Virtual Scanning Research Articles

Understanding the structural and energetic basis of PD-1 and monoclonal antibodies bound to PD-L1: A molecular modeling perspective

BackgroundThe inhibitors blocking the interaction between programmed cell death protein 1(PD-1) and programmed death-ligand 1(PD-L1) can activate the immune response of T cell and eliminate cancer cells. The crystallographic studies have provided structural insights of the interactive interfaces between PD-L1 and its protein ligands. However, the hotspot residues on PD-L1 as well as structural and energetic basis for different protein ligands still need to be further investigated. MethodsMolecular modeling methods including molecular dynamics simulation, per-residue free energy decomposition, virtual alanine scanning mutagenesis and residue-residue contact analysis were used to qualitatively and quantitatively analyze the interactions between PD-L1 and different protein ligands. ResultsThe results of virtual alanine scanning mutagenesis suggest that Y56, Q66, M115, D122, Y123, R125 are the hotspot residues on PD-L1. The residue-residue contact analysis further shows that PD-1 interacts with PD-L1 mainly by F and G strands while monoclonal antibodies like avelumab and BMS-936559 mainly interact with PD-L1 by CDR2 and CDR3 loops of the heavy chain. ConclusionsA structurally similar β-hairpin peptide with 13 or 14 residues was extracted from each protein ligand and these β-hairpin peptides were found tightly binding to the putative hotspot residues on PD-L1. General significanceThis study recognizes the hotspot residues on PD-L1 and uncovers the common structural and energetic basis of different protein ligands binding to PD-L1. These results will be valuable for the design of small molecule or peptide inhibitors targeting on PD-L1.

Spatiotemporal resolution of spinal meningeal and parenchymal inflammation during experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) induced by active immunization of C57BL/6 mice with peptide from myelin oligodendrocyte protein (MOG35–55), is a neuroinflammatory, demyelinating disease widely recognized as an animal model of multiple sclerosis (MS). Typically, EAE presents with an ascending course of paralysis, and inflammation that is predominantly localized to the spinal cord. Recent studies have further indicated that inflammation – in both MS and EAE – might initiate within the meninges and propagate from there to the underlying parenchyma. However, the patterns of inflammation within the respective meningeal and parenchymal compartments along the length of the spinal cord, and the progression with which these patterns develop during EAE, have yet to be detailed. Such analysis could hold key to identifying factors critical for spreading, as well as constraining, inflammation along the neuraxis. To address this issue, high-resolution 3-dimensional (3D) confocal microscopy was performed to visualize, in detail, the sequence of leukocyte infiltration at distinct regions of the spinal cord. High quality virtual slide scanning for imaging the entire spinal cord using epifluorescence was further conducted to highlight the directionality and relative degree of inflammation. Meningeal inflammation was found to precede parenchymal inflammation at all levels of the spinal cord, but did not develop equally or simultaneously throughout the subarachnoid space (SAS) of the meninges. Instead, meningeal inflammation was initially most obvious in the caudal SAS, from which it progressed to the immediate underlying parenchyma, paralleling the first signs of clinical disease in the tail and hind limbs. Meningeal inflammation could then be seen to extend in the caudal-to-rostral direction, followed by a similar, but delayed, trajectory of parenchymal inflammation. To additionally determine whether the course of ascending paralysis and leukocyte infiltration during EAE is reflected in differences in inflammatory gene expression by meningeal and parenchymal microvessels along the spinal cord, laser capture microdissection (LCM) coupled with gene expression profiling was performed. Expression profiles varied between these respective vessel populations at both the cervical and caudal levels of the spinal cord during disease progression, and within each vessel population at different levels of the cord at a given time during disease. These results reinforce a significant role for the meninges in the development and propagation of central nervous system inflammation associated with MS and EAE.

Altered saccadic targets when processing facial expressions under different attentional and stimulus conditions

Depending on a subject’s attentional bias, robust changes in emotional perception occur when facial blends (different emotions expressed on upper/lower face) are presented tachistoscopically. If no instructions are given, subjects overwhelmingly identify the lower facial expression when blends are presented to either visual field. If asked to attend to the upper face, subjects overwhelmingly identify the upper facial expression in the left visual field but remain slightly biased to the lower facial expression in the right visual field. The current investigation sought to determine whether differences in initial saccadic targets could help explain the perceptual biases described above. Ten subjects were presented with full and blend facial expressions under different attentional conditions. No saccadic differences were found for left versus right visual field presentations or for full facial versus blend stimuli. When asked to identify the presented emotion, saccades were directed to the lower face. When asked to attend to the upper face, saccades were directed to the upper face. When asked to attend to the upper face and try to identify the emotion, saccades were directed to the upper face but to a lesser degree. Thus, saccadic behavior supports the concept that there are cognitive-attentional pre-attunements when subjects visually process facial expressions. However, these pre-attunements do not fully explain the perceptual superiority of the left visual field for identifying the upper facial expression when facial blends are presented tachistoscopically. Hence other perceptual factors must be in play, such as the phenomenon of virtual scanning.

Measuring the sizes of microcircuit elements of widths less than 100 nm by the method of SEM probe defocusing

Using a virtual scanning electron microscope, the scanning electron microscope (SEM) method has been tested when measuring the sizes of microcircuit elements by means of the SEM probe defocusing method. The method is based on the choice of the points of SEM signals characterizing the features of their form, and determining the distance between these points depending on the focusing of the SEM probe. The extrapolation of the dependence to a zero size of the probe determines the width of the protrusions and trenches with the trapezoidal profiles at the level of the lower base of a trapezoid.

Mechanical properties of monolayer penta-graphene and phagraphene: a first-principles study.

Two new graphene allotropes, penta-graphene and phagraphene, have been proposed recently with unique electronic properties, e.g. quasi-direct band gap, direction-dependent Dirac cones and tunable Fermi velocities. However, their mechanical properties have not been fully studied yet. In this work, we have performed extensive density functional theory calculations to evaluate the mechanical properties of these two materials and compared with graphene, graphane, and pentaheptite. Our simulations show that the ultimate tensile strength (UTS) and the strain corresponding to UTS in both penta-graphene and phagraphene are smaller than that of graphene. A complete set of nonlinear anisotropic elastic constants up to the fourth order have been determined for these two allotropes using the tenets of continuum mechanics by fitting the stress-strain responses under uniaxial and biaxial tension until the point of fracture. We propose a new physical explanation for penta-graphene's negative Poisson's ratio based on the atomic de-wrinkling mechanism, driven by the local Hellman-Feynman force on each atom. Additionally, we used charge density plot and virtual Scanning Tunneling Microscopy images to analyze the initiation of fracture under uniaxial and biaxial tensile loading in these two materials. The charge density plots reveal that the charge density in sp3 bonds is lower than that in the sp2 bonds. In phagraphene, all the broken bonds were found to belong to the largest carbon ring in the structure.

Simulation-based scanning of a structured light system for objects without overhangs

This paper proposes an automated scanning process of a structured light system for objects without overhangs. The processes for scanning those objects need to plan scanning directions that minimise the missing area on a three-dimensional surface during the scanning process. Thus, the processes require an approach that finds the next scanning direction efficiently in terms of computational costs. This paper develops a scanning simulation approach to meet this requirement. In order to apply the developed approach, the proposed process generates a solution space for candidate-scanning directions, and represents an intermediate 3D model. The developed approach traverses the solution space in a virtual environment and executes virtual scanning for the intermediate 3D model. The virtual scanning result of each candidate-scanning direction is analysed in order to evaluate the contribution for filling missing area. The proposed process defines key scanning directions in the solution space through the iterative execution of the developed approach. The proposed process has been implemented, and applied to the scanning experiments of dental impressions.

Automatic ionospheric layers detection: Algorithms analysis

Vertical sounding is a widely used technique to obtain ionosphere measurements, such as an estimation of virtual height versus frequency scanning. It is performed by high frequency radar for geophysical applications called “ionospheric sounder” (or “ionosonde”). Radar detection depends mainly on targets characteristics. While several targets behavior and correspondent echo detection algorithms have been studied, a survey to address a suitable algorithm for ionospheric sounder has to be carried out.This paper is focused on automatic echo detection algorithms implemented in particular for an ionospheric sounder, target specific characteristics were studied as well. Adaptive threshold detection algorithms are proposed, compared to the current implemented algorithm, and tested using actual data obtained from the Advanced Ionospheric Sounder (AIS-INGV) at Rome Ionospheric Observatory. Different cases of study have been selected according typical ionospheric and detection conditions.

Virtual Scanning Algorithm Based on Additional-area in Road Surveillance

The road surveillance based on wireless sensor network nowadays has received great attention and its application has been extensively used in practice. In this application, when the invasion target moves from road entrance to system protection points in road network, the nodes in wireless sensor network could detect the target timely and give an alarm before the target reaches the protection points.There are three main types of algorithms for nodes awake in road surveillance application presently, namely AAU(Always Awake-Up) algorithm, DC(Duty-Cycling) algorithm and Virtual Scanning Algorithm (VISA). VISA, which tailored and optimized for road network surveillance, has better performance than the others.This paper puts forward Virtual Scanning Algorithm based on Additional-area(VISAA), which introduces the more sleep time of the nodes based on the Additional Communication Area, to ensure the surveillance more reliability and effectively.The simulation results show that our algorithm has positive significance to improve the performance of road surveillance.

Virtual scanning electron microscope. 5. Application in nanotechnology and in micro- and nanoelectronics

The provided examples demonstrate the application of a simulator-based virtual scanning electron microscope (SEM) in certification of test object sizes on a low-voltage SEM and in calibration of a high-voltage SEM operating in the slow secondary electron detection mode. Using the virtual SEM, the problem of comparing different SEM calibration techniques is solved.

TU‐CD‐304‐07: Intensity Modulated Electron Beam Therapy Employing Small Fields in Virtual Scanning Mode

Purpose:Dynamic electron radiation therapies such as dynamic electron arc radiotherapy (DEAR) utilize small fields to provide target conformity and fluence modulation. The purpose of this study is to demonstrate the feasibility of virtual scanning mode using small fields.Methods:Monte Carlo simulations (EGSnrc/BEAMnrc/DOSXYZnrc) were performed using validated Varian TrueBeam phase space files for electron beam energies of 6, 9, 12, and 16 MeV and square/circular fields (1×1/1, 2×2/2, 3×3/3, 4×4/4, 5×5/5 cm2/cm diameter). Resulting dose distributions (kernels) were used for subsequent calculations. The following analyses were performed: (1) Comparison of composite square fields and reference 10×10 cm2 dose distributions and (2) Scanning beam deliveries for square and circular fields realized as the convolution of kernels and scanning pattern. Preliminary beam weight and pattern optimization were also performed. Two linear scans of 10 cm with/without overlap were modeled. Comparison metrics included depth and orthogonal profiles at dmax.Results:(1) Composite fields regained reference depth dose profiles for most energies and fields within 5%. Smaller kernels and higher energies increased dose in the build‐up and Bremsstrahlung region (30%, 16MeV and 1×1 cm2), while reference dmax was maintained for all energies and composite fields. Smaller kernels (<2×2 cm2) maintained penumbra and field size within 0.2 cm, and flatness within 2%. Deterioration of penumbra for larger kernels (5×5 cm2) were observed. Balancing desirable dosimetry and efficiencies suggests that smaller kernels are used at edges and larger kernels in the center of the target. (2) Beam weight optimization improved cross‐plane penumbra (0.2 cm) and increased the field size (0.4 cm) on average. In‐plane penumbra and field size remained unchanged. Overlap depended on kernel size and optimal overlap resulted in flatness ±2%.Conclusion:Dynamic electron beam therapy in virtual scanning mode is feasible by employing small fields to achieve desired dose distributions and acceptable efficiencies.

Decreased PBRM1 expression predicts unfavorable prognosis in patients with clear cell renal cell carcinoma

AimsPBRM1 is one of the histone and chromatin regulators. A mutation in PBRM1 was recently identified in clear cell renal cell carcinoma (ccRCC). The aim of this study was to determine the clinicopathologic and prognostic significance of PBRM1 expression in ccRCC. Methods and resultsImmunohistochemistry was performed for PBRM1 in 657 ccRCC cases. The number of positive cells was determined using image analyzer after virtual microscope scanning. There was a strong correlation between decreased PBRM1 expression and old age, increased tumor size, higher Fuhrman grade, higher pT stage, and higher stage (all P <0.001). Patients with decreased PBRM1 expression showed significantly worse cancer-specific survival (CSS) and progression-free survival (PFS) (both P<0.001). In multivariate analysis, PBRM1 expression was an independent predictor of shorter PFS (P = 0.007). In lower-stage group (stages I and II), decreased expression of PBRM1 exhibited significantly worse CSS and PFS (both P<0.001) but not in higher-stage group (stages III and IV). In multivariate analysis of lower-stage group, decreased expression of PBRM1 was significantly associated with both poor CSS and PFS (P = 0.038 and 0.003, respectively). ConclusionsDecreased expression of PBRM1 predicts unfavorable clinical outcome in patients with ccRCC.

Virtual scanning electron microscope: 2. Principles of instrument construction

The principles of the construction of a virtual scanning electron microscope (SEM) are discussed. It is demonstrated that such a microscope cannot be created using a imitator of real SEM operation. It is concluded that a virtual SEM must be developed using a simulator of information similar to that which is obtained by means of a real microscope. The possibilities of reducing the time required to generate micro- and nanostructure images to values comparable with the imaging duration of real SEMs are analyzed.

Case Study: The Determination of a Complex Multi-Systemic Medical Condition by a Cognitive, Virtual Scanning Technique

The study of various medical conditions is limited by the current state of knowledge. New tech-nologies enable researchers to advance their understanding of various medical conditions and to advance their understanding of particular pathologies. Strannik Virtual Scanning (SVS) is such a technology. SVS is able to determine the genetic and non-genetic components of every pathology in each of the 30 main organs, and it is able to determine the onset of pathologies at a much earlier stage than any other technologies or techniques. This makes it an ideal tool to screen for the onset and progression of pathologies which are implicated in multi-systemic conditions and to determine the spectrum of pathologies i.e. comorbidities which are involved in diabetes, cardiovascular disease, migraine, chronic fatigue syndrome, fibromyalgia, depression, chronic kidney disease, etc. This case study illustrates how the technology can be usefully and cost-effectively deployed to determine the spectrum of pathologies which characterise Reynaud’s phenomenon. This includes pathologies in the liver and kidneys e.g. portal hypertension, renal insufficiency, nephritis, liver insufficiency, pre-symptomatic onset of heart attack, presymptomatic indications of dementia, pancreatic cancer, and ovarian cancer, which are difficult to diagnose and/or for which there is currently an unmet clinical need.

Capabilities of ultrasound diagnosis of tumors of the tongue and mouth floor

Objective: to study the capabilities of ultrasonography (USG) in the primary and specifying diagnosis of cancer of the tongue and mouth floor. Material and methods. The investigation was conducted with the GE logiq 9, by using the following modes: B-mode; virtual convex scanning providing a wider field of view; pulsed wave (PW) Doppler, and color Doppler mapping (CDM). A total of 128 patients, including 54 (42.2%) with tumors of the mouth floor mucosa and 74 (57.8%) with those of the tongue, were examined. There were 92 (71.2%) men and 36 (28.8%) women; their mean age was 55 years. USG was performed to estimate tumor spread to anatomically important adjacent structures. The findings were compared with magnetic resonance imaging data. Results. In all cases, tumor masses of the tongue and mouth appeared echographically as infiltrative changes mainly of hypoechoic (99.2%), heterogeneous and/or slightly heterogeneous (61%) patterns with uneven (93.8%) and indistinct (95.3%) outlines. In other cases, the changes presented with nodular masses (4.7%); in these cases, their outline was distinct, in places uneven. CDM revealed that blood flow was increased in the majority of cases (72.3%). Blood flow in the tumor did not differ from the rate of that in healthy tissue in 3.3% of cases and it was absent in other cases (24.4%). Conclusion. USG makes it possible to visualize well changes in the oral mucosal tumore and to estimate its spread to important anatomic structures.

Local imaging of high mobility two-dimensional electron systems with virtual scanning tunneling microscopy

Correlated electron states in high mobility two-dimensional electron systems (2DESs), including charge density waves and microemulsion phases intermediate between a Fermi liquid and Wigner crystal, are predicted to exhibit complex local charge order. Existing experimental studies, however, have mainly probed these systems at micron to millimeter scales rather than directly mapping spatial organization. Scanning probes should be well-suited to study the spatial structure of these states, but high mobility 2DESs are found at buried semiconductor interfaces, beyond the reach of conventional scanning tunneling microscopy. Scanning techniques based on electrostatic coupling to the 2DES deliver important insights, but generally with resolution limited by the depth of the 2DES. In this letter, we present our progress in developing a technique called “virtual scanning tunneling microscopy” that allows local tunneling into a high mobility 2DES. Using a specially designed bilayer GaAs/AlGaAs heterostructure where the tunnel coupling between two separate 2DESs is tunable via electrostatic gating, combined with a scanning gate, we show that the local tunneling can be controlled with sub-250 nm resolution.

A virtual scanning electron microscope. 4. Simulator-based implementation

A virtual scanning electron microscope (VSEM), which is based on a simulator of information, obtained on a real scanning electron microscope (SEM), is described. A semiempirical generation model of images in a SEM, operating in the low-voltage mode and high-voltage mode during recording backscattered and secondary slow electrons, forms the basis of a virtual SEM. A method of comparing real and virtual images is proposed. Examples of operation of the virtual SEM are given for elements of structures which are located both far from the edges of the structure and near these edges.

Virtual scanning electron microscope: 1. Objectives and tasks of virtual measuring instruments

Virtual measuring instruments, as well as their operation, are described during measurement of the characteristics of the objects under study. Their objectives and tasks are discussed in proving the correctness of solving incorrect inverse problems. It is demonstrated that a virtual scanning electron microscope must inevitably be created to solve various problems of micro- and nanotechnologies.

Regularized virtual fields method for mechanical properties identification of composite materials

This paper presents a new material parameters identification method based on the Virtual Fields Method (VFM) where a regularization term coming from a micromechanical model has been added. In this Regularized Virtual Fields Method (RVFM), the system of equations associated to the VFM is solved within a constrained optimization framework. The method was applied to virtual Scanning Electron Microscope in-situ tests aiming at determining the local properties of uni-directional composites loaded in the transverse direction and for which the strain fields were obtained through Digital Image Correlation (DIC). The method was tested for composites with various volume fractions and properties contrasts and under different boundary conditions. The potentials and limitations of the algorithm in the presence of noisy images were investigated and compared to that of the VFM and the other finite element based methods. The corresponding results indicate that the proposed RVFM is more efficient than the other identification techniques in terms of both accuracy and computational time. An optimum size of region of interest was also determined by taking into account DIC magnification requirements and based on the accuracy of the identified parameters. This kind of study can be very useful for determining, a priori, the level of resolution in the imaging system required for a favorable accuracy of the identified parameters.

Prezi Presentational Software as an Educational Tool for Analyzing Pathology Slides: Promoting a Learner Centered Environment Through Technology to Increase Student Satisfaction

Objective: To test Prezi online presentational software as a learning tool for students enrolled in a physiopathology laboratory class. Methods: A Prezi presentation was created and used in place of a virtual microscopy scanning digital pathology slide during a laboratory session attended by a total of 179 students. Review of the normal anatomical features and architecture of a tissue was followed by an annotated tour covering important aspects of its pathologic characteristics. This was also accompanied by comparisons of normal with abnormal tissue to facilitate student learning and comprehension. Student feedback was gathered for 3 successive trimesters using a survey to assess student satisfaction with use of the Prezi presentation as an effective teaching strategy in a physiopathology laboratory class. Results: Students reported that they preferred the Prezi presentation compared with the digital pathology scanning slide technology. Students overwhelmingly expressed the desire to shift to the Prezi format from the virtual scanning microscope as the type of instructional technology used in class. Conclusion: Based on student feedback, Prezi is an effective teaching tool. The overall success of this exercise and the positive student feedback warrant further development of additional Prezi presentations for continued use in physiopathology laboratory classes.

QM/MM Calculations Reveal the Different Nature of the Interaction of Two Carborane-Based Sulfamide Inhibitors of Human Carbonic Anhydrase II

The crystal structures of two novel carborane-sulfamide inhibitors in the complex with human carbonic anhydrase II (hCAII) have been studied using QM/MM calculations. Even though both complexes possess the strongly interacting sulfamide···zinc ion motif, the calculations have revealed the different nature of binding of the carborane parts of the inhibitors. The neutral closo-carborane cage was bound to hCAII mainly via dispersion interactions and formed only very weak dihydrogen bonds. On the contrary, the monoanionic nido cage interacted with the protein mainly via electrostatic interactions. It formed short and strong dihydrogen bonds (stabilization of up to 4.2 kcal/mol; H···H distances of 1.7 Å) with the polar hydrogen of protein NH2 groups. This type of binding is unique among all of the classical organic and inorganic inhibitors of hCAII. Virtual glycine scanning allowed us to identify the amino-acid side chains, which made important contributions to ligand-binding energies. In summary, using QM/MM calculations, we have provided a detailed understanding of the differences between the interactions of two carborane sulfamides, identified the amino acids of hCAII with which they interact, and thus paved the way for the computer-aided rational design of selective boron-cluster-containing hCAII inhibitors.