“Quantification by aberration corrected (S)TEM of boundaries formed by symmetry breaking phase transformations”. Schryvers D, Salje EKH, Nishida M, De Backer A, Idrissi H, Van Aert S, Ultramicroscopy 176, 194 (2017). http://doi.org/10.1016/j.ultramic.2016.12.022
Abstract: The present contribution gives a review of recent quantification work of atom displacements, atom site occupations and level of crystallinity in various systems and based on aberration corrected HR(S)TEM images. Depending on the case studied, picometer range precisions for individual distances can be obtained, boundary widths at the unit cell level determined or statistical evolutions of fractions of the ordered areas calculated. In all of these cases, these quantitative measures imply new routes for the applications of the respective materials.
Keywords: A1 Journal article; Electron microscopy for materials research (EMAT)
Impact Factor: 2.843
Times cited: 1
DOI: 10.1016/j.ultramic.2016.12.022
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“Preventing cation intermixing enables 50% quantum yield in sub-15 nm short-wave infrared-emitting rare-earth based core-shell nanocrystals”. Arteaga Cardona F, Jain N, Popescu R, Busko D, Madirov E, Arús BA, Gerthsen D, De Backer A, Bals S, Bruns OT, Chmyrov A, Van Aert S, Richards BS, Hudry D, Nature communications 14, 4462 (2023). http://doi.org/10.1038/s41467-023-40031-4
Abstract: Short-wave infrared (SWIR) fluorescence could become the new gold standard in optical imaging for biomedical applications due to important advantages such as lack of autofluorescence, weak photon absorption by blood and tissues, and reduced photon scattering coefficient. Therefore, contrary to the visible and NIR regions, tissues become translucent in the SWIR region. Nevertheless, the lack of bright and biocompatible probes is a key challenge that must be overcome to unlock the full potential of SWIR fluorescence. Although rare-earth-based core-shell nanocrystals appeared as promising SWIR probes, they suffer from limited photoluminescence quantum yield (PLQY). The lack of control over the atomic scale organization of such complex materials is one of the main barriers limiting their optical performance. Here, the growth of either homogeneous (α-NaYF<sub>4</sub>) or heterogeneous (CaF<sub>2</sub>) shell domains on optically-active α-NaYF<sub>4</sub>:Yb:Er (with and without Ce<sup>3+</sup>co-doping) core nanocrystals is reported. The atomic scale organization can be controlled by preventing cation intermixing only in heterogeneous core-shell nanocrystals with a dramatic impact on the PLQY. The latter reached 50% at 60 mW/cm<sup>2</sup>; one of the highest reported PLQY values for sub-15 nm nanocrystals. The most efficient nanocrystals were utilized for in vivo imaging above 1450 nm.
Keywords: A1 Journal article; Engineering sciences. Technology; Electron microscopy for materials research (EMAT)
Impact Factor: 16.6
Times cited: 1
DOI: 10.1038/s41467-023-40031-4
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Verhulst SL, de Backer J, Van Gaal L, de Backer W, Desager K (2008) Adenotonsillectomy as first-line treatment for sleep-disordered breathing in obese children. New York, 1399
Keywords: L1 Letter to the editor; Condensed Matter Theory (CMT); Laboratory Experimental Medicine and Pediatrics (LEMP)
Impact Factor: 13.204
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“Clinical applications of image-based airway computational fluid dynamics: assessment of inhalation medication and endobronchial devices”. de Backer JW, Vos WG, Germonpré, P, Salgado R, Parizel PM, de Backer W, Proceedings of the Society of Photo-optical Instrumentation Engineers 7262, 72621p (2009). http://doi.org/10.1117/12.811476
Abstract: Computational fluid dynamics (CFD) is a technique that is used increasingly in the biomedical field. Solving the flow equations numerically provides a convenient way to assess the efficiency of therapies and devices, ranging from cardiovascular stents and heart valves to hemodialysis workflows. Also in the respiratory field CFD has gained increasing interest, especially through the combination of three dimensional image reconstruction which results in highend patient-specific models. This paper provides an overview of clinical applications of CFD through image based modeling, resulting from recent studies performed in our center. We focused on two applications: assessment of the efficiency of inhalation medication and analysis of endobronchial valve placement. In the first application we assessed the mode of action of a novel bronchodilator in 10 treated patients and 4 controls. We assessed the local volume increase and resistance change based on the combination of imaging and CFD. We found a good correlation between the changes in volume and resistance coming from the CFD results and the clinical tests. In the second application we assessed the placement and effect of one way endobronchial valves on respiratory function in 6 patients. We found a strong patientspecific result of the therapy where in some patients the therapy resulted in complete atelectasis of the target lobe while in others the lobe remained inflated. We concluded from these applications that CFD can provide a better insight into clinically relevant therapies.
Keywords: A3 Journal article; Condensed Matter Theory (CMT); Antwerp Surgical Training, Anatomy and Research Centre (ASTARC); Laboratory Experimental Medicine and Pediatrics (LEMP)
DOI: 10.1117/12.811476
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“Quantitative annular dark field scanning transmission electron microscopy for nanoparticle atom-counting: What are the limits?”.De Backer A, De Wael A, Gonnissen J, Martinez GT, Béché, A, MacArthur KE, Jones L, Nellist PD, Van Aert S, Journal of physics : conference series 644Electron Microscopy and Analysis Group Conference (EMAG), JUN 02-JUL 02, 2015, Manchester, ENGLAND, 012034 (2015). http://doi.org/10.1088/1742-6596/644/1/012034
Abstract: Quantitative atomic resolution annular dark field scanning transmission electron microscopy (ADF STEM) has become a powerful technique for nanoparticle atom-counting. However, a lot of nanoparticles provide a severe characterisation challenge because of their limited size and beam sensitivity. Therefore, quantitative ADF STEM may greatly benefit from statistical detection theory in order to optimise the instrumental microscope settings such that the incoming electron dose can be kept as low as possible whilst still retaining single-atom precision. The principles of detection theory are used to quantify the probability of error for atom-counting. This enables us to decide between different image performance measures and to optimise the experimental detector settings for atom-counting in ADF STEM in an objective manner. To demonstrate this, ADF STEM imaging of an industrial catalyst has been conducted using the near-optimal detector settings. For this experiment, we discussed the limits for atom-counting diagnosed by combining a thorough statistical method and detailed image simulations.
Keywords: P1 Proceeding; Electron microscopy for materials research (EMAT)
DOI: 10.1088/1742-6596/644/1/012034
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“The effect of reactive oxygen and nitrogen species on the structure of cytoglobin: A potential tumor suppressor”. De Backer J, Razzokov J, Hammerschmid D, Mensch C, Hafideddine Z, Kumar N, van Raemdonck G, Yusupov M, Van Doorslaer S, Johannessen C, Sobott F, Bogaerts A, Dewilde S, Redox Biology 19, 1 (2018). http://doi.org/10.1016/j.redox.2018.07.019
Abstract: Many current anti-cancer therapies rely on increasing the intracellular reactive oxygen and nitrogen species (RONS) contents with the aim to induce irreparable damage, which subsequently results in tumor cell death. A novel tool in cancer therapy is the use of cold atmospheric plasma (CAP), which has been found to be very effective in the treatment of many different cancer cell types in vitro as well as in vivo, mainly through the vast generation of RONS. One of the key determinants of the cell's fate will be the interaction of RONS, generated by CAP, with important proteins, i.e. redox-regulatory proteins. One such protein is cytoglobin (CYGB), a recently discovered globin proposed to be involved in the protection of the cell against oxidative stress. In this study, the effect of plasma-produced RONS on CYGB was investigated through the treatment of CYGB with CAP for different treatment times. Spectroscopic analysis of CYGB showed that although chemical modifications occur, its secondary structure remains intact. Mass spectrometry experiments identified these modifications as oxidations of mainly sulfur-containing and aromatic amino acids. With longer treatment time, the treatment was also found to induce nitration of the heme. Furthermore, the two surface-exposed cysteine residues of CYGB were oxidized upon treatment, leading to the formation of intermolecular disulfide bridges, and potentially also intramolecular disulfide bridges. In addition, molecular dynamics and docking simulations confirmed, and further show, that the formation of an intramolecular disulfide bond, due to oxidative conditions, affects the CYGB 3D structure, thereby opening the access to the heme group, through gate functioning of His117. Altogether, the results obtained in this study (1) show that plasma-produced RONS can extensively oxidize proteins and (2) that the oxidation status of two redox-active cysteines lead to different conformations of CYGB.
Keywords: A1 Journal article; Plasma Lab for Applications in Sustainability and Medicine – Antwerp (PLASMANT); Molecular Spectroscopy (MolSpec)
Impact Factor: 6.337
DOI: 10.1016/j.redox.2018.07.019
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“Measuring Dynamic Structural Changes of Nanoparticles at the Atomic Scale Using Scanning Transmission Electron Microscopy”. De wael A, De Backer A, Jones L, Varambhia A, Nellist PD, Van Aert S, Physical Review Letters 124, 106105 (2020). http://doi.org/10.1103/PhysRevLett.124.106105
Abstract: We propose a new method to measure atomic scale dynamics of nanoparticles from experimental high-resolution annular dark field scanning transmission electron microscopy images. By using the so-called hidden Markov model, which explicitly models the possibility of structural changes, the number of atoms in each atomic column can be quantified over time. This newly proposed method outperforms the current atom-counting procedure and enables the determination of the probabilities and cross sections for surface diffusion. This method is therefore of great importance for revealing and quantifying the atomic structure when it evolves over time via adatom dynamics, surface diffusion, beam effects, or during in situ experiments.
Keywords: A1 Journal article; Electron microscopy for materials research (EMAT)
Impact Factor: 8.6
DOI: 10.1103/PhysRevLett.124.106105
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“Quantifying Strain and Dislocation Density at Nanocube Interfaces after Assembly and Epitaxy”. Agrawal H, Patra BK, Altantzis T, De Backer A, Garnett EC, Acs Applied Materials &, Interfaces 12, 8788 (2020). http://doi.org/10.1021/acsami.9b17779
Abstract: Nanoparticle self-assembly and epitaxy are utilized extensively to make 1D and 2D structures with complex shapes. High-resolution transmission electron microscopy (HRTEM) has shown that single-crystalline interfaces can form, but little is known about the strain and dislocations at these interfaces. Such information is critically important for applications: drastically reducing
dislocation density was the key breakthrough enabling widespread implementation of light-emitting diodes, while strain engineering has been fundamental to modern high-performance transistors, solar cells, and thermoelectrics. In this work, the interfacial defect and strain formation after selfassembly and room temperature epitaxy of 7 nm Pd nanocubes capped with polyvinylpyrrolidone (PVP) is examined. It is observed that, during ligand removal, the cubes move over large distances on the substrate, leading to both spontaneous self-assembly and epitaxy to form single crystals. Subsequently, atomically resolved images are used to quantify the strain and dislocation density at the epitaxial interfaces between cubes with different lateral and angular misorientations. It is shown that dislocation- and strain-free interfaces form when the nanocubes align parallel to each other. Angular misalignment between adjacent cubes does not necessarily lead to grain boundaries but does cause dislocations, with higher densities associated with larger rotations.
Keywords: A1 Journal article; Engineering sciences. Technology; Electron microscopy for materials research (EMAT); Applied Electrochemistry & Catalysis (ELCAT)
Impact Factor: 9.5
DOI: 10.1021/acsami.9b17779
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“Hidden Markov model for atom-counting from sequential ADF STEM images: Methodology, possibilities and limitations”. De wael A, De Backer A, Van Aert S, Ultramicroscopy 219, 113131 (2020). http://doi.org/10.1016/j.ultramic.2020.113131
Abstract: We present a quantitative method which allows us to reliably measure dynamic changes in the atomic structure of monatomic crystalline nanomaterials from a time series of atomic resolution annular dark field scanning transmission electron microscopy images. The approach is based on the so-called hidden Markov model and estimates the number of atoms in each atomic column of the nanomaterial in each frame of the time series. We discuss the origin of the improved performance for time series atom-counting as compared to the current state-of-the-art atom-counting procedures, and show that the so-called transition probabilities that describe the probability for an atomic column to lose or gain one or more atoms from frame to frame are particularly important. Using these transition probabilities, we show that the method can also be used to estimate the probability and cross section related to structural changes. Furthermore, we explore the possibilities for applying the method to time series recorded under variable environmental conditions. The method is shown to be promising for a reliable quantitative analysis of dynamic processes such as surface diffusion, adatom dynamics, beam effects, or in situ experiments.
Keywords: A1 Journal article; Electron microscopy for materials research (EMAT)
Impact Factor: 2.2
DOI: 10.1016/j.ultramic.2020.113131
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“Structural modification of NADPH oxidase activator (Noxa 1) by oxidative stress: An experimental and computational study”. Attri P, Park J-H, De Backer J, Kim M, Yun J-H, Heo Y, Dewilde S, Shiratani M, Choi EH, Lee W, Bogaerts A, International Journal Of Biological Macromolecules 163, 2405 (2020). http://doi.org/10.1016/j.ijbiomac.2020.09.120
Abstract: NADPH oxidases 1 (NOX1) derived reactive oxygen species (ROS) play an important role in the progression of cancer through signaling pathways. Therefore, in this paper, we demonstrate the effect of cold atmospheric plasma (CAP) on the structural changes of Noxa1 SH3 protein, one of the regulatory subunits of NOX1. For this purpose, firstly we purified the Noxa1 SH3 protein and analyzed the structure using X-ray crystallography, and subsequently, we treated the protein with two types of CAP reactors such as pulsed dielectric barrier discharge (DBD) and Soft Jet for different time intervals. The structural deformation of Noxa1 SH3 protein was analyzed by various experimental methods (circular dichroism, fluorescence, and NMR spectroscopy) and by MD simulations. Additionally, we demonstrate the effect of CAP (DBD and Soft Jet) on the viability and expression of NOX1 in A375 cancer cells. Our results are useful to understand the structural modification/oxidation occur in protein due to reactive oxygen and nitrogen (RONS) species generated by CAP.
Keywords: A1 Journal article; Plasma Lab for Applications in Sustainability and Medicine – Antwerp (PLASMANT)
Impact Factor: 8.2
DOI: 10.1016/j.ijbiomac.2020.09.120
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“Plasma treatment causes structural modifications in lysozyme, and increases cytotoxicity towards cancer cells”. Attri P, Kaushik NK, Kaushik N, Hammerschmid D, Privat-Maldonado A, De Backer J, Shiratani M, Choi EH, Bogaerts A, International Journal Of Biological Macromolecules 182, 1724 (2021). http://doi.org/10.1016/j.ijbiomac.2021.05.146
Abstract: Bacterial and mammalian proteins, such as lysozyme, are gaining increasing interest as anticancer drugs. This study aims to modify the lysozyme structure using cold atmospheric plasma to boost its cancer cell killing effect. We investigated the structure at acidic and neutral pH using various experimental techniques (circular dichroism, fluorescence, and mass spectrometry) and molecular dynamics simulations. The controlled structural modification of lysozyme at neutral pH enhances its activity, while the activity was lost at acidic pH at the same treatment conditions. Indeed, a larger number of amino acids were oxidized at acidic pH after plasma treatment, which results in a greater distortion of the lysozyme structure, whereas only limited structural changes were observed in lysozyme after plasma treatment at neutral pH. We found that the plasma-treated lysozyme significantly induced apoptosis to the cancer cells. Our results reveal that plasma-treated lysozyme could have potential as a new cancer cell killing drug.
Keywords: A1 Journal Article; Lysozyme; Cold atmospheric plasma; Cancer cell death; Plasma, laser ablation and surface modeling Antwerp (PLASMANT) ;
Impact Factor: 3.671
DOI: 10.1016/j.ijbiomac.2021.05.146
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“Oxidation of Innate Immune Checkpoint CD47 on Cancer Cells with Non-Thermal Plasma”. Lin A, Razzokov J, Verswyvel H, Privat-Maldonado A, De Backer J, Yusupov M, Cardenas De La Hoz E, Ponsaerts P, Smits E, Bogaerts A, Cancers 13, 579 (2021). http://doi.org/10.3390/cancers13030579
Abstract: Non-thermal plasma (NTP) therapy has been emerging as a promising cancer treatment strategy, and recently, its ability to locally induce immunogenic cancer cell death is being unraveled. We hypothesized that the chemical species produced by NTP reduce immunosuppressive surface proteins and checkpoints that are overexpressed on cancerous cells. Here, 3D in vitro tumor models, an in vivo mouse model, and molecular dynamics simulations are used to investigate the effect of NTP on CD47, a key innate immune checkpoint. CD47 is immediately modulated after NTP treatment and simulations reveal the potential oxidized salt-bridges responsible for conformational changes. Umbrella sampling simulations of CD47 with its receptor, signal-regulatory protein alpha (SIRPα), demonstrate that the induced-conformational changes reduce its binding affinity. Taken together, this work provides new insight into fundamental, chemical NTP-cancer cell interaction mechanisms and a previously overlooked advantage of present NTP cancer therapy: reducing immunosuppressive signals on the surface of cancer cells.
Keywords: A1 Journal article; Plasma Lab for Applications in Sustainability and Medicine – Antwerp (PLASMANT); Laboratory for Experimental Hematology (LEH); Center for Oncological Research (CORE)
DOI: 10.3390/cancers13030579
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“Atom column detection”. Fatermans J, de Backer A, den Dekker AJ, Van Aert S Advances in imaging and electron physics
T2 – Advances in imaging and electron physics. page 177 (2021).
Abstract: By combining statistical parameter estimation and model-order selection using a Bayesian framework, the maximum a posteriori (MAP) probability rule is proposed in this chapter as an objective and quantitative method to detect atom columns from high-resolution scanning transmission electron microscopy (HRSTEM) images. The validity and usefulness of this approach is demonstrated to both simulated and experimental annular dark-field (ADF) STEM images, but also to simultaneously acquired annular bright-field (ABF) and ADF STEM image data.
Keywords: H2 Book chapter; Electron microscopy for materials research (EMAT); Vision lab
DOI: 10.1016/BS.AIEP.2021.01.006
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“Atom counting”. de Backer A, Fatermans J, den Dekker AJ, Van Aert S Advances in imaging and electron physics
T2 – Advances in imaging and electron physics. page 91 (2021).
Abstract: In this chapter, a statistical model-based method to count the number of atoms of monotype crystalline nanostructures from high-resolution annular dark-field (ADF) scanning transmission electron microscopy (STEM) images is discussed in detail together with a thorough study on the possibilities and inherent limitations. We show that this method can be applied to nanocrystals of arbitrary shape, size, and atom type. The validity of the atom-counting results is confirmed by means of detailed image simulations and it is shown that the high sensitivity of our method enables us to count atoms with single atom sensitivity.
Keywords: H2 Book chapter; Electron microscopy for materials research (EMAT); Vision lab
DOI: 10.1016/BS.AIEP.2021.01.004
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“Efficient fitting algorithm”. de Backer A, Fatermans J, den Dekker AJ, Van Aert S Advances in imaging and electron physics
T2 – Advances in imaging and electron physics. page 73 (2021).
Abstract: An efficient model-based estimation algorithm is introduced to quantify the atomic column positions and intensities from atomic-resolution (scanning) transmission electron microscopy ((S)TEM) images. This algorithm uses the least squares estimator on image segments containing individual columns fully accounting for overlap between neighboring columns, enabling the analysis of a large field of view. To provide end-users with this well-established quantification method, a user friendly program, StatSTEM, is developed which is freely available under a GNU public license. In this chapter, this efficient algorithm is applied to three different nanostructures for which the analysis of a large field of view is required.
Keywords: H2 Book chapter; Electron microscopy for materials research (EMAT)
DOI: 10.1016/BS.AIEP.2021.01.003
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“General conclusions and future perspectives”. de Backer A, Fatermans J, den Dekker AJ, Van Aert S Advances in imaging and electron physics
T2 – Advances in imaging and electron physics. page 243 (2021).
Abstract: This chapter provides an overview of statistical and quantitative methodologies that have pushed (scanning) transmission electron microscopy ((S)TEM) toward accurate and precise measurements of unknown structure parameters for understanding the relation between the structure of a material and its properties. Hereby, statistical parameter estimation theory has extensively been used which enabled not only measuring atomic column positions, but also quantifying the number of atoms, and detecting atomic columns as accurately and precisely as possible from experimental images. As a general conclusion, it can be stated that advanced statistical techniques are ideal tools to perform quantitative electron microscopy at the atomic scale. In the future, statistical methods will continue to be developed and novel quantification procedures will open up new possibilities for studying material structures at the atomic scale.
Keywords: H2 Book chapter; Electron microscopy for materials research (EMAT); Vision lab
DOI: 10.1016/BS.AIEP.2021.01.008
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“Image-quality evaluation and model selection with maximum a posteriori probability”. Fatermans J, de Backer A, den Dekker AJ, Van Aert S Advances in imaging and electron physics
T2 – Advances in imaging and electron physics. page 215 (2021).
Abstract: The maximum a posteriori (MAP) probability rule for atom column detection can also be used as a tool to evaluate the relation between scanning transmission electron microscopy (STEM) image quality and atom detectability. In this chapter, a new image-quality measure is proposed that correlates well with atom detectability, namely the integrated contrast-to-noise ratio (ICNR). Furthermore, the working principle of the MAP probability rule is described in detail showing a close relation to the principles of model-selection methods.
Keywords: H2 Book chapter; Electron microscopy for materials research (EMAT); Vision lab
DOI: 10.1016/BS.AIEP.2021.01.007
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“Introduction”. de Backer A, Fatermans J, den Dekker AJ, Van Aert S Advances in imaging and electron physics
T2 – Advances in imaging and electron physics. page 1 (2021).
Keywords: H2 Book chapter; Electron microscopy for materials research (EMAT)
DOI: 10.1016/BS.AIEP.2021.01.001
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“Optimal experiment design for nanoparticle atom counting from ADF STEM images”. de Backer A, Fatermans J, den Dekker AJ, Van Aert S Advances in imaging and electron physics
T2 – Advances in imaging and electron physics. page 145 (2021).
Abstract: In this chapter, the principles of detection theory are used to quantify the probability of error for atom counting from high-resolution scanning transmission electron microscopy (HRSTEM) images. Binary and multiple hypothesis testing have been investigated in order to determine the limits to the precision with which the number of atoms in a projected atomic column can be estimated. The probability of error has been calculated when using STEM images, scattering cross-sections or peak intensities as a criterion to count atoms. Based on this analysis, we conclude that scattering cross-sections perform almost equally well as images and perform better than peak intensities. Furthermore, the optimal STEM detector design can be derived for atom counting using the expression of the probability of error. We show that for very thin objects the low-angle annular dark-field (LAADF) regime is optimal and that for thicker objects the optimal inner detector angle increases.
Keywords: H2 Book chapter; Electron microscopy for materials research (EMAT); Vision lab
DOI: 10.1016/BS.AIEP.2021.01.005
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“Statistical parameter estimation theory : principles and simulation studies”. de Backer A, Fatermans J, den Dekker AJ, Van Aert S Advances in imaging and electron physics
T2 – Advances in imaging and electron physics. page 29 (2021).
Abstract: In this chapter, the principles of statistical parameter estimation theory for a quantitative analysis of atomic-resolution electron microscopy images are introduced. Within this framework, electron microscopy images are described by a parametric statistical model. Here, parametric models are introduced for different types of electron microscopy images: reconstructed exit waves, annular dark-field (ADF) scanning transmission electron microscopy (STEM) images, and simultaneously acquired ADF and annular bright-field (ABF) STEM images. Furthermore, the Cramér-Rao lower bound (CRLB) is introduced, i.e. a theoretical lower bound on the variance of any unbiased estimator. This CRLB is used to quantify the precision of the structure parameters of interest, such as the atomic column positions and the integrated atomic column intensities.
Keywords: H2 Book chapter; Electron microscopy for materials research (EMAT); Vision lab
DOI: 10.1016/BS.AIEP.2021.01.002
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“Modelling ADF STEM images using elliptical Gaussian peaks and its effects on the quantification of structure parameters in the presence of sample tilt”. De wael A, De Backer A, Lobato I, Van Aert S, Ultramicroscopy , 113391 (2021). http://doi.org/10.1016/j.ultramic.2021.113391
Abstract: A small sample tilt away from a main zone axis orientation results in an elongation of the atomic columns in ADF STEM images. An often posed research question is therefore whether the ADF STEM image intensities of tilted nanomaterials should be quantified using a parametric imaging model consisting of elliptical rather than the currently used symmetrical peaks. To this purpose, simulated ADF STEM images corresponding to different amounts of sample tilt are studied using a parametric imaging model that consists of superimposed 2D elliptical Gaussian peaks on the one hand and symmetrical Gaussian peaks on the other hand. We investigate the quantification of structural parameters such as atomic column positions and scattering cross sections using both parametric imaging models. In this manner, we quantitatively study what can be gained from this elliptical model for quantitative ADF STEM, despite the increased parameter space and computational effort. Although a qualitative improvement can be achieved, no significant quantitative improvement in the estimated structure parameters is achieved by the elliptical model as compared to the symmetrical model. The decrease in scattering cross sections with increasing sample tilt is even identical for both types of parametric imaging models. This impedes direct comparison with zone axis image simulations. Nonetheless, we demonstrate how reliable atom-counting can still be achieved in the presence of small sample tilt.
Keywords: A1 Journal article; Electron microscopy for materials research (EMAT)
Impact Factor: 2.843
DOI: 10.1016/j.ultramic.2021.113391
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Lin A, De Backer J, Quatannens D, Cuypers B, Verswyvel H, De La Hoz EC, Ribbens B, Siozopoulou V, Van Audenaerde J, Marcq E, Lardon F, Laukens K, Vanlanduit S, Smits E, Bogaerts A (2022) The effect of local non‐thermal plasma therapy on the<scp>cancer‐immunity</scp>cycle in a melanoma mouse model
Abstract: Melanoma remains a deadly cancer despite significant advances in immune checkpoint blockade and targeted therapies. The incidence of melanoma is also growing worldwide, which highlights the need for novel treatment options and strategic combination of therapies. Here, we investigate non-thermal plasma (NTP), an ionized gas, as a promising, therapeutic option. In a melanoma mouse model, direct treatment of tumors with NTP results in reduced tumor burden and prolonged survival. Physical characterization of NTP treatment in situ reveals the deposited NTP energy and temperature associated with therapy response, and whole transcriptome analysis of the tumor identified several modulated pathways. NTP treatment also enhances the cancer-immunity cycle, as immune cells in both the tumor and tumor-draining lymph nodes appear more stimulated to perform their anti-cancer functions. Thus, our data suggest that local NTP therapy stimulates systemic, anti-cancer immunity. We discuss, in detail, how these fundamental insights will help direct the translation of NTP technology into the clinic and inform rational combination strategies to address the challenges in melanoma therapy.
Keywords: University Hospital Antwerp; A1 Journal article; Pharmacology. Therapy; Engineering sciences. Technology; ADReM Data Lab (ADReM); Plasma Lab for Applications in Sustainability and Medicine – Antwerp (PLASMANT); Center for Oncological Research (CORE); Proteinscience, proteomics and epigenetic signaling (PPES)
DOI: 10.1002/btm2.10314
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“Cytoglobin inhibits non-thermal plasma-induced apoptosis in melanoma cells through regulation of the NRF2-mediated antioxidant response”. De Backer J, Lin A, Berghe WV, Bogaerts A, Hoogewijs D, Redox Biology 55, 102399 (2022). http://doi.org/10.1016/j.redox.2022.102399
Abstract: Melanoma arises from pigment-producing cells called melanocytes located in the basal layers of the epidermis of the skin. Cytoglobin (CYGB) is a ubiquitously expressed hexacoordinated globin that is highly enriched in melanocytes and frequently downregulated during melanomagenesis. Previously, we showed that non-thermal plasma (NTP)-produced reactive oxygen and nitrogen species (RONS) lead to the formation of an intra molecular disulfide bridge that would allow CYGB to function as a redox-sensitive protein. Here, we investigate the cytotoxic effect of indirect NTP treatment in two melanoma cell lines with divergent endogenous CYGB expression levels, and we explore the role of CYGB in determining treatment outcome. Our findings are consistent with previous studies supporting that NTP cytotoxicity is mediated through the production of RONS and leads to apoptotic cell death in melanoma cells. Furthermore, we show that NTP-treated solutions elicit an antioxidant response through the activation of nuclear factor erythroid 2–related factor 2 (NRF2). The knock down and overexpression of CYGB respectively sensitizes and protects melanoma cells from RONS-induced apoptotic cell death. The presence of CYGB enhances heme-oxygenase 1 (HO-1) and NRF2 protein expression levels, whereas the absence impairs their expression. Moreover, analysis of the CYGB-dependent transcriptome demonstrates the tumor suppressor long non-coding RNA maternally expressed 3 (MEG3) as a hitherto unde scribed link between CYGB and NRF2. Thus, the presence of CYGB, at least in melanoma cells, seems to play a central role in determining the therapeutic outcome of RONS-inducing anticancer therapies, like NTP-treated solutions, possessing both tumor-suppressive and oncogenic features. Hence, CYGB expression could be of in terest either as a biomarker or as a candidate for future targeted therapies in melanoma.
Keywords: A1 Journal article; Plasma Lab for Applications in Sustainability and Medicine – Antwerp (PLASMANT); Proteinscience, proteomics and epigenetic signaling (PPES)
Impact Factor: 11.4
DOI: 10.1016/j.redox.2022.102399
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“Cytoglobin Silencing Promotes Melanoma Malignancy but Sensitizes for Ferroptosis and Pyroptosis Therapy Response”. De Backer J, Maric D, Zuhra K, Bogaerts A, Szabo C, Vanden Berghe W, Hoogewijs D, Antioxidants 11, 1548 (2022). http://doi.org/10.3390/antiox11081548
Abstract: Despite recent advances in melanoma treatment, there are still patients that either do not respond or develop resistance. This unresponsiveness and/or acquired resistance to therapy could be explained by the fact that some melanoma cells reside in a dedifferentiated state. Interestingly, this dedifferentiated state is associated with greater sensitivity to ferroptosis, a lipid peroxidation-reliant, iron-dependent form of cell death. Cytoglobin (CYGB) is an iron hexacoordinated globin that is highly enriched in melanocytes and frequently downregulated during melanomagenesis. In this study, we investigated the potential effect of CYGB on the cellular sensitivity towards (1S, 3R)-RAS-selective lethal small molecule (RSL3)-mediated ferroptosis in the G361 melanoma cells with abundant endogenous expression. Our findings show that an increased basal ROS level and higher degree of lipid peroxidation upon RSL3 treatment contribute to the increased sensitivity of CYGB knockdown G361 cells to ferroptosis. Furthermore, transcriptome analysis demonstrates the enrichment of multiple cancer malignancy pathways upon CYGB knockdown, supporting a tumor-suppressive role for CYGB. Remarkably, CYGB knockdown also triggers activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome and subsequent induction of pyroptosis target genes. Altogether, we show that silencing of CYGB expression modulates cancer therapy sensitivity via regulation of ferroptosis and pyroptosis cell death signaling pathways.
Keywords: A1 Journal article; Pharmacology. Therapy; Plasma Lab for Applications in Sustainability and Medicine – Antwerp (PLASMANT); Proteinscience, proteomics and epigenetic signaling (PPES)
Impact Factor: 7
DOI: 10.3390/antiox11081548
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“Experimental reconstructions of 3D atomic structures from electron microscopy images using a Bayesian genetic algorithm”. De Backer A, Van Aert S, Faes C, Arslan Irmak E, Nellist PD, Jones L, N P J Computational Materials 8, 216 (2022). http://doi.org/10.1038/s41524-022-00900-w
Abstract: We introduce a Bayesian genetic algorithm for reconstructing atomic models of monotype crystalline nanoparticles from a single projection using Z-contrast imaging. The number of atoms in a projected atomic column obtained from annular dark field scanning transmission electron microscopy images serves as an input for the initial three-dimensional model. The algorithm minimizes the energy of the structure while utilizing a priori information about the finite precision of the atom-counting results and neighbor-mass relations. The results show promising prospects for obtaining reliable reconstructions of beam-sensitive nanoparticles during dynamical processes from images acquired with sufficiently low incident electron doses.
Keywords: A1 Journal article; Electron microscopy for materials research (EMAT)
DOI: 10.1038/s41524-022-00900-w
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“Three Approaches for Representing the Statistical Uncertainty on Atom-Counting Results in Quantitative ADF STEM”. De wael A, De Backer A, Yu C-P, Sentürk DG, Lobato I, Faes C, Van Aert S, Microscopy and microanalysis , 1 (2022). http://doi.org/10.1017/S1431927622012284
Abstract: A decade ago, a statistics-based method was introduced to count the number of atoms from annular dark-field scanning transmission electron microscopy (ADF STEM) images. In the past years, this method was successfully applied to nanocrystals of arbitrary shape, size, and composition (and its high accuracy and precision has been demonstrated). However, the counting results obtained from this statistical framework are so far presented without a visualization of the actual uncertainty about this estimate. In this paper, we present three approaches that can be used to represent counting results together with their statistical error, and discuss which approach is most suited for further use based on simulations and an experimental ADF STEM image.
Keywords: A1 Journal article; Electron microscopy for materials research (EMAT)
Impact Factor: 2.8
DOI: 10.1017/S1431927622012284
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“Optimal experiment design for element specific atom counting using multiple annular dark field scanning transmission electron microscopy detectors”. Sentürk DG, De Backer A, Friedrich T, Van Aert S, Ultramicroscopy 242, 113626 (2022). http://doi.org/10.1016/j.ultramic.2022.113626
Abstract: This paper investigates the possible benefits for counting atoms of different chemical nature when analysing multiple 2D scanning transmission electron microscopy (STEM) images resulting from independent annular dark field (ADF) detector regimes. To reach this goal, the principles of statistical detection theory are used to quantify the probability of error when determining the number of atoms in atomic columns consisting of multiple types of elements. In order to apply this theory, atom-counting is formulated as a statistical hypothesis test, where each hypothesis corresponds to a specific number of atoms of each atom type in an atomic column. The probability of error, which is limited by the unavoidable presence of electron counting noise, can then be computed from scattering-cross sections extracted from multiple ADF STEM images. Minimisation of the probability of error as a function of the inner and outer angles of a specified number of independent ADF collection regimes results in optimal experimental designs. Based on simulations of spherical Au@Ag and Au@Pt core–shell nanoparticles, we investigate how the combination of two non-overlapping detector regimes helps to improve the probability of error when unscrambling two types of atoms. In particular, the combination of a narrow low angle ADF detector with a detector formed by the remaining annular collection regime is found to be optimal. The benefit is more significant if the atomic number Z difference becomes larger. In
addition, we show the benefit of subdividing the detector regime into three collection areas for heterogeneous nanostructures based on a structure consisting of three types of elements, e.g., a mixture of Au, Ag and Al atoms. Finally, these results are compared with the probability of error resulting when one would ultimately use a pixelated 4D STEM detector and how this could help to further reduce the incident electron dose.
Keywords: A1 Journal article; Electron microscopy for materials research (EMAT)
Impact Factor: 2.2
DOI: 10.1016/j.ultramic.2022.113626
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“Acquired non-thermal plasma resistance mediates a shift towards aerobic glycolysis and ferroptotic cell death in melanoma”. Lin A, Sahun M, Biscop E, Verswyvel H, De Waele J, De Backer J, Theys C, Cuypers B, Laukens K, Berghe WV, Smits E, Bogaerts A, Drug resistance updates 67, 100914 (2023). http://doi.org/10.1016/j.drup.2022.100914
Abstract: To gain insights into the underlying mechanisms of NTP therapy sensitivity and resistance, using the firstever
NTP-resistant cell line derived from sensitive melanoma cells (A375).
Methods: Melanoma cells were exposed to NTP and re-cultured for 12 consecutive weeks before evaluation
against the parental control cells. Whole transcriptome sequencing analysis was performed to identify differentially
expressed genes and enriched molecular pathways. Glucose uptake, extracellular lactate, media acidification,
and mitochondrial respiration was analyzed to determine metabolic changes. Cell death inhibitors were
used to assess the NTP-induced cell death mechanisms, and apoptosis and ferroptosis was further validated via
Annexin V, Caspase 3/7, and lipid peroxidation analysis.
Results: Cells continuously exposed to NTP became 10 times more resistant to NTP compared to the parental cell
line of the same passage, based on their half-maximal inhibitory concentration (IC50). Sequencing and metabolic
analysis indicated that NTP-resistant cells had a preference towards aerobic glycolysis, while cell death analysis
revealed that NTP-resistant cells exhibited less apoptosis but were more vulnerable to lipid peroxidation and
ferroptosis.
Conclusions: A preference towards aerobic glycolysis and ferroptotic cell death are key physiological changes in
NTP-resistance cells, which opens new avenues for further, in-depth research into other cancer types.
Keywords: A1 Journal article; Pharmacology. Therapy; ADReM Data Lab (ADReM); Center for Oncological Research (CORE); Proteinscience, proteomics and epigenetic signaling (PPES); Plasma Lab for Applications in Sustainability and Medicine – Antwerp (PLASMANT)
Impact Factor: 24.3
DOI: 10.1016/j.drup.2022.100914
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“Fast generation of calculated ADF-EDX scattering cross-sections under channelling conditions”. Zhang Z, Lobato I, De Backer A, Van Aert S, Nellist P, Ultramicroscopy 246, 113671 (2023). http://doi.org/10.1016/j.ultramic.2022.113671
Abstract: Advanced materials often consist of multiple elements which are arranged in a complicated structure. Quantitative scanning transmission electron microscopy is useful to determine the composition and thickness of nanostructures at the atomic scale. However, significant difficulties remain to quantify mixed columns by comparing the resulting atomic resolution images and spectroscopy data with multislice simulations where dynamic scattering needs to be taken into account. The combination of the computationally intensive nature of these simulations and the enormous amount of possible mixed column configurations for a given composition indeed severely hamper the quantification process. To overcome these challenges, we here report the development of an incoherent non-linear method for the fast prediction of ADF-EDX scattering cross-sections of mixed columns under channelling conditions. We first explain the origin of the ADF and EDX incoherence from scattering physics suggesting a linear dependence between those two signals in the case of a high-angle ADF detector. Taking EDX as a perfect incoherent reference mode, we quantitatively examine the ADF longitudinal incoherence under different microscope conditions using multislice simulations. Based on incoherent imaging, the atomic lensing model previously developed for ADF is now expanded to EDX, which yields ADF-EDX scattering cross-section predictions in good agreement with multislice simulations for mixed columns in a core–shell nanoparticle and a high entropy alloy. The fast and accurate prediction of ADF-EDX scattering cross-sections opens up new opportunities to explore the wide range of ordering possibilities of heterogeneous materials with multiple elements.
Keywords: A1 Journal article; Electron microscopy for materials research (EMAT)
Impact Factor: 2.2
DOI: 10.1016/j.ultramic.2022.113671
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“Real-time simulations of ADF STEM probe position-integrated scattering cross-sections for single element fcc crystals in zone axis orientation using a densely connected neural network”. Lobato I, De Backer A, Van Aert S, Ultramicroscopy 251, 113769 (2023). http://doi.org/10.1016/j.ultramic.2023.113769
Abstract: Quantification of annular dark field (ADF) scanning transmission electron microscopy (STEM) images in terms
of composition or thickness often relies on probe-position integrated scattering cross sections (PPISCS). In
order to compare experimental PPISCS with theoretically predicted ones, expensive simulations are needed for
a given specimen, zone axis orientation, and a variety of microscope settings. The computation time of such
simulations can be in the order of hours using a single GPU card. ADF STEM simulations can be efficiently
parallelized using multiple GPUs, as the calculation of each pixel is independent of other pixels. However, most
research groups do not have the necessary hardware, and, in the best-case scenario, the simulation time will
only be reduced proportionally to the number of GPUs used. In this manuscript, we use a learning approach and
present a densely connected neural network that is able to perform real-time ADF STEM PPISCS predictions as
a function of atomic column thickness for most common face-centered cubic (fcc) crystals (i.e., Al, Cu, Pd, Ag,
Pt, Au and Pb) along [100] and [111] zone axis orientations, root-mean-square displacements, and microscope
parameters. The proposed architecture is parameter efficient and yields accurate predictions for the PPISCS
values for a wide range of input parameters that are commonly used for aberration-corrected transmission
electron microscopes.
Keywords: A1 Journal article; Electron microscopy for materials research (EMAT)
Impact Factor: 2.2
DOI: 10.1016/j.ultramic.2023.113769
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