• Automatic recognition of macaque facial expressions for detection of affective states

      Morozov, A.; Parr, L.A.; Gothard, K.; Paz, R.; Pryluk, R.; Department of Physiology, College of Medicine, University of Arizona (Society for Neuroscience, 2021)
      Internal affective states produce external manifestations such as facial expressions. In humans, the Facial Action Coding System (FACS) is widely used to objectively quantify the elemental facial action units (AUs) that build complex facial expressions. A similar system has been developed for macaque monkeys—the Macaque FACS (MaqFACS); yet, unlike the human counterpart, which is already partially replaced by automatic algorithms, this system still requires labor-intensive coding. Here, we developed and implemented the first prototype for automatic MaqFACS coding. We applied the approach to the analysis of behavioral and neural data recorded from freely interacting macaque monkeys. The method achieved high performance in the recognition of six dominant AUs, generalizing between conspecific individuals (Macaca mulatta) and even between species (Macaca fascicularis). The study lays the foundation for fully automated detection of facial expressions in animals, which is crucial for investigating the neural substrates of social and affective states. © 2021 Morozov et al.
    • Qualitative Coding in the Computational Era: A Hybrid Approach to Improve Reliability and Reduce Effort for Coding Ethnographic Interviews

      Li, Z.; Dohan, D.; Abramson, C.M.; University of Arizona (SAGE Publications Inc., 2021)
      Sociologists have argued that there is value in incorporating computational tools into qualitative research, including using machine learning to code qualitative data. Yet standard computational approaches do not neatly align with traditional qualitative practices. The authors introduce a hybrid human-machine learning approach (HHMLA) that combines a contemporary iterative approach to qualitative coding with advanced word embedding models that allow contextual interpretation beyond what can be reliably accomplished with conventional computational approaches. The results, drawn from an analysis of 87 human-coded ethnographic interview transcripts, demonstrate that HHMLA can code data sets at a fraction of the effort of human-only strategies, saving hundreds of hours labor in even modestly sized qualitative studies, while improving coding reliability. The authors conclude that HHMLA may provide a promising model for coding data sets where human-only coding would be logistically prohibitive but conventional computational approaches would be inadequate given qualitative foci. © The Author(s) 2021.
    • To Amputate or Not to Amputate: Management of Iatrogenic LASIK Flap Dehiscence and Epithelial Ingrowth with Overlying Pseudopterygium

      Ouano, D.; Huynh, R.; Tukan, A.N.; Bundogji, N.; Moshirfar, M.; University of Arizona, College of Medicine - Phoenix (S. Karger AG, 2021)
      A 73-year-old male with a history of myopic laser-assisted in situ keratomileusis (LASIK) 20 years earlier presented with a late LASIK flap dehiscence, epithelial ingrowth, conjunctivalization, and the development of a pseudopterygium in the right eye. The findings were consistent with surgical trauma, likely occurring after corneal epithelial debridement to improve visualization during pars plana vitrectomy for retinal detachment repair 3 months earlier. The patient underwent epithelial ingrowth debridement, LASIK flap reapproximation and suturing, and a conjunctival limbal autograft from the contralateral eye. The surgery was completed successfully without the need for flap amputation. Postoperatively, the patient had an uneventful course with a well-healing conjunctival graft and no interface opacity or evidence of recurrent pseudopterygium of the right eye. The graft and corneal topography remained stable after subsequent cataract surgery. © 2021 The Author(s). Published by S. Karger AG, Basel.
    • A Qualitative Analysis of Mexican-Origin Men’s Knowledge and Cultural Attitudes Toward Non-Alcoholic Fatty Liver Disease and Interest in Risk Reduction

      Villavicencio, E.A.; Crocker, R.M.; Garcia, D.O.; Department of Health Promotion Sciences, Mel and Enid Zuckerman College of Public Health, The University of Arizona (SAGE Publications Inc., 2021)
      Mexican-origin men are at increased risk of developing non-alcoholic fatty liver disease (NAFLD). The purpose of this qualitative research was to assess Mexican-origin men’s knowledge and cultural attitudes toward NAFLD and their interest in risk reduction. Semi-structured interviews were conducted with 11 Spanish-speaking Mexican-origin men who were considered high-risk of having NAFLD according to transient elastography (FibroScan®) continuous attenuation parameter (CAP) scores (≥280). Audio recordings of these interviews were transcribed and interpreted in their respective language to facilitate data analysis using NVivo 12. A thematic codebook was developed, from which the research team identified emerging themes. Findings demonstrated limited knowledge about NAFLD and in general chronic liver disease among Mexican-origin men. Cultural attitudes appeared to both enhance and mitigate their perceived risk for NAFLD. Interviews also revealed high interest levels for reducing NAFLD risk, with family and loved ones acting as the main motivators for engagement in healthier behaviors. Inclination toward family-based interventions was reported as a subject of interest for this high-risk population. This qualitative study suggests that the development of a NAFLD-specific intervention approach for Mexican-origin men may be feasible and should consider a familial and cultural context centered in improving lifestyle health behaviors. © The Author(s) 2021.
    • Myeloid-associated differentiation marker is a novel SP-A-associated transmembrane protein whose expression on airway epithelial cells correlates with asthma severity

      Dy, A.B.C.; Langlais, P.R.; Barker, N.K.; Addison, K.J.; Tanyaratsrisakul, S.; Boitano, S.; Christenson, S.A.; Kraft, M.; Meyers, D.; Bleecker, E.R.; et al. (Nature Research, 2021)
      Surfactant protein A (SP-A) is well-known for its protective role in pulmonary immunity. Previous studies from our group have shown that SP-A mediates eosinophil activities, including degranulation and apoptosis. In order to identify potential binding partners on eosinophils for SP-A, eosinophil lysates were subjected to SP-A pull-down and tandem mass spectrometry (MS/MS) analysis. We identified one membrane-bound protein, myeloid-associated differentiation marker (MYADM), as a candidate SP-A binding partner. Blocking MYADM on mouse and human eosinophils ex vivo prevented SP-A from inducing apoptosis; blocking MYADM in vivo led to increased persistence of eosinophilia and airway hyper-responsiveness in an ovalbumin (OVA) allergy model and increased airways resistance and mucus production in a house dust mite (HDM) asthma model. Examination of a subset of participants in the Severe Asthma Research Program (SARP) cohort revealed a significant association between epithelial expression of MYADM in asthma patients and parameters of airway inflammation, including: peripheral blood eosinophilia, exhaled nitric oxide (FeNO) and the number of exacerbations in the past 12 months. Taken together, our studies provide the first evidence of MYADM as a novel SP-A-associated protein that is necessary for SP-A to induce eosinophil apoptosis and we bring to light the potential importance of this previously unrecognized transmembrane protein in patients with asthma. © 2021, The Author(s).
    • Molecular drivers of tumor progression in microsatellite stable APC mutation-negative colorectal cancers

      Grant, A.; Xicola, R.M.; Nguyen, V.; Lim, J.; Thorne, C.; Salhia, B.; Llor, X.; Ellis, N.; Padi, M.; University of Arizona Cancer Center, University of Arizona; et al. (Nature Research, 2021)
      The tumor suppressor gene adenomatous polyposis coli (APC) is the initiating mutation in approximately 80% of all colorectal cancers (CRC), underscoring the importance of aberrant regulation of intracellular WNT signaling in CRC development. Recent studies have found that early-onset CRC exhibits an increased proportion of tumors lacking an APC mutation. We set out to identify mechanisms underlying APC mutation-negative (APCmut–) CRCs. We analyzed data from The Cancer Genome Atlas to compare clinical phenotypes, somatic mutations, copy number variations, gene fusions, RNA expression, and DNA methylation profiles between APCmut– and APC mutation-positive (APCmut+) microsatellite stable CRCs. Transcriptionally, APCmut– CRCs clustered into two approximately equal groups. Cluster One was associated with enhanced mitochondrial activation. Cluster Two was strikingly associated with genetic inactivation or decreased RNA expression of the WNT antagonist RNF43, increased expression of the WNT agonist RSPO3, activating mutation of BRAF, or increased methylation and decreased expression of AXIN2. APCmut– CRCs exhibited evidence of increased immune cell infiltration, with significant correlation between M2 macrophages and RSPO3. APCmut– CRCs comprise two groups of tumors characterized by enhanced mitochondrial activation or increased sensitivity to extracellular WNT, suggesting that they could be respectively susceptible to inhibition of these pathways. © 2021, The Author(s).
    • Linking solar minimum, space weather, and night sky brightness

      Grauer, A.D.; Grauer, P.A.; Lunar and Planetary Laboratory, University of Arizona (Nature Research, 2021)
      This paper presents time-series observations and analysis of broadband night sky airglow intensity 4 September 2018 through 30 April 2020. Data were obtained at 5 sites spanning more than 8500 km during the historically deep minimum of Solar Cycle 24 into the beginning of Solar Cycle 25. New time-series observations indicate previously unrecognized significant sources of broadband night sky brightness variations, not involving corresponding changes in the Sun's 10.7 cm solar flux, occur during deep solar minimum. New data show; (1) Even during a deep solar minimum the natural night sky is rarely, if ever, constant in brightness. Changes with time-scales of minutes, hours, days, and months are observed. (2) Semi-annual night sky brightness variations are coincident with changes in the orientation of Earth's magnetic field relative to the interplanetary magnetic field. (3) Solar wind plasma streams from solar coronal holes arriving at Earth’s bow shock nose are coincident with major night sky brightness increase events. (4) Sites more than 8500 km along the Earth's surface experience nights in common with either very bright or very faint night sky airglow emissions. The reason for this observational fact remains an open question. (5) It is plausible, terrestrial night airglow and geomagnetic indices have similar responses to the solar energy input into Earth's magnetosphere. Our empirical results contribute to a quantitative basis for understanding and predicting broadband night sky brightness variations. They are applicable in astronomical, planetary science, space weather, light pollution, biological, and recreational studies. © 2021, The Author(s).
    • Experimental classical entanglement in a 16 acoustic qubit-analogue

      Hasan, M.A.; Runge, K.; Deymier, P.A.; Department of Materials Science and Engineering, University of Arizona (Nature Research, 2021)
      The possibility of achieving and controlling scalable classically entangled, i.e., inseparable, multipartite states, would fundamentally challenge the advantages of quantum systems in harnessing the power of complexity in information science. Here, we investigate experimentally the extent of classical entanglement in a 16 acoustic qubit-analogue platform. The acoustic qubit-analogue, a.k.a., logical phi-bit, results from the spectral partitioning of the nonlinear acoustic field of externally driven coupled waveguides. Each logical phi-bit is a two-level subsystem characterized by two independently measurable phases. The phi-bits are co-located within the same physical space enabling distance independent interactions. We chose a vector state representation of the 16 -phi-bit system which lies in a 2 16-dimensional Hilbert space. The calculation of the entropy of entanglement demonstrates the possibility of achieving inseparability of the vector state and of navigating the corresponding Hilbert space. This work suggests a new direction in harnessing the complexity of classical inseparability in information science. © 2021, The Author(s).
    • Bacterial vaginosis and health-associated bacteria modulate the immunometabolic landscape in 3D model of human cervix

      Łaniewski, P.; Herbst-Kralovetz, M.M.; Department of Basic Medical Sciences, College of Medicine – Phoenix, University of Arizona; Department of Obstetrics and Gynecology, College of Medicine – Phoenix, University of Arizona (Nature Research, 2021)
      Bacterial vaginosis (BV) is an enigmatic polymicrobial condition characterized by a depletion of health-associated Lactobacillus and an overgrowth of anaerobes. Importantly, BV is linked to adverse gynecologic and obstetric outcomes: an increased risk of sexually transmitted infections, preterm birth, and cancer. We hypothesized that members of the cervicovaginal microbiota distinctly contribute to immunometabolic changes in the human cervix, leading to these sequelae. Our 3D epithelial cell model that recapitulates the human cervical epithelium was infected with clinical isolates of cervicovaginal bacteria, alone or as a polymicrobial community. We used Lactobacillus crispatus as a representative health-associated commensal and four common BV-associated species: Gardnerella vaginalis, Prevotella bivia, Atopobium vaginae, and Sneathia amnii. The immunometabolic profiles of these microenvironments were analyzed using multiplex immunoassays and untargeted global metabolomics. A. vaginae and S. amnii exhibited the highest proinflammatory potential through induction of cytokines, iNOS, and oxidative stress-associated compounds. G. vaginalis, P. bivia, and S. amnii distinctly altered physicochemical barrier-related proteins and metabolites (mucins, sialic acid, polyamines), whereas L. crispatus produced an antimicrobial compound, phenyllactic acid. Alterations to the immunometabolic landscape correlate with symptoms and hallmarks of BV and connected BV with adverse women’s health outcomes. Overall, this study demonstrated that 3D cervical epithelial cell colonized with cervicovaginal microbiota faithfully reproduce the immunometabolic microenvironment previously observed in clinical studies and can successfully be used as a robust tool to evaluate host responses to commensal and pathogenic bacteria in the female reproductive tract. © 2021, The Author(s).
    • Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

      UK National PAH Cohort Study Consortium; Department of Cellular and Molecular Medicine, University of Arizona (Nature Research, 2021)
      Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH. © 2021, The Author(s).
    • The long noncoding RNA H19 regulates tumor plasticity in neuroendocrine prostate cancer

      Singh, N.; Ramnarine, V.R.; Song, J.H.; Pandey, R.; Padi, S.K.R.; Nouri, M.; Olive, V.; Kobelev, M.; Okumura, K.; McCarthy, D.; et al. (Nature Research, 2021)
      Neuroendocrine (NE) prostate cancer (NEPC) is a lethal subtype of castration-resistant prostate cancer (PCa) arising either de novo or from transdifferentiated prostate adenocarcinoma following androgen deprivation therapy (ADT). Extensive computational analysis has identified a high degree of association between the long noncoding RNA (lncRNA) H19 and NEPC, with the longest isoform highly expressed in NEPC. H19 regulates PCa lineage plasticity by driving a bidirectional cell identity of NE phenotype (H19 overexpression) or luminal phenotype (H19 knockdown). It contributes to treatment resistance, with the knockdown of H19 re-sensitizing PCa to ADT. It is also essential for the proliferation and invasion of NEPC. H19 levels are negatively regulated by androgen signaling via androgen receptor (AR). When androgen is absent SOX2 levels increase, driving H19 transcription and facilitating transdifferentiation. H19 facilitates the PRC2 complex in regulating methylation changes at H3K27me3/H3K4me3 histone sites of AR-driven and NEPC-related genes. Additionally, this lncRNA induces alterations in genome-wide DNA methylation on CpG sites, further regulating genes associated with the NEPC phenotype. Our clinical data identify H19 as a candidate diagnostic marker and predictive marker of NEPC with elevated H19 levels associated with an increased probability of biochemical recurrence and metastatic disease in patients receiving ADT. Here we report H19 as an early upstream regulator of cell fate, plasticity, and treatment resistance in NEPC that can reverse/transform cells to a treatable form of PCa once therapeutically deactivated. © 2021, The Author(s).
    • Development of a deep learning emulator for a distributed groundwater–surface water model: Parflow-ml

      Tran, H.; Leonarduzzi, E.; De la Fuente, L.; Hull, R.B.; Bansal, V.; Chennault, C.; Gentine, P.; Melchior, P.; Condon, L.E.; Maxwell, R.M.; et al. (MDPI, 2021)
      Integrated hydrologic models solve coupled mathematical equations that represent natural processes, including groundwater, unsaturated, and overland flow. However, these models are computationally expensive. It has been recently shown that machine leaning (ML) and deep learning (DL) in particular could be used to emulate complex physical processes in the earth system. In this study, we demonstrate how a DL model can emulate transient, three-dimensional integrated hydrologic model simulations at a fraction of the computational expense. This emulator is based on a DL model previously used for modeling video dynamics, PredRNN. The emulator is trained based on physical parameters used in the original model, inputs such as hydraulic conductivity and topography, and produces spatially distributed outputs (e.g., pressure head) from which quantities such as streamflow and water table depth can be calculated. Simulation results from the emulator and ParFlow agree well with average relative biases of 0.070, 0.092, and 0.032 for streamflow, water table depth, and total water storage, respectively. Moreover, the emulator is up to 42 times faster than ParFlow. Given this promising proof of concept, our results open the door to future applications of full hydrologic model emulation, particularly at larger scales. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
    • A physics-informed, machine learning emulator of a 2d surface water model: What temporal networks and simulation-based inference can help us learn about hydrologic processes

      Maxwell, R.M.; Condon, L.E.; Melchior, P.; Department of Hydrology and Atmospheric Sciences, University of Arizona (MDPI, 2021)
      While machine learning approaches are rapidly being applied to hydrologic problems, physics-informed approaches are still relatively rare. Many successful deep-learning applications have focused on point estimates of streamflow trained on stream gauge observations over time. While these approaches show promise for some applications, there is a need for distributed approaches that can produce accurate two-dimensional results of model states, such as ponded water depth. Here, we demonstrate a 2D emulator of the Tilted V catchment benchmark problem with solutions provided by the integrated hydrology model ParFlow. This emulator model can use 2D Convolution Neural Network (CNN), 3D CNN, and U-Net machine learning architectures and produces time-dependent spatial maps of ponded water depth from which hydrographs and other hydrologic quantities of interest may be derived. A comparison of different deep learning architectures and hyperparameters is presented with particular focus on approaches such as 3D CNN (that have a time-dependent learning component) and 2D CNN and U-Net approaches (that use only the current model state to predict the next state in time). In addition to testing model performance, we also use a simplified simulation based inference approach to evaluate the ability to calibrate the emulator to randomly selected simulations and the match between ML calibrated input parameters and underlying physics-based simulation. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
    • Jordan and einstein frames hamiltonian analysis for flrw brans-dicke theory

      Galaverni, M.; Gabriele Gionti, S.J.; Steward Observatory, University of Arizona (MDPI, 2022)
      We analyze the Hamiltonian equivalence between Jordan and Einstein frames considering a mini-superspace model of the flat Friedmann–Lemaître–Robertson–Walker (FLRW) Universe in the Brans–Dicke theory. Hamiltonian equations of motion are derived in the Jordan, Einstein, and anti-gravity (or anti-Newtonian) frames. We show that, when applying the Weyl (conformal) transformations to the equations of motion in the Einstein frame, we did not obtain the equations of motion in the Jordan frame. Vice-versa, we re-obtain the equations of motion in the Jordan frame by applying the anti-gravity inverse transformation to the equations of motion in the anti-gravity frame. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
    • Parametric mid-spatial frequency surface error synthesis

      Hefferan, T.; Graves, L.; Trumper, I.; Pak, S.; Kim, D.; Wyant College of Optical Sciences, University of Arizona; Department of Astronomy and Steward Observatory, University of Arizona (MDPI, 2021)
      Standard mid-spatial frequency tooling mark errors were parameterized into a series of characteristic features and systematically investigated. Diffraction encircled and ensquared energy radii at the 90% levels from an unpowered optical surface were determined as a function of the root-mean-square surface irregularity, characteristic tooling mark parameters, fold mirror rotation angle, and incident beam f-number. Tooling mark frequencies on the order of 20 cycles per aperture or less were considered. This subset encompasses small footprints on single-point diamond turned optics or large footprints on sub-aperture tool polished optics. Of the characteristic features, off-axis fabrication distance held the highest impact to encircled and ensquared energy radii. The transverse oscillation of a tooling path was found to be the second highest contributor. Both impacts increased with radial tooling mark frequency. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
    • Surface measurement of a large inflatable reflector in cryogenic vacuum

      Quach, H.; Kang, H.; Sirsi, S.; Chandra, A.; Choi, H.; Esparza, M.; Karrfalt, K.; Berkson, J.; Takashima, Y.; Palisoc, A.; et al. (MDPI, 2022)
      The metrology of membrane structures, especially inflatable, curved, optical surfaces, remains challenging. Internal pressure, mechanical membrane properties, and circumferential bound-ary conditions imbue highly dynamic slopes to the final optic surface. Here, we present our method and experimental results for measuring a 1 m inflatable reflector’s shape response to dynamic pertur-bations in a thermal vacuum chamber. Our method uses phase-measuring deflectometry to track shape change in response to pressure change, thermal gradient, and controlled puncture. We use an initial measurement as a virtual null reference, allowing us to compare 500 mm of measurable aperture of the concave f/2, 1-meter diameter inflatable optic. We built a custom deflectometer that attaches to the TVAC window to make full use of its clear aperture, with kinematic references behind the test article for calibration. Our method produces 500 × 500 pixel resolution 3D surface maps with a repeatability of 150 nm RMS within a cryogenic vacuum environment (T = 140 K, P = 0.11 Pa). © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
    • Release of nanoparticles in the environment and catalytic converters ageing

      Navarro-Espinoza, S.; Meza-Figueroa, D.; Guzmán, R.; Duarte-Moller, A.; Esparza-Ponce, H.; Paz-Moreno, F.; González-Grijalva, B.; Álvarez-Bajo, O.; Schiavo, B.; Soto-Puebla, D.; et al. (MDPI, 2021)
      A Three-Way Catalyst (TWC) contains a cordierite ceramic monolith coated with a layer of Al2 O3, Cex Zr1−x O2 and platinoids mixture. Under standard operation, the platinoid concentration decreases, exposing the remaining washcoat structure. After that particle release stage, the sintering process follows where the crystalline Cex Zr1−x O2 solution is broken and begins to separate into ZrO2 and CeO2 phases. ZrO2 is released to the environment as micro and nanoparticles, while a small amount of CeO2 generates a new Alx Ce1−x O2 composite. The main effect of Ce capture is the growth in the size of the polycrystal structure from 86.13 ± 16.58 nm to 225.35 ± 69.51 nm. Moreover, a transformation of cordierite to mullite was identified by XRD analysis. Raman spectra showed that the oxygen vacancies (Vö) concentration decreased as Cex Zr1−x O2 phases separation occurred. The SEM-EDS revealed the incorporation of new spurious elements and microfractures favouring the detachment of the TWC support structure. The release of ultrafine particles is a consequence of catalytic devices overusing. The emission of refractory micro to nanocrystals to the atmosphere may represent an emerging public health issue underlining the importance of implementing strict worldwide regulations on regular TWCs replacement. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
    • A low-glucose eating pattern improves biomarkers of postmenopausal breast cancer risk: An exploratory secondary analysis of a randomized feasibility trial

      Schembre, S.M.; Jospe, M.R.; Giles, E.D.; Sears, D.D.; Liao, Y.; Basen-Engquist, K.M.; Thomson, C.A.; Department of Family and Community Medicine, College of Medicine-Tucson, University of Arizona; Department of Health Promotion Sciences, Mel and Enid Zuckerman College of Public Health, University of Arizona (MDPI, 2021)
      Postmenopausal breast cancer is the most common obesity-related cancer death among women in the U.S. Insulin resistance, which worsens in the setting of obesity, is associated with higher breast cancer incidence and mortality. Maladaptive eating patterns driving insulin resistance represent a key modifiable risk factor for breast cancer. Emerging evidence suggests that time-restricted feeding paradigms (TRF) improve cancer-related metabolic risk factors; however, more flexible approaches could be more feasible and effective. In this exploratory, secondary analysis, we identified participants following a low-glucose eating pattern (LGEP), defined as consuming energy when glucose levels are at or below average fasting levels, as an alternative to TRF. Results show that following an LGEP regimen for at least 40% of reported eating events improves insulin resistance (HOMA-IR) and other cancer-related serum biomarkers. The magnitude of serum biomarkers changes observed here has previously been shown to favorably modulate benign breast tissue in women with overweight and obesity who are at risk for postmenopausal breast cancer. By comparison, the observed effects of LGEP were similar to results from previously published TRF studies in similar populations. These preliminary findings support further testing of LGEP as an alternative to TRF and a postmenopausal breast cancer prevention strategy. However, results should be interpreted with caution, given the exploratory nature of analyses. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
    • Set-theoretic formalism for treating ligand-target datasets

      Maggiora, G.; Vogt, M.; BIO5 Institute, University of Arizona (MDPI, 2021)
      Data on ligand–target (LT) interactions has played a growing role in drug research for several decades. Even though the amount of data has grown significantly in size and coverage during this period, most datasets remain difficult to analyze because of their extreme sparsity, as there is no activity data whatsoever for many LT pairs. Even within clusters of data there tends to be a lack of data completeness, making the analysis of LT datasets problematic. The current effort extends earlier works on the development of set-theoretic formalisms for treating thresholded LT datasets. Unlike many approaches that do not address pairs of unknown interaction, the current work specifically takes account of their presence in addition to that of active and inactive pairs. Because a given LT pair can be in any one of three states, the binary logic of classical set-theoretic methods does not strictly apply. The current work develops a formalism, based on ternary set-theoretic relations, for treating thresholded LT datasets. It also describes an extension of the concept of data completeness, which is typically applied to sets of ligands and targets, to the local data completeness of individual ligands and targets. The set-theoretic formalism is applied to the analysis of simple and joint polypharmacologies based on LT activity profiles, and it is shown that null pairs provide a means for determining bounds to these values. The methodology is applied to a dataset of protein kinase inhibitors as an illustration of the method. Although not dealt with here, work is currently underway on a more refined treatment of activity values that is based on increasing the number of activity classes. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
    • Devs-based building blocks and architectural patterns for intelligent hybrid cyberphysical system design

      Zeigler, B.; Department of Electrical and Computer Engineering, University of Arizona (MDPI, 2021)
      The DEVS formalism has been recognized to support generic open architectures that allow incorporating multiple engineering domains within integrated simulation models. What is missing for accelerated adoption of DEVS-based methodology for intelligent cyberphysical system design is a set of building blocks and architectural patterns that can be replicated and reused in system development. As a start in this direction, this paper offers a notional architecture for intelligent hybrid cyberphysical system design and proceeds to focus on the decision layer to consider DEVS models for basic behaviors such as choice of alternatives, perception of temporal event relations, and recognition and generation of finite state languages cast into DEVS time segments. We proceed to describe a methodology to define DEVS-based building blocks and architectural patterns for design of systems employing fast, frugal, and accurate heuristics. We identify some elements of this kind and establish their status as minimal realizations of their defined behaviors. As minimal realizations such designs must ipso facto underlie any implementation of the same cognitive behaviors. We discuss architectures drawn from the cognitive science literature to show that the fundamental elements drawn from the fast, frugal, and accurate paradigm provide insights into intelligent hybrid cyberphysical system design. We close with open questions and research needed to confirm the proposed concepts. © 2021 by the author. Licensee MDPI, Basel, Switzerland.