers. Nevertheless, the capture capacity remains poor due to limited available surface area. In this study, we have proposed a nanocoating strategy using metal-organic framework (MOF) materials, in particular, Zeolitic Imidazolate Framework-8 (ZIF-8), for highly efficient capturing of low concentration of exosomes from minimally processed samples. In this method, a ZIF-8 thin film was formed on polydopamine-polyethyleneimine (PDA-PEI) coated polystyrene microbeads to improve antibody immobilization due to the larger surface area provided by the MOF microstructures. This novel coating enabled us to detect as little as 50 exosomes per 10 µm polystyrene bead functionalized with ZIF-8/PDA-PEI, which is 180 times higher than the previously reported methods using naked microbeads. This coating requires a lower concentration of antibody to capture exosomes on the surface of microbeads compared to the standard protocols. More importantly, the higher concentration of exosomes on each bead surface provides the opportunity (i.e., higher signal intensity) to sort the beads using fluorescence-activated cell sorting, facilitating molecular analysis of post fractionation exosomes. Additionally, the exosomes can easily be detached from the coated microbeads using EDTA, limiting the usage of harsh chemicals. The procedure described here can be easily reproduced and employed regardless of the biological sample used to obtain exosomes.

Zhang, G, Morrison, D, Bao, G, Yu, H, Yoon, CW, Song, T, Lee, J, Ung, AT & Huang, Z 2021, 'An Amine–Borane System Featuring Room‐Temperature Dehydrogenation and Regeneration', Angewandte Chemie International Edition, vol. 60, no. 21, pp. 11725-11729.
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AbstractAmine–borane complexes have been extensively studied as hydrogen storage materials. Herein, we report a new amine–borane system featuring a reversible dehydrogenation and regeneration at room temperature. In addition to high purity H2, the reaction between ethylenediamine bisborane (EDAB) and ethylenediamine (ED) leads to unique boron–carbon–nitrogen 5‐membered rings in the dehydrogenation product where one boron is tricoordinated by three nitrogen atoms. Owing to the unique cyclic structure, the dehydrogenation product can be efficiently converted back to EDAB by NaBH4 and H2O at room temperature. This finding could lead to the discovery of new amine boranes with potential usage as hydrogen storage materials.

Zhang, G, Morrison, D, Bao, G, Yu, H, Yoon, CW, Song, T, Lee, J, Ung, AT & Huang, Z 2021, 'An Amine–Borane System Featuring Room‐Temperature Dehydrogenation and Regeneration', Angewandte Chemie, vol. 133, no. 21, pp. 11831-11835.
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AbstractAmine–borane complexes have been extensively studied as hydrogen storage materials. Herein, we report a new amine–borane system featuring a reversible dehydrogenation and regeneration at room temperature. In addition to high purity H2, the reaction between ethylenediamine bisborane (EDAB) and ethylenediamine (ED) leads to unique boron–carbon–nitrogen 5‐membered rings in the dehydrogenation product where one boron is tricoordinated by three nitrogen atoms. Owing to the unique cyclic structure, the dehydrogenation product can be efficiently converted back to EDAB by NaBH4 and H2O at room temperature. This finding could lead to the discovery of new amine boranes with potential usage as hydrogen storage materials.

Zhang, H, Li, J, Chen, Y, Wu, J, Wang, K, Chen, L, Wang, Y, Jiang, X, Liu, Y, Wu, Y, Jin, D & Bu, W 2021, 'Magneto‐Electrically Enhanced Intracellular Catalysis of FePt‐FeC Heterostructures for Chemodynamic Therapy', Advanced Materials, vol. 33, no. 17, pp. 1-10.
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AbstractIntracellular catalytic reactions can tailor tumor cell plasticity toward high‐efficiency treatments, but the application is hindered by the low efficiency of intracellular catalysis. Here, a magneto‐electronic approach is developed for efficient intracellular catalysis by inducing eddy currents of FePt‐FeC heterostructures in mild alternating magnetic fields (frequency of f = 96 kHz and amplitude of B ≤ 70 mT). Finite element simulation shows a high density of induced charges gathering at the interface of FePt‐FeC heterostructure in the alternating magnetic field. As a result, the concentration of an essential coenzyme—β‐nicotinamide adenine dinucleotide—in cancer cells is significantly reduced by the enhanced catalytic hydrogenation reaction of FePt‐FeC heterostructures under alternating magnetic stimulation, leading to over 80% of senescent cancer cells—a vulnerable phenotype that facilitates further treatment. It is further demonstrated that senescent cancer cells can be efficiently killed by the chemodynamic therapy based on the enhanced Fenton‐like reaction. By promoting intracellular catalytic reactions in tumors, this approach may enable precise catalytic tumor treatment.

Zhang, L, Chen, C, Tay, SS, Wen, S, Cao, C, Biro, M, Jin, D & Stenzel, MH 2021, 'Optimizing the Polymer Cloak for Upconverting Nanoparticles: An Evaluation of Bioactivity and Optical Performance', ACS Applied Materials & Interfaces, vol. 13, no. 14, pp. 16142-16154.
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The ability of upconversion nanoparticles (UCNPs) to convert low-energy near-infrared (NIR) light into high-energy visible-ultraviolet light has resulted in their development as novel contrast agents for biomedical imaging. However, UCNPs often succumb to poor colloidal stability in aqueous media, which can be conquered by decorating the nanoparticle surface with polymers. The polymer cloak, therefore, plays an instrumental role in ensuring good stability in biological media. This study aims to understand the relationship between the length and grafting density of the polymer shell on the physicochemical and biological properties of these core-shell UCNPs. Poly(ethylene glycol) methyl ether methacrylate block ethylene glycol methacrylate phosphate (PPEGMEMAn-b-PEGMP3) with different numbers of PEGMEMA repeating units (26, 38, and 80) was prepared and attached to the UCNPs via the phosphate ligand of the poly(ethylene glycol methacrylate phosphate) (PEGMP) block at different polymer densities. The in vitro and in vivo protein corona, cellular uptake in two-dimensional (2D) monolayer and three-dimensional (3D) multicellular tumor spheroid (MCTS) models, and in vivo biodistribution in mice were evaluated. Furthermore, the photoluminescence of single-polymer-coated UCNPs was compared in solid state and cancer cells using laser scanning confocal microscopy (LSCM). Our results showed that the bioactivity and luminescence properties are chain length and grafting density dependent. The UCNPs coated with the longest PPEGMEMA chain, grafted at low brush density, were able to reduce the formation of the protein corona in vitro and in vivo, while these UCNPs also showed the brightest upconversion luminescence in the solid state. Moreover, these particular polymer-coated UCNPs showed enhanced cellular uptake, extended in vivo blood circulation time, and more accumulation in the liver, brain, and heart.

Zhang, L, Jin, D & Stenzel, MH 2021, 'Polymer-Functionalized Upconversion Nanoparticles for Light/Imaging-Guided Drug Delivery', Biomacromolecules, vol. 22, no. 8, pp. 3168-3201.
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The strong upconversion luminescence (UCL) of upconversion nanoparticles (UCNPs) endows the nanoparticles with attractive features for combined imaging and drug delivery. UCNPs convert near-infrared (NIR) light into light of shorter wavelengths such as light in the ultraviolet (UV) and visible regions, which can be used for light-guided drug delivery. Although light-responsive drug delivery systems as such have been known for many years, their application in medicine is limited, as strong UV-light can be damaging to tissue; moreover, UV light will not penetrate deeply into the skin, an issue that UCNPs can now address. However, UCNPs, as obtained after synthesis, are usually hydrophobic and require further surface functionalization to be stable in plasma. Polymers can serve as versatile surface coatings, as they can provide good colloidal stability, prevent the formation of a protein corona, provide a matrix for drugs, and be stimuli-responsive. In this Review, we provide a brief overview of the most recent progress in the synthesis of UCNPs with different shapes/sizes. We will then discuss the purpose of polymer coating for drug delivery before summarizing the strategies to coat UCNPs with various polymers. We will introduce the different polymers that have so far been used to coat UCNPs with the purpose to create a drug delivery system, focusing in detail on light-responsive polymers. To expand the application of UCNPs to allow photothermal therapy or magnetic resonance imaging (MRI) or to simply enhance the loading capacity of drugs, UCNPs were often combined with other materials to generate multifunctional nanoparticles such as carbon-based NPs and nanoMOFs. We then conclude with a discussion on drug loading and release and summarize the current knowledge on the toxicity of these polymer-coated UCNPs.

Zhang, Y, Wang, Q, Li, L, Le, Y, Liu, L, Yang, J, Li, Y, Bao, G & Yan, L 2021, 'Synthesis and preliminary structure-activity relationship study of 3-methylquinazolinone derivatives as EGFR inhibitors with enhanced antiproliferative activities against tumour cells', Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 36, no. 1, pp. 1205-1216.
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In this paper, a set of 3-methylquniazolinone derivatives were designed, synthesised, and studied the preliminary structure-activity relationship for antiproliferative activities. All target compounds performed significantly inhibitory effects against wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and tumour cells (A431, A549, MCF-7, and NCI-H1975). In particular, compound 4d 3-fluoro-N-(4-((3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methoxy)phenyl)benzamide showed higher antiproliferative activities against all tumour cells than Gefitinib (IC50 of 3.48, 2.55, 0.87 and 6.42 μM, respectively). Furthermore, compound 4d could induce apoptosis of MCF-7 cells and arrest in G2/M phase at the tested concentration. Molecular docking and ADMET studies showed that compound 4d could closely form many hydrogen bonds with EGFRwt-TK. Therefore, compound 4d is potential to develop as novel anti-cancer drug.

Zhang, Y, Xu, Y, Wang, D, Kuang, T, Wu, W, Xu, X, Jin, D & Lou, W 2021, 'Prognostic value of preoperative glucose to lymphocyte ratio in patients with resected pancreatic cancer', International Journal of Clinical Oncology, vol. 26, no. 1, pp. 135-144.
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Zhu, Y & Reece, PJ 2021, 'Differential Interference Contrast-Based Interrogation of Plasmonic Gold Nanohole Arrays for Label-Free Imaging Sensing', ACS Applied Nano Materials, vol. 4, no. 10, pp. 10657-10664.
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Plasmonic nanostructures provide a robust platform for label-free, refractive-index-based optical sensing. Most readout strategies for plasmonic sensing rely on the measurement of angle, wavelength, or intensity changes. The phase response, though it changes much more abruptly at plasmonic resonances, has been rarely investigated because of the requirement of a more sophisticated optical arrangement. Here, we present a phase-based imaging approach using differential interference contrast (DIC) as means of label-free optical sensing with plasmonic nanohole arrays. We develop a colorimetric-based imaging readout and evaluate the refractive-index sensing capability using a layer-by-layer polyelectrolyte deposition model. We cross-validate the DIC imaging approach using the corresponding DIC intensity and reflectance spectrum as well as numerical simulation and show good agreement among different measurements. Our platform opens an avenue for exploiting the phase response of nanoplasmonic structures for rapid and multiplexed sensing application.

Alqudah, A, Suvakov, S, Richards, C, Todd, N, Eastwood, K-A, Hunter, AJ, Holmes, VA, Mccance, DR, Young, IS, Furlong, F, Ali, A, Krasnodembskaya, A, Lopez-Campos, G, Garovic, VD & Mcclements, L 1970, 'NOVEL MIRNAS AS TARGETS OF MESENCHYMAL STEM CELLS-BASED THERAPY FOR TREATMENT OF PREECLAMPSIA', Journal of Hypertension, ESH-ISH, Ovid Technologies (Wolters Kluwer Health), ON-AIR, pp. e26-e27.
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Bark, JM, Kulasinghe, A, Leo, P, Hartel, G, Warkiani, ME, Jeffree, RL, Chua, B, Day, BW & Punyadeera, C 1970, 'Circulating tumor cells as prognostic biomarkers in glioblastoma.', CANCER RESEARCH, Annual Meeting of the American-Association-for-Cancer-Research (AACR), AMER ASSOC CANCER RESEARCH, PA, Philadelphia.

Bazaz, SR & Warkiani, ME 1970, 'Design and characterization of an inertial microfluidic channel to enhance the process of CAR-T cell therapy', MicroTAS 2021 - 25th International Conference on Miniaturized Systems for Chemistry and Life Sciences, pp. 1215-1216.
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Chimeric Antigen Receptor T (CAR-T) cell therapy is a novel approach that reprograms and strengthens the patients' T cells to attack cancer cells. During the process of CAR-T cell manufacturing, a significant number of cells should be discarded as their viability become compromised. Here, we have demonstrated that inertial microfluidics can assist in the rapid and high throughput separation of viable CAR-T cells from non-viable ones.

Deplazes, E, Hartmann, LM, Cranfield, CG & Garcia, A 1970, 'Cation-Selectivity of a Self-Assembled Peptide Pore in Planar Phospholipid Bilayers using Electrical Impedance Spectroscopy', Biophysical Journal, Elsevier BV, pp. 141a-141a.
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Elsemary, MT, Maritz, MF, Smith, L, Warkiani, M & Thierry, B 1970, 'Microfluidic purification of T lymphocytes separated from blood for chimeric antigen receptor T-cell manufacturing.', CANCER IMMUNOLOGY RESEARCH, AMER ASSOC CANCER RESEARCH.

Elsemary, MT, Maritz, MF, Smith, L, Warkiani, M & Thierry, B 1970, 'Microfluidic purification of T lymphocytes separated from blood for chimeric antigen receptor T-cell manufacturing.', CANCER IMMUNOLOGY RESEARCH, AMER ASSOC CANCER RESEARCH.

Kulasinghe, A, Monkman, J, Taheri, T, Warkiani, M, O'leary, C, Ladwa, R, Richard, D & O'Byrne, K 1970, 'High-Plex Digital Spatial Profiling of Non-Small-Cell Lung Cancer (NSCLC)', JOURNAL OF THORACIC ONCOLOGY, ELSEVIER SCIENCE INC, pp. S50-S50.

Lin, G, Liu, Y, Huang, G, Chen, Y, Makarov, D & Jin, D 1970, 'Rotating Micromachines with Stratified Disk Architecture for Dynamic Bioanalysis', The 1st International Conference on Micromachines and Applications, ICMA 2021, MDPI, pp. 9572-46.
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Magnetic microrobots with versatile mechanical motion will enable many ex- and in vivo applications. Unfortunately, monolithic integration of multiple functions in a streamlined microrobotic body is still challenging due to the compromise between fabrication throughput, device footprints, and material choices. In this talk, I will present a unified framework architecture for microrobotic functionalization to enable magnetically steered locomotion, chemical sensing and in vivo tracking. This has been achieved through stratifying stimuli-responsive nanoparticles in a hydrogelmicro-disk. We uncovered the key mechanism of leveraging spatially alternating magnetic energy potential to control a Euler’s disk-like microrobot to locomote swiftly on its sidewall. The results suggest great potential for microrobots to locomote while cooperating a wide range of functions, tailorable for universal application scenarios.

Rad, DM, Zhang, Z & Warkiani, ME 1970, 'Engineering of the mammalian cells with hand-held microfiltroporation platform', MicroTAS 2021 - 25th International Conference on Miniaturized Systems for Chemistry and Life Sciences, pp. 607-608.
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Recent breakthroughs have focused on reinvigorating conventional delivery methods as they critically suffer from low cell viability, expensive protocols, and inconsistent material delivery. Thus, we developed a hand-held microfiltroporation (MFP) platform to overcome these issues and achieve instant cargo delivery into the cells of interest without requiring a complex setup.

Radfar, P, Ding, L, Rezaei, M & Warkiani, ME 1970, 'RETRIEVAL OF STATIC DROPLETS: A STEP TOWARDS SINGLE-CELL ANALYSIS OF RARE CELLS', MicroTAS 2021 - 25th International Conference on Miniaturized Systems for Chemistry and Life Sciences, pp. 555-556.
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Single-cell Analysis (SA) of rare cells has shed new lights in diagnosis and management of patients. Yet, majority of SA workflows face difficulties to analyse low-input samples in a cost- and time-effective manner. Static Droplet Arrays offer a handheld and affordable solution for SA of low-input samples; however, they are limited in downstream applications due to the inability of recovering the droplets. To overcome this limitation, we have developed droplet retrieval methods for different rare cell analysis at single-cell resolution. The entire methods are operated manually using a handheld pipette, without relying on specialised equipment.

Tripathi, A, Kruk, S, Shang, Y, Zhou, J, Kravchenko, I, Jin, D & Kivshar, Y 1970, 'Topology-controlled Polarized Photoluminescence from Rare-earth Doped Nanocrystals', Conference on Lasers and Electro-Optics, CLEO: Science and Innovations, Optica Publishing Group.
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We show topology-controlled polarization of photoluminescence from rare-earth doped nanocrystals using disorder-immune zigzag arrays of dielectric nanoparticles. Topological control is verified by comparing emission from nanocrystals deposited on trivial and nontrivial arrays of nanoparticles.

Zhand, S, Bazaz, SR, Sayyadi, N & Warkiani, ME 1970, 'Affibody functionalized microbeads: A novel and facile platform for ultra-sensitive detection of exosomes', MicroTAS 2021 - 25th International Conference on Miniaturized Systems for Chemistry and Life Sciences, pp. 1427-1428.
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Exosomes regarded as a promising source of cancer biomarkers in liquid biopsy. Thus, accurate, sensitive, and specific quantification of these nano-sized particles is of significant importance. Affibody biomolecules are a type of engineered protein scaffold with small size, high thermal stability, affinity, and specificity. For the first time, we have proposed a novel strategy by using Anti-EGFR-Affibody functionalized microbeads (AffiBeads) for the detection of A549 cancer cell-derived exosomes. Results illustrate that the affibody probe can detect 15.6 ng exosomes/mL (~12 exosomes per AffiBead). This approach could be used for sensitive detection of low expressed cancer markers, providing a basis for early-stage cancer diagnosis.

Zhang, X, Tang, K, Hughes, B, Vasani, S, Liu, Z, Warkiani, M, Hartel, G, Ladwa, R, Kenny, L & Punyadeera, C 1970, 'Prognostic utility of circulating tumor cells/cell clusters in head and neck cancers.', CANCER RESEARCH, Annual Meeting of the American-Association-for-Cancer-Research (AACR), AMER ASSOC CANCER RESEARCH, PA, Philadelphia.

Zhanghao, K, Xi, P & Jin, D 1970, 'Super-resolution fluorescence polarization microscopy and its biological applications', Asia Communications and Photonics Conference 2021, Asia Communications and Photonics Conference, Optica Publishing Group, p. t2g.3.
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Fluorescent dipoles reflect the spatial orientation of the fluorophores, which indicates structural information of the targeted proteins. Imaging of fluorescent dipoles has been widely applied in structural research of cell membranes, biological filaments, and macromolecules. However, it suffers from the Abbe's diffraction limit, which deteriorates the imaging accuracy of both position and orientation of the fluorescent dipoles. Recently we developed several super-resolution tools to image the molecular orientation of fluorophores, including super-resolution dipole orientation mapping (SDOM) [1] and polarized structured illumination microscopy (pSIM) [2]. Our techniques model the fluorophores in the spatio-angular domain, describing both their position and orientation, which adds not only further super-resolution but also valuable biological insights. For the first time, our technique revealed the “side-by­side” organization the actin filaments in the “actin ring” structure of Membrane- associated Periodic Structure (MPS) in hippocampal neurons. Together with spectral detection, we also uncover the lipid heterogeneities of ten subcellular compartments [3], during different developmental stages of organelles, and even within the same organelle. The versatile applications of our technique suggest the broad application of super-resolution fluorescence polarization in future biological research.

Zhao, ZW, Su, QP, Xie, SX & Sun, Y 1970, 'Super-resolution imaging reveals spatio-temporal propagation of human replication foci mediated by CTCF-organized chromatin structures', Single Molecule Spectroscopy and Superresolution Imaging XIV, Single Molecule Spectroscopy and Superresolution Imaging XIV, SPIE.
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Zhao, ZW, Su, QP, Xie, XS & Sun, Y 1970, 'Super-resolution imaging reveals spatio-temporal propagation of human replication foci mediated by CTCF-organized chromatin structures', EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS, SPRINGER, pp. 192-192.

Alqudah, A, Wedyan, M, Qnais, E, Jawarneh, H & McClements, L 2021, 'Plasma Amino Acids Metabolomics’ Profile Important for Glucose Management in Jordanian people with Type 2 Diabetes', Cold Spring Harbor Laboratory.
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Chen, C, Liu, B, Liu, Y, Liao, J, Shan, X, Wang, F & Jin, D 2021, 'Upconversion Nanoparticles: Heterochromatic Nonlinear Optical Responses in Upconversion Nanoparticles for Super‐Resolution Nanoscopy (Adv. Mater. 23/2021)', Wiley, pp. 2170182-2170182.
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Chen, J, Yao, B, Yang, Z, Shi, W, Luo, T, Xi, P, Jin, D & Li, Y 2021, 'Ratiometric 4Pi single molecule localization with optimal resolution and color assignment', Cold Spring Harbor Laboratory.
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Deplazes, E, Domingo Tafalla, B, Murphy, C, White, J, Cranfield, CG & Garcia, A 2021, 'The Role of Ion-Phospholipid Interactions in the Permeation of Cations Across Zwitterionic Phospholipid Bilayers', Elsevier BV, pp. 42a-43a.
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Li, H, Wu, Z, Yang, Z, Zhanghao, K, Xi, P & Jin, D 2021, 'Axially Overlapped Multi-Focus Light Sheet with Enlarged Field of View'.

Liu, Y, Lin, G & Jin, D 2021, 'Off-axis gyration induces large-area circular motion of anisotropic microparticles in a dynamic magnetic trap'.

Mahmodi, H, Piloni, A, Utama, R & Kabakova, I 2021, 'Mechanical Mapping of Bioprinted Hydrogel Models by Brillouin Microscopy', Cold Spring Harbor Laboratory.
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Rad, MA, Mahmodi, H, Filipe, EC, Cox, TR, Kabakova, I & Tipper, JL 2021, 'Micromechanical Characterisation of 3D Bioprinted neural cell models using Brillouin Microscopy', Cold Spring Harbor Laboratory.
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Shi, Y, Wu, Y, Chin, LK, Chen, MK, Wang, S, Zhang, Y, Li, Z, Liu, PY, Zhou, X, Cai, H, Yu, Y, Yap, PH, Ser, W, Nguyen, B, Liao, J, Wang, F, Chan, CT, Kivshar, Y, Tsai, DP & Liu, AQ 2021, 'Digital virus manipulation chip with a large array of all-dielectric nanocavities', Research Square Platform LLC.
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Shojaei, M, Shamshirian, A, Monkman, J, Grice, L, Tran, M, Tan, CW, Rossi, GR, McCulloch, TR, Nalos, M, Chew, KY, Zhu, Y, Xia, Y, Wells, TJ, Senegaglia, AC, Rebelatto, CLK, Franck, CL, dos Santos, AFR, de Noronha, L, Motamen, S, Valadan, R, Amjadi, O, Gogna, R, Madan, E, Alizadeh-Navaei, R, Lamperti, L, Zuñiga, F, Nova-Lamperti, E, Labarca, G, Knippenberg, B, Herwanto, V, Wang, Y, Phu, A, Chew, T, Kwan, T, Kim, K, Teoh, S, Pelaia, TM, Kuan, WS, Jee, Y, Iredell, J, O’Byrne, K, Fraser, JF, Davis, MJ, Belz, G, Warkiani, M, Gallo, CS, Souza-Fonseca-Guimaraes, F, Nguyen, Q, Mclean, A, Kulasinghe, A, Short, KR & Tang, B 2021, 'IFI27 transcription is an early predictor for COVID-19 outcomes; a multi-cohort observational study', Cold Spring Harbor Laboratory.
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Zhanghao, K, Li, M, Chen, X, Liu, W, Wang, Y, Wu, Z, Shan, C, Wu, J, Zhang, Y, Xi, P & Jin, D 2021, 'Fast, live-cell imaging of 15 intracellular compartments by deep learning segmentation of super-resolution data', Cold Spring Harbor Laboratory.
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