Role of Multifidelity Data in Sequential Active Learning Materials Discovery Campaigns: Case Study of Electronic Bandgap

Materials discovery and design typically proceeds through iterative evaluation (both experimental and computational) to obtain data, generally targeting improvement of one or more properties under one or more constraints (e.g., time or budget). However, there can be great variation in the quality and cost of different data, and when they are mixed together in what we here call multifidelity data the optimal approaches to their utilization are not established. It is therefore important to develop strategies to acquire and use multifidelity data to realize the most efficient iterative materials exploration. In this work, we assess the impact of using multifidelity data through mock demonstration of designing solar cell materials, using the electronic bandgap as the target property. We propose a new approach of using multifidelity data through leveraging machine learning models of both low- and high-fidelity data, where using predicted low-fidelity data as an input feature in the high-fidelity model can improve the impact of a multifidelity data approach. We show how tradeoffs of low- versus high-fidelity measurement cost and acquisition can impact the materials discovery process, and find that the use of multifidelity data has maximal impact on the materials discovery campaign when approximately five low-fidelity measurements per high-fidelity measurement are performed, and when the cost of low-fidelity measurements is approximately 5% or less than that of high-fidelity measurements. This work provides practical guidance and useful qualitative measures for improving materials discovery campaigns that involve multifidelity data

Vegetative and Adaptive Traits Predict Different Outcomes for Restoration Using Hybrids

Hybridization has been implicated as a driver of speciation, extinction, and invasiveness, but can also provide resistant breeding stock following epidemics. However, evaluating the appropriateness of hybrids for use in restoration programs is difficult. Past the F1 generation, the proportion of a progenitor’s genome can vary widely, as can the combinations of parental genomes. Detailed genetic analysis can reveal this information, but cannot expose phenotypic alterations due to heterosis, transgressive traits, or changes in metabolism or development. In addition, because evolution is often driven by extreme individuals, decisions based on phenotypic averages of hybrid classes may have unintended results. We demonstrate a strategy to evaluate hybrids for use in restoration by visualizing hybrid phenotypes across selected groups of traits relative to both progenitor species. Specifically, we used discriminant analysis to differentiate among butternut (Juglans cinerea L.), black walnut (J. nigra L.), and Japanese walnut (J. ailantifolia Carr. var. cordiformis) using vegetative characters and then with functional adaptive traits associated with seedling performance. When projected onto the progenitor trait space, naturally occurring hybrids (J. × bixbyi Rehd.) between butternut and Japanese walnut showed introgression toward Japanese walnut at vegetative characters but exhibited a hybrid swarm at functional traits. Both results indicate that hybrids have morphological and ecological phenotypes that distinguish them from butternut, demonstrating a lack of ecological equivalency that should not be carried into restoration breeding efforts. Despite these discrepancies, some hybrids were projected into the space occupied by butternut seedlings’ 95% confidence ellipse, signifying that some hybrids were similar at the measured traits. Determining how to consistently identify these individuals is imperative for future breeding and species restoration efforts involving hybrids. Discriminant analysis provides a useful technique to visualize past selection mechanisms and current variation in hybrid populations, especially when key ecological traits that distinguish progenitors are unknown. Furthermore, discriminant analysis affords a tool to assess ecological equivalency of hybrid populations and breeding program efforts to select for certain traits and monitor the amount of variability of those traits, relative to progenitors

Epirubicin With Cyclophosphamide Followed by Docetaxel With Trastuzumab and Bevacizumab as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group, FB-5

Background The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). Patients and Methods Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m2) followed by 4 cycles of docetaxel (100 mg/m2). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met. Results A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval [CI], 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively. Conclusion The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations

Correction:Kinome-wide analysis of the effect of statins in colorectal cancer (British Journal of Cancer, (2021), 124, 12, (1978-1987), 10.1038/s41416-021-01318-9)

The original version of this article unfortunately contained a mistake in an author name. Lucas J. A. C. Hawinkels should be Lukas J. A. C. Hawinkels. The authors apologize for the oversight. The original article has been corrected

Kinome-wide analysis of the effect of statins in colorectal cancer

Background Epidemiological studies and meta-analyses show an association between statin use and a reduced incidence of colorectal cancer (CRC). We have shown that statins act on CRC through bone morphogenetic protein (BMP) signalling, but the exact cellular targets and underlying mechanism of statin action remain elusive. In this study, we set out to assess the influence of statins on global cancer cell signalling by performing an array-based kinase assay using immobilised kinase substrates spanning the entire human kinome. Methods CRC cells with or without Lovastatin treatment were used for kinome analysis. Findings on kinome arrays were further confirmed by immunoblotting with activity-specific antibodies. Experiments in different CRC cell lines using immunoblotting, siRNA-mediated knockdown and treatment with specific BMP inhibitor Noggin were performed. The relevance of in vitro findings was confirmed in xenografts and in CRC patients treated with Simvastatin. Results Kinome analysis can distinguish between non-specific, toxic effects caused by 10 mu M of Lovastatin and specific effects on cell signalling caused by 2 mu M Lovastatin. Statins induce upregulation of PTEN activity leading to downregulation of the PI3K/Akt/mTOR signalling. Treatment of cells with the specific BMP inhibitor Noggin as well as PTEN knockdown and transfection of cells with a constitutively active form of AKT abolishes the effect of Lovastatin on mTOR phosphorylation. Experiments in xenografts and in patients treated with Simvastatin confirm statin-mediated BMP pathway activation, activation of PTEN and downregulation of mTOR signalling. Conclusions Statins induce BMP-specific activation of PTEN and inhibition of PI3K/Akt/mTOR signalling in CRC

Planning for Sustainability in Small Municipalities: The Influence of Interest Groups, Growth Patterns, and Institutional Characteristics

How and why small municipalities promote sustainability through planning efforts is poorly understood. We analyzed ordinances in 451 Maine municipalities and tested theories of policy adoption using regression analysis.We found that smaller communities do adopt programs that contribute to sustainability relevant to their scale and context. In line with the political market theory, we found that municipalities with strong environmental interests, higher growth, and more formal governments were more likely to adopt these policies. Consideration of context and capacity in planning for sustainability will help planners better identify and benefit from collaboration, training, and outreach opportunities

Driven diffusion in a periodically compartmentalized tube: homogeneity versus intermittency of particle motion

We study the effect of a driving force F on drift and diffusion of a point Brownian particle in a tube formed by identical ylindrical compartments, which create periodic entropy barriers for the particle motion along the tube axis. The particle transport exhibits striking features: the effective mobility monotonically decreases with increasing F, and the effective diffusivity diverges as F → ∞, which indicates that the entropic effects in diffusive transport are enhanced by the driving force. Our consideration is based on two different scenarios of the particle motion at small and large F, homogeneous and intermittent, respectively. The scenarios are deduced from the careful analysis of statistics of the particle transition times between neighboring openings. From this qualitative picture, the limiting small-F and large-F behaviors of the effective mobility and diffusivity are derived analytically. Brownian dynamics simulations are used to find these quantities at intermediate values of the driving force for various compartment lengths and opening radii. This work shows that the driving force may lead to qualitatively different anomalous transport features, depending on the geometry design

Antarctic penguin response to habitat change as Earth's troposphere reaches 2°C above preindustrial levels

Author Posting. © Ecological Society of America, 2010. This article is posted here by permission of Ecological Society of America for personal use, not for redistribution. The definitive version was published in Ecological Monographs 80 (2010): 49–66, doi:10.1890/08-2289.1.We assess the response of pack ice penguins, Emperor (Aptenodytes forsteri) and Adélie (Pygoscelis adeliae), to habitat variability and, then, by modeling habitat alterations, the qualitative changes to their populations, size and distribution, as Earth's average tropospheric temperature reaches 2°C above preindustrial levels (ca. 1860), the benchmark set by the European Union in efforts to reduce greenhouse gases. First, we assessed models used in the Intergovernmental Panel on Climate Change Fourth Assessment Report (AR4) on penguin performance duplicating existing conditions in the Southern Ocean. We chose four models appropriate for gauging changes to penguin habitat: GFDL-CM2.1, GFDL-CM2.0, MIROC3.2(hi-res), and MRI-CGCM2.3.2a. Second, we analyzed the composited model ENSEMBLE to estimate the point of 2°C warming (2025–2052) and the projected changes to sea ice coverage (extent, persistence, and concentration), sea ice thickness, wind speeds, precipitation, and air temperatures. Third, we considered studies of ancient colonies and sediment cores and some recent modeling, which indicate the (space/time) large/centennial-scale penguin response to habitat limits of all ice or no ice. Then we considered results of statistical modeling at the temporal interannual-decadal scale in regard to penguin response over a continuum of rather complex, meso- to large-scale habitat conditions, some of which have opposing and others interacting effects. The ENSEMBLE meso/decadal-scale output projects a marked narrowing of penguins' zoogeographic range at the 2°C point. Colonies north of 70° S are projected to decrease or disappear: 50% of Emperor colonies (40% of breeding population) and 75% of Adélie colonies (70% of breeding population), but limited growth might occur south of 73° S. Net change would result largely from positive responses to increase in polynya persistence at high latitudes, overcome by decreases in pack ice cover at lower latitudes and, particularly for Emperors, ice thickness. Adélie Penguins might colonize new breeding habitat where concentrated pack ice diverges and/or disintegrating ice shelves expose coastline. Limiting increase will be decreased persistence of pack ice north of the Antarctic Circle, as this species requires daylight in its wintering areas. Adélies would be affected negatively by increasing snowfall, predicted to increase in certain areas owing to intrusions of warm, moist marine air due to changes in the Polar Jet Stream.This project was funded by the World Wildlife Fund and the National Science Foundation, NSF grant OPP-0440643 (D. G. Ainley), and a Marie-Curie Fellowship to S. Jenouvrier

Loss of gastrokine-2 drives premalignant gastric inflammation and tumor progression

Chronic mucosal inflammation is associated with a greater risk of gastric cancer (GC) and, therefore, requires tight control by suppressive counter mechanisms. Gastrokine-2 (GKN2) belongs to a family of secreted proteins expressed within normal gastric mucosal cells. GKN2 expression is frequently lost during GC progression, suggesting an inhibitory role; however, a causal link remains unsubstantiated. Here, we developed Gkn2 knockout and transgenic overexpressing mice to investigate the functional impact of GKN2 loss in GC pathogenesis. In mouse models of GC, decreased GKN2 expression correlated with gastric pathology that paralleled human GC progression. At baseline, Gkn2 knockout mice exhibited defective gastric epithelial differentiation but not malignant progression. Conversely, Gkn2 knockout in the IL-11/STAT3-dependent gp130[superscript F/F] GC model caused tumorigenesis of the proximal stomach. Additionally, gastric immunopathology was accelerated in Helicobacter pylori–infected Gkn2 knockout mice and was associated with augmented T helper cell type 1 (Th1) but not Th17 immunity. Heightened Th1 responses in Gkn2 knockout mice were linked to deregulated mucosal innate immunity and impaired myeloid-derived suppressor cell activation. Finally, transgenic overexpression of human gastrokines (GKNs) attenuated gastric tumor growth in gp130[superscript F/F] mice. Together, these results reveal an antiinflammatory role for GKN2, provide in vivo evidence that links GKN2 loss to GC pathogenesis, and suggest GKN restoration as a strategy to restrain GC progression

PanSNPdb: The Pan-Asian SNP Genotyping Database

The HUGO Pan-Asian SNP consortium conducted the largest survey to date of human genetic diversity among Asians by sampling 1,719 unrelated individuals among 71 populations from China, India, Indonesia, Japan, Malaysia, the Philippines, Singapore, South Korea, Taiwan, and Thailand. We have constructed a database (PanSNPdb), which contains these data and various new analyses of them. PanSNPdb is a research resource in the analysis of the population structure of Asian peoples, including linkage disequilibrium patterns, haplotype distributions, and copy number variations. Furthermore, PanSNPdb provides an interactive comparison with other SNP and CNV databases, including HapMap3, JSNP, dbSNP and DGV and thus provides a comprehensive resource of human genetic diversity. The information is accessible via a widely accepted graphical interface used in many genetic variation databases. Unrestricted access to PanSNPdb and any associated files is available at: http://www4a.biotec.or.th/PASNP