Search results for: modeling accuracy

Authors: Wiam El Kheir, Anais Dumais, Maude Beaudoin, Bernard Marcos, Nick Virgilio, Benoit Paquette, Nathalie Faucheux, Marc-Antoine Lauzon

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The high infiltrative pattern of glioblastoma multiforme cells (GBM) is the main cause responsible for the actual standard treatments failure. The tumor high heterogeneity, the interstitial fluid flow (IFF) and chemokines guides GBM cells migration in the brain parenchyma resulting in tumor recurrence. Drug delivery systems emerged as an alternative approach to develop effective treatments for the disease. Some recent studies have proposed to harness the effect CXC-lchemokine-ligand-12 to direct and control the cancer cell migration through delivery system. However, the dynamics of the brain environment on the delivery system remains poorly understood. Nanoparticles (NPs) and hydrogels are known as good carriers for the encapsulation of different agents and control their release. We studied the release of CXCL12 (free or loaded into NPs) from an alginate-based hydrogel under static and indirect perfusion (IP) conditions. Under static conditions, the main phenomena driving CXCL12 release from the hydrogel was diffusion with the presence of strong interactions between the positively charged CXCL12 and the negatively charge alginate. CXCL12 release profiles were independent from the initial mass loadings. Afterwards, we demonstrated that the release could tuned by loading CXCL12 into Alginate/Chitosan-Nanoparticles (Alg/Chit-NPs) and embedded them into alginate-hydrogel. The initial burst release was substantially attenuated and the overall cumulative release percentages of 21%, 16% and 7% were observed for initial mass loadings of 0.07, 0.13 and 0.26 µg, respectively, suggesting stronger electrostatic interactions. Results were mathematically modeled based on Fick’s second law of diffusion framework developed previously to estimate the effective diffusion coefficient (Deff) and the mass transfer coefficient. Embedding the CXCL12 into NPs decreased the Deff an order of magnitude, which was coherent with experimental data. Thereafter, we developed an in-vitro 3D model that takes into consideration the convective contribution of the brain IFF to study CXCL12 release in an in-vitro microenvironment that mimics as faithfully as possible the human brain. From is unique design, the model also allowed us to understand the effect of IP on CXCL12 release in respect to time and space. Four flow rates (0.5, 3, 6.5 and 10 µL/min) which may increase CXCL12 release in-vivo depending on the tumor location were assessed. Under IP, cumulative percentages varying between 4.5-7.3%, 23-58.5%, 77.8-92.5% and 89.2-95.9% were released for the three initial mass loadings of 0.08, 0.16 and 0.33 µg, respectively. As the flow rate increase, IP culture conditions resulted in a higher release of CXCL12 compared to static conditions as the convection contribution became the main driving mass transport phenomena. Further, depending on the flow rate, IP had a direct impact on CXCL12 distribution within the simulated brain tissue, which illustrates the importance of developing such 3D in-vitro models to assess the efficiency of a delivery system targeting the brain. In future work, using this very model, we aim to understand the impact of the different phenomenon occurring on GBM cell behaviors in response to the resulting chemokine gradient subjected to various flow while allowing them to express their invasive characteristics in an in-vitro microenvironment that mimics the in-vivo brain parenchyma.

Keywords: 3D culture system, chemokines gradient, glioblastoma multiforme, kinetic release, mathematical modeling

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Authors: Ankur Chaudhuri, Sibani Sen Chakraborty

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In human, glutaminyl cyclase activity is highly abundant in neuronal and secretory tissues and is preferentially restricted to hypothalamus and pituitary. The N-terminal modification of β-amyloids (Aβs) peptides by the generation of a pyro-glutamyl (pGlu) modified Aβs (pE-Aβs) is an important process in the initiation of the formation of neurotoxic plaques in Alzheimer’s disease (AD). This process is catalyzed by glutaminyl cyclase (QC). The expression of QC is characteristically up-regulated in the early stage of AD, and the hallmark of the inhibition of QC is the prevention of the formation of pE-Aβs and plaques. A computer-aided drug design (CADD) process was employed to give an idea for the designing of potentially active compounds to understand the inhibitory potency against human glutaminyl cyclase (QC). This work elaborates the ligand-based and structure-based pharmacophore exploration of glutaminyl cyclase (QC) by using the known inhibitors. Three dimensional (3D) quantitative structure-activity relationship (QSAR) methods were applied to 154 compounds with known IC50 values. All the inhibitors were divided into two sets, training-set, and test-sets. Generally, training-set was used to build the quantitative pharmacophore model based on the principle of structural diversity, whereas the test-set was employed to evaluate the predictive ability of the pharmacophore hypotheses. A chemical feature-based pharmacophore model was generated from the known 92 training-set compounds by HypoGen module implemented in Discovery Studio 2017 R2 software package. The best hypothesis was selected (Hypo1) based upon the highest correlation coefficient (0.8906), lowest total cost (463.72), and the lowest root mean square deviation (2.24Å) values. The highest correlation coefficient value indicates greater predictive activity of the hypothesis, whereas the lower root mean square deviation signifies a small deviation of experimental activity from the predicted one. The best pharmacophore model (Hypo1) of the candidate inhibitors predicted comprised four features: two hydrogen bond acceptor, one hydrogen bond donor, and one hydrophobic feature. The Hypo1 was validated by several parameters such as test set activity prediction, cost analysis, Fischer's randomization test, leave-one-out method, and heat map of ligand profiler. The predicted features were then used for virtual screening of potential compounds from NCI, ASINEX, Maybridge and Chembridge databases. More than seven million compounds were used for this purpose. The hit compounds were filtered by drug-likeness and pharmacokinetics properties. The selective hits were docked to the high-resolution three-dimensional structure of the target protein glutaminyl cyclase (PDB ID: 2AFU/2AFW) to filter these hits further. To validate the molecular docking results, the most active compound from the dataset was selected as a reference molecule. From the density functional theory (DFT) study, ten molecules were selected based on their highest HOMO (highest occupied molecular orbitals) energy and the lowest bandgap values. Molecular dynamics simulations with explicit solvation systems of the final ten hit compounds revealed that a large number of non-covalent interactions were formed with the binding site of the human glutaminyl cyclase. It was suggested that the hit compounds reported in this study could help in future designing of potent inhibitors as leads against human glutaminyl cyclase.

Keywords: glutaminyl cyclase, hit lead, pharmacophore model, simulation

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Authors: Christian J. Kennett, Mark A. Baldwin

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As several companies are working towards returning American astronauts back to space on US-made spacecraft, NASA developed a human flight certification-by-test and analysis approach due to the cost-prohibitive nature of extensive testing. This process relies heavily on the quality of analytical models to accurately predict crew injury potential specific to each spacecraft and under dynamic environments not tested. As the prime contractor on the Orion spacecraft, Lockheed Martin was tasked with quantifying the correlation of analytical anthropometric test devices (ATDs), also known as crash test dummies, against test measurements under representative impact conditions. Multiple dynamic impact sled tests were conducted to characterize Hybrid III 5th ATD lumbar, head, and neck responses with and without a modified shuttle-era advanced crew escape suit (ACES) under simulated Orion landing and abort conditions. Each ATD was restrained via a 5-point harness in a mockup Orion seat fixed to a dynamic impact sled at the Wright Patterson Air Force Base (WPAFB) Biodynamics Laboratory in the horizontal impact accelerator (HIA). ATDs were subject to multiple impact magnitudes, half-sine pulse rise times, and XZ - ‘eyeballs out/down’ or Z-axis ‘eyeballs down’ orientations for landing or an X-axis ‘eyeballs in’ orientation for abort. Several helmet constraint devices were evaluated during suited testing. Unique finite element models (FEMs) were developed of the unsuited and suited sled test configurations using an analytical 5th ATD model developed by LSTC (Livermore, CA) and deformable representations of the seat, suit, helmet constraint countermeasures, and body restraints. Explicit FE analyses were conducted using the non-linear solver LS-DYNA. Head linear and rotational acceleration, head rotational velocity, upper neck force and moment, and lumbar force time histories were compared between test and analysis using the enhanced error assessment of response time histories (EEARTH) composite score index. The EEARTH rating paired with the correlation and analysis (CORA) corridor rating provided a composite ISO score that was used to asses model correlation accuracy. NASA occupant protection subject matter experts established an ISO score of 0.5 or greater as the minimum expectation for correlating analytical and experimental ATD responses. Unsuited 5th ATD head X, Z, and resultant linear accelerations, head Y rotational accelerations and velocities, neck X and Z forces, and lumbar Z forces all showed consistent ISO scores above 0.5 in the XZ impact orientation, regardless of peak g-level or rise time. Upper neck Y moments were near or above the 0.5 score for most of the XZ cases. Similar trends were found in the XZ and Z-axis suited tests despite the addition of several different countermeasures for restraining the helmet. For the X-axis ‘eyeballs in’ loading direction, only resultant head linear acceleration and lumbar Z-axis force produced ISO scores above 0.5 whether unsuited or suited. The analytical LSTC 5th ATD model showed good correlation across multiple head, neck, and lumbar responses in both the unsuited and suited configurations when loaded in the XZ ‘eyeballs out/down’ direction. Upper neck moments were consistently the most difficult to predict, regardless of impact direction or test configuration.

Keywords: impact biomechanics, manned spaceflight, model correlation, multi-axial loading

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Authors: Savvas Rogotis, Nikolaos Kalatzis, Stergios Dimou-Sakellariou, Nikolaos Marianos

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As precision holds the key for the introduction of distinct benefits in agriculture (e.g., energy savings, reduced labor costs, optimal application of inputs, improved products, and yields), it steadily becomes evident that new initiatives should focus on rendering Precision Agriculture (PA) more accessible to the average farmer. PA leverages on technologies such as the Internet of Things (IoT), earth observation, robotics and positioning systems (e.g., the Global Navigation Satellite System – GNSS - as well as individual positioning systems like GPS, Glonass, Galileo) that allow: from simple data georeferencing to optimal navigation of agricultural machinery to even more complex tasks like Variable Rate Applications. An identified customer pain point is that, from one hand, typical triangulation-based positioning systems are not accurate enough (with errors up to several meters), while on the other hand, high precision positioning systems reaching centimeter-level accuracy, are very costly (up to thousands of euros). Within this paper, a Ground-Based Augmentation System (GBAS) is introduced, that can be adapted to any existing IoT field-sensing station infrastructure. The latter should cover a minimum set of requirements, and in particular, each station should operate as a fixed, obstruction-free towards the sky, energy supplying unit. Station augmentation will allow them to function in pairs with GNSS rovers following the differential GNSS base-rover paradigm. This constitutes a key innovation element for the proposed solution that encompasses differential GNSS capabilities into an IoT field-sensing infrastructure. Integrating this kind of information supports the provision of several additional PA beneficial services such as spatial mapping, route planning, and automatic field navigation of unmanned vehicles (UVs). Right at the heart of the designed system, there is a high-end GNSS toolkit with base-rover variants and Real-Time Kinematic (RTK) capabilities. The GNSS toolkit had to tackle all availability, performance, interfacing, and energy-related challenges that are faced for a real-time, low-power, and reliable in the field operation. Specifically, in terms of performance, preliminary findings exhibit a high rover positioning precision that can even reach less than 10-centimeters. As this precision is propagated to the full dataset collection, it enables tractors, UVs, Android-powered devices, and measuring units to deal with challenging real-world scenarios. The system is validated with the help of Gaiatrons, a mature network of agro-climatic telemetry stations with presence all over Greece and beyond ( > 60.000ha of agricultural land covered) that constitutes part of “gaiasense” (www.gaiasense.gr) smart farming (SF) solution. Gaiatrons constantly monitor atmospheric and soil parameters, thus, providing exact fit to operational requirements asked from modern SF infrastructures. Gaiatrons are ultra-low-cost, compact, and energy-autonomous stations with a modular design that enables the integration of advanced GNSS base station capabilities on top of them. A set of demanding pilot demonstrations has been initiated in Stimagka, Greece, an area with a diverse geomorphological landscape where grape cultivation is particularly popular. Pilot demonstrations are in the course of validating the preliminary system findings in its intended environment, tackle all technical challenges, and effectively highlight the added-value offered by the system in action.

Keywords: GNSS, GBAS, precision agriculture, RTK, smart farming

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Authors: Sam Weber, Deepak Mishra, Susan Wilde, Elizabeth Kramer

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The frequency and severity of cyanobacteria harmful blooms (CyanoHABs) have been increasing over time, with point and non-point source eutrophication and shifting climate paradigms being blamed as the primary culprits. Excessive nutrients, warm temperatures, quiescent water, and heavy and less regular rainfall create more conducive environments for CyanoHABs. CyanoHABs have the potential to produce a spectrum of toxins that cause gastrointestinal stress, organ failure, and even death in humans and animals. To promote enhanced, proactive CyanoHAB management, risk modeling using geospatial tools can act as predictive mechanisms to supplement current CyanoHAB monitoring, management and mitigation efforts. The risk maps would empower water managers to focus their efforts on high risk water bodies in an attempt to prevent CyanoHABs before they occur, and/or more diligently observe those waterbodies. For this research, exploratory spatial data analysis techniques were used to identify the strongest predicators for CyanoHAB blooms based on remote sensing-derived cyanobacteria cell density values for 771 waterbodies in the Georgia Piedmont and landscape characteristics of their watersheds. In-situ datasets for cyanobacteria cell density, nutrients, temperature, and rainfall patterns are not widely available, so free gridded geospatial datasets were used as proxy variables for assessing CyanoHAB risk. For example, the percent of a watershed that is agriculture was used as a proxy for nutrient loading, and the summer precipitation within a watershed was used as a proxy for water quiescence. Cyanobacteria cell density values were calculated using atmospherically corrected images from the European Space Agency’s Sentinel-2A satellite and multispectral instrument sensor at a 10-meter ground resolution. Seventeen explanatory variables were calculated for each watershed utilizing the multi-petabyte geospatial catalogs available within the Google Earth Engine cloud computing interface. The seventeen variables were then used in a multiple linear regression model, and the strongest predictors of cyanobacteria cell density were selected for the final regression model. The seventeen explanatory variables included land cover composition, winter and summer temperature and precipitation data, topographic derivatives, vegetation index anomalies, and soil characteristics. Watershed maximum summer temperature, percent agriculture, percent forest, percent impervious, and waterbody area emerged as the strongest predictors of cyanobacteria cell density with an adjusted R-squared value of 0.31 and a p-value ~ 0. The final regression equation was used to make a normalized cyanobacteria cell density index, and a Jenks Natural Break classification was used to assign waterbodies designations of low, medium, or high risk. Of the 771 waterbodies, 24.38% were low risk, 37.35% were medium risk, and 38.26% were high risk. This study showed that there are significant relationships between free geospatial datasets representing summer maximum temperatures, nutrient loading associated with land use and land cover, and the area of a waterbody with cyanobacteria cell density. This data analytics approach to CyanoHAB risk assessment corroborated the literature-established environmental triggers for CyanoHABs, and presents a novel approach for CyanoHAB risk mapping in waterbodies across the greater southeastern United States.

Keywords: cyanobacteria, land use/land cover, remote sensing, risk mapping

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Authors: Kaori Nakamura, Shun Su, Yusak Sulio, Daisuke Fukuda

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Active modes of transportation, such as walking and cycling, are crucial in promoting healthy and sustainable urban environments. Encouraging the use of these modes requires a well-designed road environment that ensures safety and comfort. Understanding what constitutes a safe environment for these users is essential. While previous research mainly focuses on subjective safety or the likelihood of collisions, there needs to be more analysis of the real-time experiences of travelers and dynamic transitions of their discomfort perceptions. Post-ride surveys or pre-ride impressions, the typical evaluation methods in past studies, may not accurately capture the immediate reactions and discomforts experienced during their rides. Though past experimental studies may also use physiological and behavioral data to evaluate road designs, they evaluated road design by comparing time-average physiological and behavioral data across different designs. This study aims to investigate the effects of the dynamic riding environmental changes experienced by cyclists during their rides on their dynamic physiological and behavioral responses and then explore how these conditions contribute to cyclists' overall subjective safety and comfort. We conducted an experiment with 24 participants who cycled approximately 500 meters in a virtual reality (VR) environment designed to mimic a typical road environment of Japanese local towns where lanes for cyclists and regular cars are adjacent in limited road spaces. Participants experienced six road designs varying in width, separation type, and bike lane color. We measured their physiological data, such as heart rate and skin conductance, and behavioral data, including steering, acceleration, and coordination of bicycles. Questionnaires for eliciting subjective impressions were conducted before and after each ride. The data analysis results indicate that wider paths (i.e., 1.5m and 2m width) are preferred, enhancing perceived safety and reducing stress, as supported by lower heart rates and skin conductance levels over narrower ones (1m width). Designs with clear divisions from car lanes may enhance perceived safety and reduce stress. The analysis of the physiological data also supports these arguments, showing that lower heart rates and skin conductance levels are found in wider, clearly marked paths. Further, the drift-diffusion decision model was performed to reveal whether different road environment designs may impact dynamic decision-making processes and physiological attributes. Designing a 1.5m wide bike lane with clear divisions from car lanes showed the highest level of clarity and safety in decision-making parameters. In contrast, designs without clear separations from car lanes resulted in less favorable decision-making outcomes. These results coincide with previous primary research indicating a preference for bike lane widths more significant than 1.5m. In conclusion, the analysis using the drift-diffusion decision model showed that decision-making ease slightly differs from subjective safety perceptions, providing a comprehensive understanding of how different road designs impact users. This study offers a solid foundation for assessing the perceptions of active mode users and highlights the importance of considering both real-time physiological and subjective data in designing road environments that encourage active transportation modes.

Keywords: active transport modes, cognitive and decision-making modeling, road environment designs, virtual reality experiment

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Authors: Nanine Fouche

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The Cape Flats is a low-lying sand-covered expanse of approximately 460 square kilometres, situated to the southeast of the central business district of Cape Town in the Western Cape of South Africa. The aeolian sands masking this area are often loose and compressible in the upper 1m to 1.5m of the surface, and there is a general exceedance of the maximum allowable settlement in these sands. The settlement of shallow foundations on Cape Flats sands is commonly predicted using the results of in-situ tests such as the SPT or DPSH due to the difficulty of retrieving undisturbed samples for laboratory testing. Varying degrees of accuracy and reliability are associated with these methods. More recently, shear wave velocity (Vs) profiles obtained from seismic testing, such as continuous surface wave tests (CSW), are being used for settlement prediction. Such predictions have the advantage of considering non-linear stress-strain behaviour of soil and the degradation of stiffness with increasing strain. CSW tests are rarely executed in the Cape Flats, whereas SPT’s are commonly performed. For this reason, and to facilitate better settlement predictions in Cape Flats sand, equations representing shear wave velocity (Vs) as a function of SPT blow count (N60) and vertical effective stress (v’) were generated by statistical regression of site investigation data. To reveal the most appropriate method of overburden correction, analyses were performed with a separate overburden term (Pa/σ’v) as well as using stress corrected shear wave velocity and SPT blow counts (correcting Vs. and N60 to Vs1and (N1)60respectively). Shear wave velocity profiles and SPT blow count data from three sites masked by Cape Flats sands were utilised to generate 80 Vs-SPT N data pairs for analysis. Investigated terrains included sites in the suburbs of Athlone, Muizenburg, and Atlantis, all underlain by windblown deposits comprising fine and medium sand with varying fines contents. Elastic settlement analysis was also undertaken for the Cape Flats sands, using a non-linear stepwise method based on small-strain stiffness estimates, which was obtained from the best Vs-N60 model and compared to settlement estimates using the general elastic solution with stiffness profiles determined using Stroud’s (1989) and Webb’s (1969) SPT N60-E transformation models. Stroud’s method considers strain level indirectly whereasWebb’smethod does not take account of the variation in elastic modulus with strain. The expression of Vs. in terms of N60 and Pa/σv’ derived from the Atlantis data set revealed the best fit with R2 = 0.83 and a standard error of 83.5m/s. Less accurate Vs-SPT N relations associated with the combined data set is presumably the result of inversion routines used in the analysis of the CSW results showcasing significant variation in relative density and stiffness with depth. The regression analyses revealed that the inclusion of a separate overburden term in the regression of Vs and N60, produces improved fits, as opposed to the stress corrected equations in which the R2 of the regression is notably lower. It is the correction of Vs and N60 to Vs1 and (N1)60 with empirical constants ‘n’ and ‘m’ prior to regression, that introduces bias with respect to overburden pressure. When comparing settlement prediction methods, both Stroud’s method (considering strain level indirectly) and the small strain stiffness method predict higher stiffnesses for medium dense and dense profiles than Webb’s method, which takes no account of strain level in the determination of soil stiffness. Webb’s method appears to be suitable for loose sands only. The Versak software appears to underestimate differences in settlement between square and strip footings of similar width. In conclusion, settlement analysis using small-strain stiffness data from the proposed Vs-N60 model for Cape Flats sands provides a way to take account of the non-linear stress-strain behaviour of the sands when calculating settlement.

Keywords: sands, settlement prediction, continuous surface wave test, small-strain stiffness, shear wave velocity, penetration resistance

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Authors: Kalaumari Mayoral-Peña, Ana I. Montejano-Montelongo, Josué Reyes-Muñoz, Gonzalo A. Ortiz-Mancilla, Mayrin Rodríguez-Cruz, Víctor Hernández-Villalobos, Jesús A. Guzmán-López, Santiago García-Jacobo, Iván Licona-Vázquez, Grisel Fierros-Romero, Rosario Flores-Vallejo

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The group B-lactamic antibiotics include some of the most frequently used small drug molecules against bacterial infections. Nevertheless, an alarming decrease in their efficacy has been reported due to the emergence of antibiotic-resistant bacteria. Infections caused by bacteria expressing extended Spectrum B-lactamases (ESBLs) are difficult to treat and account for higher morbidity and mortality rates, delayed recovery, and high economic burden. According to the Global Report on Antimicrobial Resistance Surveillance, it is estimated that mortality due to resistant bacteria will ascend to 10 million cases per year worldwide. These facts highlight the importance of developing low-cost and readily accessible detection methods of drug-resistant ESBLs bacteria to prevent their spread and promote accurate and fast diagnosis. Bacterial detection is commonly done using molecular diagnostic techniques, where PCR stands out for its high performance. However, this technique requires specialized equipment not available everywhere, is time-consuming, and has a high cost. Loop-Mediated Isothermal Amplification (LAMP) is an alternative technique that works at a constant temperature, significantly decreasing the equipment cost. It yields double-stranded DNA of several lengths with repetitions of the target DNA sequence as a product. Although positive and negative results from LAMP can be discriminated by colorimetry, fluorescence, and turbidity, there is still a large room for improvement in the point-of-care implementation. DNA origami is a technique that allows the formation of 3D nanometric structures by folding a large single-stranded DNA (scaffold) into a determined shape with the help of short DNA sequences (staples), which hybridize with the scaffold. This research aimed to generate DNA origami structures using LAMP products as scaffolds to improve the sensitivity to detect ESBLs in point-of-care diagnosis. For this study, the coding sequence of the CTM-X-15 ESBL of E. coli was used to generate the LAMP products. The set of LAMP primers were designed using PrimerExplorerV5. As a result, a target sequence of 200 nucleotides from CTM-X-15 ESBL was obtained. Afterward, eight different DNA origami structures were designed using the target sequence in the SDCadnano and analyzed with CanDo to evaluate the stability of the 3D structures. The designs were constructed minimizing the total number of staples to reduce costs and complexity for point-of-care applications. After analyzing the DNA origami designs, two structures were selected. The first one was a zig-zag flat structure, while the second one was a wall-like shape. Given the sequence repetitions in the scaffold sequence, both were able to be assembled with only 6 different staples each one, ranging between 18 to 80 nucleotides. Simulations of both structures were performed using scaffolds of different sizes yielding stable structures in all the cases. The generation of the LAMP products were tested by colorimetry and electrophoresis. The formation of the DNA structures was analyzed using electrophoresis and colorimetry. The modeling of novel detection methods through bioinformatics tools allows reliable control and prediction of results. To our knowledge, this is the first study that uses LAMP products and DNA-origami in combination to delect ESBL-producing bacterial strains, which represent a promising methodology for diagnosis in the point-of-care.

Keywords: beta-lactamases, antibiotic resistance, DNA origami, isothermal amplification, LAMP technique, molecular diagnosis

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Authors: Rowan Moore, Kai Scheffler, Eugen Damoc, Jennifer Sutton, Aaron Bailey, Stephane Houel, Simon Cubbon, Jonathan Josephs

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Purpose: MS analysis of monoclonal antibodies (mAbs) at the protein and peptide levels is critical during development and production of biopharmaceuticals. The compositions of current generation therapeutic proteins are often complex due to various modifications which may affect efficacy. Intact proteins analyzed by MS are detected in higher charge states that also provide more complexity in mass spectra. Protein analysis in native or native-like conditions with zero or minimal organic solvent and neutral or weakly acidic pH decreases charge state value resulting in mAb detection at higher m/z ranges with more spatial resolution. Methods: Three commercially available mAbs were used for all experiments. Intact proteins were desalted online using size exclusion chromatography (SEC) or reversed phase chromatography coupled on-line with a mass spectrometer. For streamlined use of the LC- MS platform we used a single SEC column and alternately selected specific mobile phases to perform separations in either denaturing or native-like conditions: buffer A (20 % ACN, 0.1 % FA) with Buffer B (100 mM ammonium acetate). For peptide analysis mAbs were proteolytically digested with and without prior reduction and alkylation. The mass spectrometer used for all experiments was a commercially available Thermo Scientific™ hybrid Quadrupole-Orbitrap™ mass spectrometer, equipped with the new BioPharma option which includes a new High Mass Range (HMR) mode that allows for improved high mass transmission and mass detection up to 8000 m/z. Results: We have analyzed the profiles of three mAbs under reducing and native conditions by direct infusion with offline desalting and with on-line desalting via size exclusion and reversed phase type columns. The presence of high salt under denaturing conditions was found to influence the observed charge state envelope and impact mass accuracy after spectral deconvolution. The significantly lower charge states observed under native conditions improves the spatial resolution of protein signals and has significant benefits for the analysis of antibody mixtures, e.g. lysine variants, degradants or sequence variants. This type of analysis requires the detection of masses beyond the standard mass range ranging up to 6000 m/z requiring the extended capabilities available in the new HMR mode. We have compared each antibody sample that was analyzed individually with mixtures in various relative concentrations. For this type of analysis, we observed that apparent native structures persist and ESI is benefited by the addition of low amounts of acetonitrile and formic acid in combination with the ammonium acetate-buffered mobile phase. For analyses on the peptide level we analyzed reduced/alkylated, and non-reduced proteolytic digests of the individual antibodies separated via reversed phase chromatography aiming to retrieve as much information as possible regarding sequence coverage, disulfide bridges, post-translational modifications such as various glycans, sequence variants, and their relative quantification. All data acquired were submitted to a single software package for analysis aiming to obtain a complete picture of the molecules analyzed. Here we demonstrate the capabilities of the mass spectrometer to fully characterize homogeneous and heterogeneous therapeutic proteins on one single platform. Conclusion: Full characterization of heterogeneous intact protein mixtures by improved mass separation on a quadrupole-Orbitrap™ mass spectrometer with extended capabilities has been demonstrated.

Keywords: disulfide bond analysis, intact analysis, native analysis, mass spectrometry, monoclonal antibodies, peptide mapping, post-translational modifications, sequence variants, size exclusion chromatography, therapeutic protein analysis, UHPLC

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Authors: Atish Bagchi, Siva Chandrasekaran

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Background: According to World Bank national accounts data, the estimated global manufacturing value-added output in 2020 was 13.74 trillion USD. These manufacturing processes are monitored, modelled, and controlled by advanced, real-time, computer-based systems, e.g., Industrial IoT, PLC, SCADA, etc. These systems measure and manipulate a set of physical variables, e.g., temperature, pressure, etc. Despite the use of IoT, SCADA etc., in manufacturing, studies suggest that unplanned downtime leads to economic losses of approximately 864 billion USD each year. Therefore, real-time, accurate detection, classification and prediction of machine behaviour are needed to minimise financial losses. Although vast literature exists on time-series data processing using machine learning, the challenges faced by the industries that lead to unplanned downtimes are: The current algorithms do not efficiently handle the high-volume streaming data from industrial IoTsensors and were tested on static and simulated datasets. While the existing algorithms can detect significant 'point' outliers, most do not handle contextual outliers (e.g., values within normal range but happening at an unexpected time of day) or subtle changes in machine behaviour. Machines are revamped periodically as part of planned maintenance programmes, which change the assumptions on which original AI models were created and trained. Aim: This research study aims to deliver a Graph Neural Network(GNN)based hybrid forecasting model that interfaces with the real-time machine control systemand can detect, predict machine behaviour and behavioural changes (anomalies) in real-time. This research will help manufacturing industries and utilities, e.g., water, electricity etc., reduce unplanned downtimes and consequential financial losses. Method: The data stored within a process control system, e.g., Industrial-IoT, Data Historian, is generally sampled during data acquisition from the sensor (source) and whenpersistingin the Data Historian to optimise storage and query performance. The sampling may inadvertently discard values that might contain subtle aspects of behavioural changes in machines. This research proposed a hybrid forecasting and classification model which combines the expressive and extrapolation capability of GNN enhanced with the estimates of entropy and spectral changes in the sampled data and additional temporal contexts to reconstruct the likely temporal trajectory of machine behavioural changes. The proposed real-time model belongs to the Deep Learning category of machine learning and interfaces with the sensors directly or through 'Process Data Historian', SCADA etc., to perform forecasting and classification tasks. Results: The model was interfaced with a Data Historianholding time-series data from 4flow sensors within a water treatment plantfor45 days. The recorded sampling interval for a sensor varied from 10 sec to 30 min. Approximately 65% of the available data was used for training the model, 20% for validation, and the rest for testing. The model identified the anomalies within the water treatment plant and predicted the plant's performance. These results were compared with the data reported by the plant SCADA-Historian system and the official data reported by the plant authorities. The model's accuracy was much higher (20%) than that reported by the SCADA-Historian system and matched the validated results declared by the plant auditors. Conclusions: The research demonstrates that a hybrid GNN based approach enhanced with entropy calculation and spectral information can effectively detect and predict a machine's behavioural changes. The model can interface with a plant's 'process control system' in real-time to perform forecasting and classification tasks to aid the asset management engineers to operate their machines more efficiently and reduce unplanned downtimes. A series of trialsare planned for this model in the future in other manufacturing industries.

Keywords: GNN, Entropy, anomaly detection, industrial time-series, AI, IoT, Industry 4.0, Machine Learning

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Authors: Sitira Williams, Georgina Cherry, Andrea Wright, Kevin Wells, Taran Rai, Richard Brown, Travis Street, Alasdair Cook

Abstract:

Social media sources (50) were identified, keywords defined by veterinarians and organised into 6 topics known to be indicative of feline pruritus: body areas, behaviors, symptoms, diagnosis, and treatments. These were augmented using academic literature, a cat owner survey, synonyms, and Google Trends. The content was collected using a social intelligence solution, with keywords tagged and filtered. Data were aggregated and de-duplicated. SL content matching body areas, behaviors and symptoms were reviewed manually, and posts were marked relevant if: posted by a pet owner, identifying an itchy cat and not duplicated. A sub-set of 493 posts published from 2009-2022 was used for reflexive thematic analysis in NVIVO (Burlington, MA) to identify themes. Five themes were identified: allergy, pruritus, additional behaviors, unusual or undesirable behaviors, diagnosis, and treatment. Most (258) posts reported the cat was excessively licking, itching, and scratching. The majority were indoor cats and were less playful and friendly when itchy. Half of these posts did not indicate a known cause of pruritus. Bald spots and scabs (123) were reported, often causing swelling and fur loss, and 56 reported bumps, lumps, and dry patches. Other impacts on the cat’s quality of life were ear mites, cat self-trauma and stress. Seven posts reported their cats’ symptoms caused them ongoing anxiety and depression. Cats with food allergies to poultry (often chicken and beef) causing bald spots featured in 23 posts. Veterinarians advised switching to a raw food diet and/or changing their bowls. Some cats got worse after switching, leaving owners’ needs unmet. Allergic reactions to flea bites causing excessive itching, red spots, scabs, and fur loss were reported in 13 posts. Some (3) posts indicated allergic reactions to medication. Cats with seasonal and skin allergies, causing sneezing, scratching, headshaking, watery eyes, and nasal discharge, were reported 17 times. Eighty-five posts identified additional behaviors. Of these, 13 reported their cat’s burst pimple or insect bite. Common behaviors were headshaking, rubbing, pawing at their ears, and aggressively chewing. In some cases, bites or pimples triggered previously unseen itchiness, making the cat irritable. Twenty-four reported their cat had anxiety: overgrooming, itching, losing fur, hiding, freaking out, breathing quickly, sleeplessness, hissing and vocalising. Most reported these cats as having itchy skin, fleas, and bumps. Cats were commonly diagnosed with an ear infection, ringworm, acne, or kidney disease. Acne was diagnosed in cats with an allergy flare-up or overgrooming. Ear infections were diagnosed in itchy cats with mites or other parasites. Of the treatments mentioned, steroids were most frequently used, then anti-parasitics, including flea treatments and oral medication (steroids, antibiotics). Forty-six posts reported distress following poor outcomes after medication or additional vet consultations. SL provides veterinarians with unique insights. Verbatim comments highlight the detrimental effects of pruritus on pets and owner quality of life. This study demonstrates the need for veterinarians to communicate management and treatment options more effectively to relieve owner frustrations. Data analysis could be scaled up using machine learning for topic modeling.

Keywords: content analysis, feline, itch, pruritus, social media, thematic analysis, veterinary dermatology

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Authors: Ali R. Alshawawreh, Francisco Liébana-Cabanillas, Francisco J. Blanco-Encomienda

Abstract:

Collaboration between marketing and business intelligence (BI) is crucial in today's ever-evolving business landscape. These two domains play pivotal roles in molding customers' experiential knowledge. Marketing insights offer valuable information regarding customer needs, preferences, and behaviors, thus refining marketing strategies and enhancing overall customer experiences. Conversely, BI facilitates data-driven decision-making, leading to heightened operational efficiency, product quality, and customer satisfaction. The analysis of customer data through BI unveils patterns and trends, informing product development, marketing campaigns, and customer service initiatives aimed at enriching experiences and knowledge. Customer experiential knowledge (CEK) encompasses customers' implicit comprehension of consumption experiences influenced by diverse factors, including social and cultural influences. This study primarily focuses on telecommunications companies in Jordan, scrutinizing how experiential customer knowledge mediates the relationship between marketing intelligence, business intelligence, and innovation in product and service offerings. Drawing on theoretical frameworks such as the resource-based view (RBV) and service-dominant logic (SDL), the research aims to comprehend how organizations utilize their resources, particularly knowledge, to foster innovation. Employing a quantitative research approach, the study collected and analyzed primary data to explore hypotheses. The chosen method was justified for its efficacy in handling large sample sizes. Structural equation modeling (SEM) facilitated by Smart PLS software evaluated the relationships between the constructs, followed by mediation analysis to assess the indirect associations in the model. The study findings offer insights into the intricate dynamics of organizational innovation, uncovering the interconnected relationships between business intelligence, customer experiential knowledge-based innovation (CEK-DI), marketing intelligence (MI), and product and service innovation (PSI), underscoring the pivotal role of advanced intelligence capabilities in developing innovative practices rooted in a profound understanding of customer experiences. Organizations equipped with cutting-edge BI tools are better positioned to devise strategies informed by precise insights into customer needs and behaviors. Furthermore, the positive impact of BI on PSI reaffirms the significance of data-driven decision-making in shaping the innovation landscape. Companies leveraging BI demonstrate adeptness in identifying market opportunities guiding the development of novel products and services. The substantial impact of CEK-DI on PSI highlights the crucial role of customer experiences in driving organizational innovation. Firms actively integrating customer insights into their innovation processes are more likely to create offerings aligned with customer expectations, fostering higher levels of product and service innovation. Additionally, the positive and significant effect of MI on CEK-DI underscores the critical role of market insights in shaping innovative strategies. While the relationship between MI and PSI is positive, a slightly weaker significance level indicates a nuanced association, suggesting that while MI contributes to innovation, other factors may also influence the innovation landscape, warranting further exploration. In conclusion, the study underscores the essential role of intelligence capabilities, particularly artificial intelligence, in driving innovation, emphasizing the necessity for organizations to leverage market and customer intelligence for effective and competitive innovation practices. Collaborative efforts between marketing and business intelligence serve as pivotal drivers of innovation, influencing experiential customer knowledge and shaping organizational strategies and practices, ultimately enhancing overall customer experiences and organizational performance.

Keywords: marketing intelligence, business intelligence, product, customer experiential knowledge-driven innovation

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Authors: Mehmet Salih Bayraktutan

Abstract:

Geomechanical properties of Rock Salt Deposits in Tuzluca Salt Mine Area (Eastern Turkey) are studied for modeling the operation- excavation strategy. The purpose of this research focused on calculating the critical value of span height- which will meet the safety requirements. The Mine Site Tuzluca Hills consist of alternating parallel bedding of Salt ( NaCl ) and Gypsum ( CaS04 + 2 H20) rocks. Rock Salt beds are more resistant than narrow Gypsum interlayers. Rock Salt beds formed almost 97 percent of the total height of the Hill. Therefore, the geotechnical safety of Galleries depends on the mechanical criteria of Rock Salt Cores. General deposition of Tuzluca Basin was finally completed by Tuzluca Evaporites, as for the uppermost stratigraphic unit. They are currently running mining operations performed by classic mechanical excavation, room and pillar method. Rooms and Pillars are currently experiencing an initial stage of fracturing in places. Geotechnical safety of the whole mining area evaluated by Rock Mass Rating (RMR), Rock Quality Designation (RQD) spacing of joints, and the interaction of groundwater and fracture system. In general, bedded rock salt Show large lateral deformation capacity (while deformation modulus stays in relative small values, here E= 9.86 GPa). In such litho-stratigraphic environments, creep is a critical mechanism in failure. Rock Salt creep rate in steady-state is greater than interbedding layers. Under long-lasted compressive stresses, creep may cause shear displacements, partly using bedding planes. Eventually, steady-state creep in time returns to accelerated stages. Uniaxial compression creep tests on specimens were performed to have an idea of rock salt strength. To give an idea, on Rock Salt cores, average axial strength and strain are found as 18 - 24 MPa and 0.43-0.45 %, respectively. Uniaxial Compressive strength of 26- 32 MPa, from bedded rock salt cores. Elastic modulus is comparatively low, but lateral deformation of the rock salt is high under the uniaxial compression stress state. Poisson ratio = 0.44, break load = 156 kN, cohesion c= 12.8 kg/cm2, specific gravity SG=2.17 gr/cm3. Fracture System; spacing of fractures, joints, faults, offsets are evaluated under acting geodynamic mechanism. Two sand beds, each 4-6 m thick, exist near to upper level and at the top of the evaporating sequence. They act as aquifers and keep infiltrated water on top for a long duration, which may result in the failure of roofs or pillars. Two major active seismic ( N30W and N70E ) striking Fault Planes and parallel fracture strands have seismically triggered moderate risk of structural deformation of rock salt bedding sequence. Earthquakes and Floods are two prevailing sources of geohazards in this region—the seismotectonic activity of the Mine Site based on the crossing framework of Kagizman Faults and Igdir Faults. Dominant Hazard Risk sources include; a) Weak mechanical properties of rock salt, gypsum, anhydrite beds-creep. b) Physical discontinuities cutting across the thick parallel layers of Evaporite Mass, c) Intercalated beds of weak cemented or loose sand, clayey sandy sediments. On the other hand, absorbing the effects of salt-gyps parallel bedded deposits on seismic wave amplitudes has a reducing effect on the Rock Mass.

Keywords: bedded rock salt, creep, failure mechanism, geotechnical safety

Procedia PDF Downloads 175

Authors: David J. Foran, Nhan Do, Samuel Ajjarapu, Wenjin Chen, Tahsin Kurc, Joel H. Saltz

Abstract:

The large-scale data and computational requirements of investigators throughout the clinical and research communities demand an informatics infrastructure that supports both existing and new investigative and translational projects in a robust, secure environment. In some subspecialties of medicine and research, the capacity to generate data has outpaced the methods and technology used to aggregate, organize, access, and reliably retrieve this information. Leading health care centers now recognize the utility of establishing an enterprise-wide, clinical data warehouse. The primary benefits that can be realized through such efforts include cost savings, efficient tracking of outcomes, advanced clinical decision support, improved prognostic accuracy, and more reliable clinical trials matching. The overarching objective of the work presented here is the development and implementation of a flexible Intelligent Retrieval and Interrogation System (IRIS) that exploits the combined use of computational imaging, genomics, and data-mining capabilities to facilitate clinical assessments and translational research in oncology. The proposed System includes a multi-modal, Clinical & Research Data Warehouse (CRDW) that is tightly integrated with a suite of computational and machine-learning tools to provide insight into the underlying tumor characteristics that are not be apparent by human inspection alone. A key distinguishing feature of the System is a configurable Extract, Transform and Load (ETL) interface that enables it to adapt to different clinical and research data environments. This project is motivated by the growing emphasis on establishing Learning Health Systems in which cyclical hypothesis generation and evidence evaluation become integral to improving the quality of patient care. To facilitate iterative prototyping and optimization of the algorithms and workflows for the System, the team has already implemented a fully functional Warehouse that can reliably aggregate information originating from multiple data sources including EHR’s, Clinical Trial Management Systems, Tumor Registries, Biospecimen Repositories, Radiology PAC systems, Digital Pathology archives, Unstructured Clinical Documents, and Next Generation Sequencing services. The System enables physicians to systematically mine and review the molecular, genomic, image-based, and correlated clinical information about patient tumors individually or as part of large cohorts to identify patterns that may influence treatment decisions and outcomes. The CRDW core system has facilitated peer-reviewed publications and funded projects, including an NIH-sponsored collaboration to enhance the cancer registries in Georgia, Kentucky, New Jersey, and New York, with machine-learning based classifications and quantitative pathomics, feature sets. The CRDW has also resulted in a collaboration with the Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC) at the U.S. Department of Veterans Affairs to develop algorithms and workflows to automate the analysis of lung adenocarcinoma. Those studies showed that combining computational nuclear signatures with traditional WHO criteria through the use of deep convolutional neural networks (CNNs) led to improved discrimination among tumor growth patterns. The team has also leveraged the Warehouse to support studies to investigate the potential of utilizing a combination of genomic and computational imaging signatures to characterize prostate cancer. The results of those studies show that integrating image biomarkers with genomic pathway scores is more strongly correlated with disease recurrence than using standard clinical markers.

Keywords: clinical data warehouse, decision support, data-mining, intelligent databases, machine-learning.

Procedia PDF Downloads 94