56,698 results on '"Farley A"'
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2. Estimating Atmospheric Wind Speeds From Gemini Planet Imager AO Telemetry
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Du, Zhenxi, Perera, Saavidra, Levinstein, Daniel, Konopacky, Quinn, Madurowicz, Alex, Macintosh, Bruce, Poyneer, Lisa, Wilson, Richard, and Farley, Ollie
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Astrophysics - Instrumentation and Methods for Astrophysics - Abstract
The Earth's atmosphere is comprised of turbulent layers that result in speckled and blurry images from ground-based visible and infrared observations. Adaptive Optics (AO) systems are employed to measure the perturbed wavefront with a wavefront sensor (WFS) and correct for these distortions with a deformable mirror. Therefore, understanding and characterising the atmosphere is crucial for the design and functionality of AO systems. One parameter for characterizing the atmosphere is the atmospheric coherence time, which is a function of the effective wind velocity of the atmosphere. This parameter dictates how fast the AO system needs to correct for the atmosphere. If not fast enough, phenomena such as the wind butterfly effect can occur, hindering high-contrast coronographic imaging. This effect is a result of fast, strong, high-altitude turbulent layers. This paper presents two methods for estimating the effective wind velocity, using pseudo-open loop WFS slopes. The first method uses a spatial-temporal covariance map and the second uses the power spectral density of the defocus term. We show both simulated results and preliminary results from the Gemini Planet Imager AO telemetry., Comment: 7 pages, 7 figures, submitted to SPIE Astronomical + Telescopes 2024
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- 2024
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3. Does Co-Development with AI Assistants Lead to More Maintainable Code? A Registered Report
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Borg, Markus, Hewett, Dave, Graham, Donald, Couderc, Noric, Söderberg, Emma, Church, Luke, and Farley, Dave
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Computer Science - Software Engineering - Abstract
[Background/Context] AI assistants like GitHub Copilot are transforming software engineering; several studies have highlighted productivity improvements. However, their impact on code quality, particularly in terms of maintainability, requires further investigation. [Objective/Aim] This study aims to examine the influence of AI assistants on software maintainability, specifically assessing how these tools affect the ability of developers to evolve code. [Method] We will conduct a two-phased controlled experiment involving professional developers. In Phase 1, developers will add a new feature to a Java project, with or without the aid of an AI assistant. Phase 2, a randomized controlled trial, will involve a different set of developers evolving random Phase 1 projects - working without AI assistants. We will employ Bayesian analysis to evaluate differences in completion time, perceived productivity, code quality, and test coverage., Comment: Accepted as In-Principal Acceptance (IPA) for a Stage 1 registration of the Registered Report Track at the 40th IEEE International Conference on Software Maintenance and Evolution (ICSME)
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- 2024
4. Sonographer Training Pathways -- A Discussion Paper on Curriculum Design and Implementation
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Christopher Edwards, Ricky Tunny, Heather Allen, Danielle Bowles, Angela Farley, Sandra O'Hara, Jane Wardle, and Tristan Reddan
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Sonography is a highly specialized diagnostic imaging profession facing significant workforce challenges due to increased service delivery demands and a shortage of clinical training opportunities. Developing sustainable solutions is crucial for workforce growth. Using examples from the Australian workforce and education context, this paper explores the current sonography training pathways available and the benefits and challenges of each, highlighting the importance of work-integrated learning (WIL) in facilitating the development of professional identity, clinical competence and the quality of sonographer education. Conclusions are drawn that WIL is integral to the future of the sonography profession to improve patient outcomes and address workforce shortages. However, effective implementation requires careful planning and consideration of many factors, including regulatory requirements, industry partnerships, student and supervisor/tutor support, and issues related to equitable access and participation in WIL. Key recommendations are provided to encourage ethical student learning, university-industry collaboration, effective resource allocation, and WIL-specific research.
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- 2024
5. Ammonia volatilization and agronomical efficiency of a mixture of urea with natural zeolite for rose fertilization
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Carlos Guarino Werneck, Patrick Gesualdi Haim, Farley Alexandre da Fonseca Breda, Marisa Bezerra de Mello Monte, Alberto Carlos de Campos Bernardi, Nelson Mazur, and José Carlos Polidoro
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Rosa ,aluminosilicates ,ammonium trapping ,slow release ,stilbite ,Agriculture (General) ,S1-972 - Abstract
Abstract The objective of this work was to evaluate the losses of N-NH3 by volatilization and the agronomic efficiency of a mixture of urea with natural zeolite, as topdressing fertilization, in an area for the commercial production of roses (Rosa spp.). The treatments were: two rates of urea (60 and 120 kg ha-1), with and without zeolite. The N sources were applied directly to soil surface, and volatilization was determined using a free semi-open static chamber. The quantitative and qualitative variables of the collected flower stems were used to determine the agronomical efficiency of the fertilizers. The zeolite mixture reduces N-NH3 losses in 30%, compared with the commercial urea fertilizer, and shows a higher agronomic efficiency, resulting in an increase of 25 dozen of flower stems per each kilogram of N applied.
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- 2022
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6. Protocol to electroporate DNA plasmids into Ciona robusta embryos at the 1-cell stage
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Jindal, Granton A, Lim, Fabian, Tellez, Krissie, Song, Benjamin P, Bantle, Alexis T, and Farley, Emma K
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,1.1 Normal biological development and functioning ,Generic health relevance ,Developmental biology ,Model Organisms ,Molecular Biology - Abstract
Electroporation is a technique to introduce DNA constructs into cells using electric current. Here, we present a protocol to electroporate DNA plasmids into Ciona robusta embryos at the 1-cell stage. We describe steps for setting up and conducting electroporation. We then detail procedures for collecting, fixing, and mounting embryos and counting expression. This protocol can be used to study the expression of enhancers via reporter assays, manipulating cells using genes or modified genes such as dominant negatives, and genome editing. For complete details on the use and execution of this protocol, please refer to Song, et al.1.
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- 2024
7. Neural Compression of Atmospheric States
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Mirowski, Piotr, Warde-Farley, David, Rosca, Mihaela, Grimes, Matthew Koichi, Hasson, Yana, Kim, Hyunjik, Rey, Mélanie, Osindero, Simon, Ravuri, Suman, and Mohamed, Shakir
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Computer Science - Machine Learning ,Computer Science - Computer Vision and Pattern Recognition ,Physics - Atmospheric and Oceanic Physics - Abstract
Atmospheric states derived from reanalysis comprise a substantial portion of weather and climate simulation outputs. Many stakeholders -- such as researchers, policy makers, and insurers -- use this data to better understand the earth system and guide policy decisions. Atmospheric states have also received increased interest as machine learning approaches to weather prediction have shown promising results. A key issue for all audiences is that dense time series of these high-dimensional states comprise an enormous amount of data, precluding all but the most well resourced groups from accessing and using historical data and future projections. To address this problem, we propose a method for compressing atmospheric states using methods from the neural network literature, adapting spherical data to processing by conventional neural architectures through the use of the area-preserving HEALPix projection. We investigate two model classes for building neural compressors: the hyperprior model from the neural image compression literature and recent vector-quantised models. We show that both families of models satisfy the desiderata of small average error, a small number of high-error reconstructed pixels, faithful reproduction of extreme events such as hurricanes and heatwaves, preservation of the spectral power distribution across spatial scales. We demonstrate compression ratios in excess of 1000x, with compression and decompression at a rate of approximately one second per global atmospheric state., Comment: 44 pages, 25 figures
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- 2024
8. Evaluating Model Bias Requires Characterizing its Mistakes
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Albuquerque, Isabela, Schrouff, Jessica, Warde-Farley, David, Cemgil, Taylan, Gowal, Sven, and Wiles, Olivia
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Computer Science - Machine Learning ,Statistics - Machine Learning - Abstract
The ability to properly benchmark model performance in the face of spurious correlations is important to both build better predictors and increase confidence that models are operating as intended. We demonstrate that characterizing (as opposed to simply quantifying) model mistakes across subgroups is pivotal to properly reflect model biases, which are ignored by standard metrics such as worst-group accuracy or accuracy gap. Inspired by the hypothesis testing framework, we introduce SkewSize, a principled and flexible metric that captures bias from mistakes in a model's predictions. It can be used in multi-class settings or generalised to the open vocabulary setting of generative models. SkewSize is an aggregation of the effect size of the interaction between two categorical variables: the spurious variable representing the bias attribute and the model's prediction. We demonstrate the utility of SkewSize in multiple settings including: standard vision models trained on synthetic data, vision models trained on ImageNet, and large scale vision-and-language models from the BLIP-2 family. In each case, the proposed SkewSize is able to highlight biases not captured by other metrics, while also providing insights on the impact of recently proposed techniques, such as instruction tuning., Comment: 17 pages, 6 figures, ICML 2024
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- 2024
9. Subspaces, subsets, and Motzkin paths
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Farley, Jonathan D. and Srinivasan, Murali K.
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Mathematics - Combinatorics - Abstract
We define a map from subspaces to Motzkin paths and show that the inverse image of every path is a disjoint union of symmetric Boolean subsets yielding an explicit symmetric Boolean decomposition of the subspace lattice.
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- 2024
10. Overwhelmed Software Developers
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Michels, Lisa-Marie, Petkova, Aleksandra, Richter, Marcel, Farley, Andreas, Graziotin, Daniel, and Wagner, Stefan
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Computer Science - Software Engineering ,Computer Science - Computers and Society - Abstract
We have conducted a qualitative psychology study to explore the experience of feeling overwhelmed in the realm of software development. Through the candid confessions of two participants who have recently faced overwhelming challenges, we have identified seven distinct categories: communication-induced, disturbance-related, organizational, variety, technical, temporal, and positive overwhelm. While most types of overwhelm tend to deteriorate productivity and increase stress levels, developers sometimes perceive overwhelm as a catalyst for heightened focus, self-motivation, and productivity. Stress was often found to be a common companion of overwhelm. Our findings align with previous studies conducted in diverse disciplines. However, we believe that software developers possess unique traits that may enable them to navigate through the storm of overwhelm more effectively., Comment: 8 pages. Published at IEEE Software. Based on the technical report arxiv:2401.02780
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- 2024
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11. Older adults at greater risk for Alzheimers disease show stronger associations between sleep apnea severity in REM sleep and verbal memory.
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Lui, Kitty, Dave, Abhishek, Sprecher, Kate, Chappel-Farley, Miranda, Riedner, Brady, Heston, Margo, Taylor, Chase, Carlsson, Cynthia, Okonkwo, Ozioma, Asthana, Sanjay, Johnson, Sterling, Bendlin, Barbara, Benca, Ruth, and Mander, Bryce
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Humans ,Female ,Male ,Alzheimer Disease ,Middle Aged ,Sleep ,REM ,Aged ,Sleep Apnea ,Obstructive ,Polysomnography ,Risk Factors ,Verbal Learning ,Apolipoprotein E4 ,Memory ,Severity of Illness Index ,Sleep Apnea Syndromes - Abstract
BACKGROUND: Obstructive sleep apnea (OSA) increases risk for cognitive decline and Alzheimers disease (AD). While the underlying mechanisms remain unclear, hypoxemia during OSA has been implicated in cognitive impairment. OSA during rapid eye movement (REM) sleep is usually more severe than in non-rapid eye movement (NREM) sleep, but the relative effect of oxyhemoglobin desaturation during REM versus NREM sleep on memory is not completely characterized. Here, we examined the impact of OSA, as well as the moderating effects of AD risk factors, on verbal memory in a sample of middle-aged and older adults with heightened AD risk. METHODS: Eighty-one adults (mean age:61.7 ± 6.0 years, 62% females, 32% apolipoprotein E ε4 allele (APOE4) carriers, and 70% with parental history of AD) underwent clinical polysomnography including assessment of OSA. OSA features were derived in total, NREM, and REM sleep. REM-NREM ratios of OSA features were also calculated. Verbal memory was assessed with the Rey Auditory Verbal Learning Test (RAVLT). Multiple regression models evaluated the relationships between OSA features and RAVLT scores while adjusting for sex, age, time between assessments, education years, body mass index (BMI), and APOE4 status or parental history of AD. The significant main effects of OSA features on RAVLT performance and the moderating effects of AD risk factors (i.e., sex, age, APOE4 status, and parental history of AD) were examined. RESULTS: Apnea-hypopnea index (AHI), respiratory disturbance index (RDI), and oxyhemoglobin desaturation index (ODI) during REM sleep were negatively associated with RAVLT total learning and long-delay recall. Further, greater REM-NREM ratios of AHI, RDI, and ODI (i.e., more events in REM than NREM) were related to worse total learning and recall. We found specifically that the negative association between REM ODI and total learning was driven by adults 60 + years old. In addition, the negative relationships between REM-NREM ODI ratio and total learning, and REM-NREM RDI ratio and long-delay recall were driven by APOE4 carriers. CONCLUSION: Greater OSA severity, particularly during REM sleep, negatively affects verbal memory, especially for people with greater AD risk. These findings underscore the potential importance of proactive screening and treatment of REM OSA even if overall AHI appears low.
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- 2024
12. Survival disparities in non-Hispanic Black and White cervical cancer patients vary by histology and are largely explained by modifiable factors
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Kucera, Calen W, Chappell, Nicole P, Tian, Chunqiao, Richardson, Michael T, Tarney, Christopher M, Hamilton, Chad A, Chan, John K, Kapp, Daniel S, Leath, Charles A, Casablanca, Yovanni, Rojas, Christine, Sitler, Collin A, Wenzel, Lari, Klopp, Ann, Jones, Nathaniel L, Rocconi, Rodney P, Farley, John H, O'Connor, Timothy D, Shriver, Craig D, Bateman, Nicholas W, Conrads, Thomas P, Phippen, Neil T, Maxwell, G Larry, and Darcy, Kathleen M
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Health Disparities ,Social Determinants of Health ,Clinical Research ,Cervical Cancer ,Minority Health ,Women's Health ,Humans ,Female ,Uterine Cervical Neoplasms ,White People ,Middle Aged ,Black or African American ,Aged ,Carcinoma ,Squamous Cell ,Adult ,Adenocarcinoma ,United States ,Healthcare Disparities ,Health Status Disparities ,Socioeconomic Factors ,Proportional Hazards Models ,Neoplasm Staging ,Cervical cancer ,Racial disparities ,Propensity score analysis ,Squamous cell carcinoma ,NCDB ,Paediatrics and Reproductive Medicine ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis ,Reproductive medicine - Abstract
PurposeWe investigated racial disparities in survival by histology in cervical cancer and examined the factors contributing to these disparities.MethodsNon-Hispanic Black and non-Hispanic White (hereafter known as Black and White) patients with stage I-IV cervical carcinoma diagnosed between 2004 and 2017 in the National Cancer Database were studied. Survival differences were compared using Cox modeling to estimate hazard ratio (HR) or adjusted HR (AHR) and 95% confidence interval (CI). The contribution of demographic, socioeconomic and clinical factors to the Black vs White differences in survival was estimated after applying propensity score weighting in patients with squamous cell carcinoma (SCC) or adenocarcinoma (AC).ResultsThis study included 10,111 Black and 43,252 White patients with cervical cancer. Black patients had worse survival than White cervical cancer patients (HR = 1.40, 95% CI = 1.35-1.45). Survival disparities between Black and White patients varied significantly by histology (HR = 1.20, 95% CI = 1.15-1.24 for SCC; HR = 2.32, 95% CI = 2.12-2.54 for AC, interaction p
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- 2024
13. Sensing quantum vacuum fluctuations with non-Gaussian electronic noise
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Farley, Clovis, Pinsolle, Edouard, and Reulet, Bertrand
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Condensed Matter - Mesoscale and Nanoscale Physics - Abstract
The statistics of electron transport in a tunnel junction is affected by fluctuations of its voltage bias, which modulates the probability for electrons to cross the junction. We exploit this phenomenon to provide a direct measurement of quantum vacuum fluctuations in the microwave domain of a resistor placed at ultra-low temperature: we show that the amplified vacuum fluctuations are correlated with the noise generated by the junction to contribute to a third moment of detected voltage fluctuations. This experiment constitutes an absolute measurement of noise, not affected by the unavoidable noise added by the detection setup., Comment: 8 pages, 7 figures
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- 2024
14. Error analysis in large area multi-Raman pulse atom interferometry due to undesired spontaneous decay
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Chrostoski, Philip, Bisson, Scott, Farley, David, Narducci, Frank, and Soh, Daniel
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Quantum Physics ,Physics - Atomic Physics - Abstract
Despite the fact that atom interferometry has been a successful application of quantum sensing, a major topic of interest is the further improvement of the sensitivity of these devices. In particular, the area enclosed by the interferometer (which controls the sensitivity) can be increased by providing a larger momentum kick to the atom cloud, increasing the extent of the momentum axis. One such atom optics technique involves increasing the number of central $\pi-$Raman pulses. This technique, while providing the prerequisite additional momentum boost, also causes the atom to remain in the intermediate high energy state for longer periods of time. This additional length of time is often neglected in many treatments due to the adiabatic elimination of the higher energy state enabled by the large optical detuning. The increased time in the intermediate high energy state results in a higher probability of undesired spontaneous decay and a loss of quantum information, thereby adding error to the atom interferometer. In this work, we consider an open quantum system using the Lindblad master equation to devise a model for the atomic state dynamics that includes the undesired spontaneous decay from the intermediate high energy state. We formulate an error figure of merit to analyze limitations of an atom interferometer configured for acceleration measurements. Our theoretical results show the error figure of merit will be dominated by a $N_{R}^{-2}$ scaling factor for low numbers of $\pi-$Raman pulses, but will be dominated by a monotonic increase in error for high number of $\pi-$Raman pulses. We determined the number of $\pi$-Raman pulses that accomplishes maximal momentum transfer with a the minimal error, depending on major system parameters.
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- 2024
15. Understanding Brokerage in Education: Forward Tracking from Research to Practice
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University of Delaware, Center for Research Use in Education (CRUE), Samantha Shewchuk, and Elizabeth N. Farley-Ripple
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Current research aiming to understand the gaps between research and practice in K-12 education often overlooks the importance of grasping the indirect relationships that develop between research and practice communities via the various people and organizations positioned to serve as knowledge brokers. The purpose of this study is to understand both how research brokerage by such individuals and organizations can lead to research use and how knowledge brokers can be leveraged to better support research use in practice. Specifically, this study aims to identify what happens in the space between research and practice by using qualitative methods to explore three areas of inquiry: (1) understanding which individuals and organizations serve as knowledge brokers, (2) understanding the types of research-based products that move through brokerage systems and how research-based products are transformed in that system, and (3) understanding the paths by which information moves from research into practice. To better understand what occurs between the production of research findings and their ultimate use, the authors focus on the set of actors, activities, motivations within which research is exchanged, transformed, and otherwise communicated--that is, the dynamic and complex phenomenon of brokerage. For the backward tracking study in 2022, four cases were examined the brokerage process through a five-step approach to produce credible stories of what happens as research moves between research and practice. This report which is the forward tracking study, researchers trace how findings from four education research projects were mobilized to encourage the use of the research.
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- 2023
16. Defining the Need for Services for Patients at High Risk of Breast Cancer at a Safety-Net Hospital: An Approach to Narrowing the Disparities Gap
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Cheng, Olivia, Fiser, Caroline, Paysour, Jamie, Aluwalia, Ruchi, Hilliard, Aysia, Arciero, Cletus, Farley, Clara R., Jones, Jade, Conyers, Jesse, and Postlewait, Lauren M.
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- 2024
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17. Mindful Parenting Group Intervention for Parents of Children with Anxiety Disorders
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Farley, Robyn, de Diaz, Natalja A. Nabinger, Emerson, Lisa Marie, Simcock, Gabrielle, Donovan, Caroline, and Farrell, Lara J.
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- 2024
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18. Vaccine Hesitancy at Nine Community Sites Across the United States, Early in COVID-19 Vaccine Rollout
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Ratnayake, Aneeka, Hernandez, Julie H., Justman, Jessica, Farley, Jason E., Hirsch-Moverman, Yael, Ho, Ken, Mayer, Stockton, Oluyomi, Abiodun, Sobieszczyk, Magdalena E., Swaminathan, Shobha, Skalland, Timothy, Tapsoba, Jean de Dieu, and Kissinger, Patricia J.
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- 2024
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19. Natural rubber, cellulose micro/nanofibrils and carnauba wax: renewable and low-cost coatings improving the barrier properties in papers
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Mendonça, Maressa Carvalho, Durães, Alisson Farley Soares, dos Santos, Allan de Amorim, Matos, Lays Camila, Mascarenhas, Adriano Reis Prazeres, Scatolino, Mário Vanoli, Martins, Caio Cesar Nemer, Damásio, Renato Augusto Pereira, Muguet, Marcelo Coelho Santos, and Tonoli, Gustavo Henrique Denzin
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- 2024
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20. High site fidelity and reduced survival of a mycophagous mammal after prescribed fire
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Pla, Mark Le, Hradsky, Bronwyn A., Di Stefano, Julian, Farley-Lehmer, Tamika C., Birnbaum, Emma K., and Pascoe, Jack H.
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- 2024
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21. A mixed methods study of education researchers’ knowledge mobilization approaches
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Farley-Ripple, Elizabeth and MacGregor, Stephen
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- 2024
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22. Microclimate and the thermal comfort during the implementation of silvopastoral systems: the windbreak countereffect
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Machado, Thiago Mombach Pinheiro, Schmitt-Filho, Abdon L., Daros, Ruan, Farley, Joshua, Sinisgalli, Paulo A., and Silva-Kazama, Daniele C.
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- 2024
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23. Knowledge Mobilization in the Production of Education Research: A Mixed Methods Study
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University of Delaware, Center for Research Use in Education (CRUE), Farley-Ripple, Elizabeth, MacGregor, Stephen, and Mazal, Mia
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Calls to improve relationships between research and practice abound, among them efforts to help researchers to work in partnership with and communicate more effectively with policy and practice audiences, informing those that govern and design educational policies and those charged with implementation in schools and classrooms, respectively. These calls range from advocacy for participatory models of research to revisions to academic incentives that presently prioritize contributions to literature above impact on policy or practice. Most recently, the National Academies of Science, Engineering, and Medicine report, "The Future of Education Research at the Institute of Education Sciences in the U.S. Department of Education" (2022), emphasizes that the largest federal funder of education research should include knowledge mobilization among its core areas of work. The end goal of these efforts is to have a more impactful research enterprise, one that both meets the needs of and is taken up in decisions made by policymakers and practitioners. The Center for Research Use in Education (CRUE) seeks to better understand how to strengthen the relationships between research and practice to the same ends--increasing the impact of research by better meeting the needs of policy and practice and by producing work that is useful and used in decision-making. CRUE has approached this work with attention to bidirectionality--focusing on both decision-processes in the practice space and the role of research in them (Farley-Ripple et al., 2022a, 2022b), as well as research production and the strategies used to increase its impact (Van Horn et al, 2023). In this paper the authors describe the work on the latter, presenting results of a mixed methods inquiry into the knowledge mobilization practices of researchers.
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- 2023
24. Overwhelmed software developers: An Interpretative Phenomenological Analysis
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Michels, Lisa-Marie, Petkova, Aleksandra, Richter, Marcel, Farley, Andreas, Graziotin, Daniel, and Wagner, Stefan
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Computer Science - Software Engineering ,Computer Science - Computers and Society - Abstract
In this paper, we report on an Interpretive Phenomenological Analysis (IPA) study on experiencing overwhelm in a software development context. The objectives of our study are, hence, to understand the experiences developers have when being overwhelmed, how this impacts their productivity and which role stress plays in the process. To this end, we interviewed two software developers who have experienced overwhelm recently. Throughout a qualitative analysis of the shared experiences, we uncover seven categories of overwhelm (communication, disturbance, organizational, variety, technical, temporal, and positive overwhelm). While the first six themes all are related to negative outcomes, including low productivity and stress, the participants reported that overwhelm can sometimes be experienced to be positive and pleasant, and it can increase their mental focus, self ambition, and productivity. Stress was the most mentioned feeling experienced when overwhelmed. Our findings, for the most, are along the same direction of similar studies from other disciplines and with other participants. However, there may be unique attributes to software developers that mitigate the negative experiences of overwhelm., Comment: 46 pages, technical report
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- 2024
25. Human Intratumoral NKp46+ Natural Killer Cells are Spatially Distanced from T and MHC-I+ Cells with Prognostic Implications in Soft Tissue Sarcoma
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Cruz, Sylvia, Sholevar, Cyrus, Judge, Sean, Darrow, Morgan, Iranpur, Khurshid, Farley, Lauren, Lammers, Marshall, Razmara, Aryana, Dunai, Cordelia, Gingrich, Alicia, Persky, Julia, Mori, Hidetoshi, Thorpe, Steve, Monjazeb, Arta, Murphy, William, and Canter, Robert
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Soft tissue sarcomas (STS) are heterogenous malignancies with an unmet need for novel immunotherapies. Tumor infiltrating lymphocytes (TILs) have previously been linked with favorable outcomes in STS patients, though the contribution of natural killer (NK) cell subsets, including NKp46 and CD56bright/dim, has yet to be investigated in detail. Despite the known role of MHC-I on immunoregulation of NK and T cells, limited data exist characterizing the spatial relationship of NK cells to MHC-I+/- cells and T cells in the STS tumor microenvironment (TME). Using STS specimens from 130 patients, we evaluated intratumoral NK cell subsets by immunohistochemistry (IHC), flow cytometry, and immunofluorescence (IF) to assess their impact on overall survival (OS) and metastasis-free survival (MFS). We also assessed the spatial localization of NK and T cells by multiplex IF in the TME, specifically analyzing the effects of MHC-I expression status on NK and T cell clustering. High intratumoral NKp46 expression was associated with improved OS by IHC (P=0.04) and IF (P=0.02). CD56dim NK cells were associated with a survival benefit (P=0.05), while higher infiltrates of CD56bright NK cells predicted worse prognosis (P=0.05). CD3-CD56+ NK cells demonstrated a significant inverse relationship with CD3+ T cells by both flow cytometry and IF. Spatial analyses showed NK cells preferentially clustering close to other NK cells with sparse CD3+ T and CD8+ T cells in range (P
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- 2024
26. Preclinical evaluation and first-in-dog clinical trials of PBMC-expanded natural killer cells for adoptive immunotherapy in dogs with cancer
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Razmara, Aryana M, Farley, Lauren E, Harris, Rayna M, Judge, Sean J, Lammers, Marshall, Iranpur, Khurshid R, Johnson, Eric G, Dunai, Cordelia, Murphy, William J, Brown, C Titus, Rebhun, Robert B, Kent, Michael S, and Canter, Robert J
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Clinical Trials and Supportive Activities ,Vaccine Related ,Biotechnology ,Genetics ,Clinical Research ,Immunization ,Immunotherapy ,Rare Diseases ,Cancer ,5.2 Cellular and gene therapies ,Dogs ,Animals ,Humans ,Immunotherapy ,Adoptive ,Leukocytes ,Mononuclear ,Cytotoxicity ,Immunologic ,Killer Cells ,Natural ,Osteosarcoma ,Bone Neoplasms ,Cytokines ,killer cells ,natural ,immunotherapy ,adoptive ,computational biology ,clinical trials as topic ,adoptive cell therapy ,Oncology and carcinogenesis - Abstract
BackgroundNatural killer (NK) cells are cytotoxic cells capable of recognizing heterogeneous cancer targets without prior sensitization, making them promising prospects for use in cellular immunotherapy. Companion dogs develop spontaneous cancers in the context of an intact immune system, representing a valid cancer immunotherapy model. Previously, CD5 depletion of peripheral blood mononuclear cells (PBMCs) was used in dogs to isolate a CD5dim-expressing NK subset prior to co-culture with an irradiated feeder line, but this can limit the yield of the final NK product. This study aimed to assess NK activation, expansion, and preliminary clinical activity in first-in-dog clinical trials using a novel system with unmanipulated PBMCs to generate our NK cell product.MethodsStarting populations of CD5-depleted cells and PBMCs from healthy beagle donors were co-cultured for 14 days, phenotype, cytotoxicity, and cytokine secretion were measured, and samples were sequenced using the 3'-Tag-RNA-Seq protocol. Co-cultured human PBMCs and NK-isolated cells were also sequenced for comparative analysis. In addition, two first-in-dog clinical trials were performed in dogs with melanoma and osteosarcoma using autologous and allogeneic NK cells, respectively, to establish safety and proof-of-concept of this manufacturing approach.ResultsCalculated cell counts, viability, killing, and cytokine secretion were equivalent or higher in expanded NK cells from canine PBMCs versus CD5-depleted cells, and immune phenotyping confirmed a CD3-NKp46+ product from PBMC-expanded cells at day 14. Transcriptomic analysis of expanded cell populations confirmed upregulation of NK activation genes and related pathways, and human NK cells using well-characterized NK markers closely mirrored canine gene expression patterns. Autologous and allogeneic PBMC-derived NK cells were successfully expanded for use in first-in-dog clinical trials, resulting in no serious adverse events and preliminary efficacy data. RNA sequencing of PBMCs from dogs receiving allogeneic NK transfer showed patient-unique gene signatures with NK gene expression trends in response to treatment.ConclusionsOverall, the use of unmanipulated PBMCs appears safe and potentially effective for canine NK immunotherapy with equivalent to superior results to CD5 depletion in NK expansion, activation, and cytotoxicity. Our preclinical and clinical data support further evaluation of this technique as a novel platform for optimizing NK immunotherapy in dogs.
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- 2024
27. Recommendations for accelerating open preprint peer review to improve the culture of science.
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Avissar-Whiting, Michele, Belliard, Frédérique, Bertozzi, Stefano, Brand, Amy, Brown, Katherine, Clément-Stoneham, Géraldine, Dawson, Stephanie, Dey, Gautam, Ecer, Daniel, Edmunds, Scott, Farley, Ashley, Fischer, Tara, Franko, Maryrose, Fraser, James, Funk, Kathryn, Ganier, Clarisse, Harrison, Melissa, Hatch, Anna, Hazlett, Haley, Hindle, Samantha, Hook, Daniel, Hurst, Phil, Kamoun, Sophien, Kiley, Robert, Lacy, Michael, LaFlamme, Marcel, Lawrence, Rebecca, Lemberger, Thomas, Leptin, Maria, Lumb, Elliott, MacCallum, Catriona, Marcum, Christopher, Marinello, Gabriele, Mendonça, Alex, Monaco, Sara, Neves, Kleber, Pattinson, Damian, Polka, Jessica, Puebla, Iratxe, Rittman, Martyn, Royle, Stephen, Saderi, Daniela, Sever, Richard, Shearer, Kathleen, Spiro, John, Stern, Bodo, Taraborelli, Dario, Vale, Ron, Vasquez, Claudia, Waltman, Ludo, Watt, Fiona, Weinberg, Zara, and Williams, Mark
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Humans ,Motion ,Peer Review ,Research Personnel - Abstract
Peer review is an important part of the scientific process, but traditional peer review at journals is coming under increased scrutiny for its inefficiency and lack of transparency. As preprints become more widely used and accepted, they raise the possibility of rethinking the peer-review process. Preprints are enabling new forms of peer review that have the potential to be more thorough, inclusive, and collegial than traditional journal peer review, and to thus fundamentally shift the culture of peer review toward constructive collaboration. In this Consensus View, we make a call to action to stakeholders in the community to accelerate the growing momentum of preprint sharing and provide recommendations to empower researchers to provide open and constructive peer review for preprints.
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- 2024
28. Affinity-optimizing enhancer variants disrupt development
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Lim, Fabian, Solvason, Joe J, Ryan, Genevieve E, Le, Sophia H, Jindal, Granton A, Steffen, Paige, Jandu, Simran K, and Farley, Emma K
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Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Infectious Diseases ,Human Genome ,2.1 Biological and endogenous factors ,Aetiology ,Humans ,Enhancer Elements ,Genetic ,Extremities ,Gain of Function Mutation ,Homeodomain Proteins ,Interferon Regulatory Factors ,Organ Specificity ,Penetrance ,Phenotype ,Polydactyly ,Polymorphism ,Single Nucleotide ,Protein Binding ,Proto-Oncogene Proteins c-ets ,Transcription Factor AP-1 ,General Science & Technology - Abstract
Enhancers control the location and timing of gene expression and contain the majority of variants associated with disease1-3. The ZRS is arguably the most well-studied vertebrate enhancer and mediates the expression of Shh in the developing limb4. Thirty-one human single-nucleotide variants (SNVs) within the ZRS are associated with polydactyly4-6. However, how this enhancer encodes tissue-specific activity, and the mechanisms by which SNVs alter the number of digits, are poorly understood. Here we show that the ETS sites within the ZRS are low affinity, and identify a functional ETS site, ETS-A, with extremely low affinity. Two human SNVs and a synthetic variant optimize the binding affinity of ETS-A subtly from 15% to around 25% relative to the strongest ETS binding sequence, and cause polydactyly with the same penetrance and severity. A greater increase in affinity results in phenotypes that are more penetrant and more severe. Affinity-optimizing SNVs in other ETS sites in the ZRS, as well as in ETS, interferon regulatory factor (IRF), HOX and activator protein 1 (AP-1) sites within a wide variety of enhancers, cause gain-of-function gene expression. The prevalence of binding sites with suboptimal affinity in enhancers creates a vulnerability in genomes whereby SNVs that optimize affinity, even slightly, can be pathogenic. Searching for affinity-optimizing SNVs in genomes could provide a mechanistic approach to identify causal variants that underlie enhanceropathies.
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- 2024
29. Finiteness properties of generalized Thompson groups via expansion sets
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Farley, Daniel
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Mathematics - Group Theory ,20F65 - Abstract
We outline a general procedure that builds classifying spaces for generalized Thompson groups $\Gamma$. The construction depends on a small number of choices: (1) an inverse semigroup $S$ of partial transformations that ``locally determine" $\Gamma$; (2) an equivalence relation on certain pairs $(f,D)$, and (3) an ``expansion" rule $\mathcal{E}$. These choices determine an \emph{expansion set} $\mathcal{B}$, which is a combinatorial device that outputs a simplicial complex $\Delta^{f}_{\mathcal{B}}$ upon which $\Gamma$ acts. Under favorable conditions, often achieved in practice, $\Delta^{f}_{\mathcal{B}}$ is contractible, and the action of $\Gamma$ has small stabilizers. The definition of $\Delta^{f}_{\mathcal{B}}$ is such that ascending and descending links in $\Delta^{f}_{\mathcal{B}}$ can be described via formulas that depend only on the expansion rule $\mathcal{E}$. The result is to facilitate the usual computations of the connectivity of the descending link. Under natural hypotheses, one can prove that the acting group has type $F_{\infty}$. The net effect of our results is to automate results of this kind. Several applications are given; in particular, we sketch unified proofs that $V$, $nV$, R\"{o}ver's group $G$, and the Lodha-Moore group have type $F_{\infty}$., Comment: 50 pages, 13 figures (The current version corrects Remark 4.12 and adds an acknowledgement at the end of the introduction. Otherwise, the paper is unchanged.)
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- 2023
30. Noise Dynamics in the Quantum Regime
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Farley, Clovis, Pinsolle, Edouard, and Reulet, Bertrand
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Condensed Matter - Mesoscale and Nanoscale Physics - Abstract
A time-dependent bias voltage on a tunnel junction generates a time-dependent modulation of its current fluctuations, and in particular of its variance. This translates into an excitation at frequency $\tilde{f}$ generating correlations between current fluctuating at any frequency $f$ and at frequency $\pm$ $\tilde{f} -f$. We report the measurement of such a correlation in the fully quantum regime, i.e. when both frequencies are much greater than $k_BT/h$ with $T$ the temperature. Such a correlator, usually referred to as the noise susceptibility, is involved in corrections to the measurements of higher-order moments and in the squeezing of noise., Comment: 4 pages, 4 figures, to be published in the 2023 International Conference on Noise and Fluctuations (ICNF) proceedings
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- 2023
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31. Solving MaxSAT with Matrix Multiplication
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Warde-Farley, David, Nair, Vinod, Li, Yujia, Lobov, Ivan, Gimeno, Felix, and Osindero, Simon
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Computer Science - Artificial Intelligence ,Computer Science - Machine Learning ,Computer Science - Logic in Computer Science - Abstract
We propose an incomplete algorithm for Maximum Satisfiability (MaxSAT) specifically designed to run on neural network accelerators such as GPUs and TPUs. Given a MaxSAT problem instance in conjunctive normal form, our procedure constructs a Restricted Boltzmann Machine (RBM) with an equilibrium distribution wherein the probability of a Boolean assignment is exponential in the number of clauses it satisfies. Block Gibbs sampling is used to stochastically search the space of assignments with parallel Markov chains. Since matrix multiplication is the main computational primitive for block Gibbs sampling in an RBM, our approach leads to an elegantly simple algorithm (40 lines of JAX) well-suited for neural network accelerators. Theoretical results about RBMs guarantee that the required number of visible and hidden units of the RBM scale only linearly with the number of variables and constant-sized clauses in the MaxSAT instance, ensuring that the computational cost of a Gibbs step scales reasonably with the instance size. Search throughput can be increased by batching parallel chains within a single accelerator as well as by distributing them across multiple accelerators. As a further enhancement, a heuristic based on unit propagation running on CPU is periodically applied to the sampled assignments. Our approach, which we term RbmSAT, is a new design point in the algorithm-hardware co-design space for MaxSAT. We present timed results on a subset of problem instances from the annual MaxSAT Evaluation's Incomplete Unweighted Track for the years 2018 to 2021. When allotted the same running time and CPU compute budget (but no TPUs), RbmSAT outperforms other participating solvers on problems drawn from three out of the four years' competitions. Given the same running time on a TPU cluster for which RbmSAT is uniquely designed, it outperforms all solvers on problems drawn from all four years.
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- 2023
32. Telehealth use by older New Yorkers during the COVID-19 Pandemic
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Chan, Kiana, Millington, Monique, Low, Andrea, Farley, Shannon M., Hoos, David, El-Sadr, Wafaa M., Reyes, Melissa, and Greenleaf, Abigail R.
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- 2024
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33. Mimicking the Psychological Effects of Capitalism in the Classroom: Using 'StarPower' to Demonstrate Unconscious Bias, Privilege, and Oppression
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Soheilan, Sepideh S., Shaffer, Katharine S., Schoepf, El H., Eyssell, Kristen M., and Farley, Sally D.
- Abstract
College students are reflective of a culturally diverse population and hold a wide range of cultural identities. As such, faculty and campus activities professionals alike, are constantly striving to meet the needs of an increasingly diverse student population. Socioeconomic status (SES) and social class are cultural variables that need more attention in higher education settings. Given that SES and social class are determinants of social power (APA, 2007), it is crucial to provide undergraduate students with focused learning experiences on these variables and how they influence identity development. Authors utilized Star Power, an educational game, to mimic three tiers of a capitalistic economy in the classroom. Qualitative data analyses suggested themes of dominance and striving for dominance across all groups. Implications for experiential learning in the classroom, multicultural education, diversity learning through campus outreach activities, and research are discussed.
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- 2023
34. Guidelines for Increasing Access to Mindfulness-Based Interventions in Under-Resourced Schools
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L. Phan, Mary, L. Renshaw, Tyler, and D. Farley, Caleb
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- 2024
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35. Global and School-Specific Subjective Well-Being as Predictors of Educational Outcomes
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Renshaw, Tyler L., Clark, Kelly N., Farley, Caleb D., Franzmann, Thomas K., and Yang, Nai-Jiin
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- 2024
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36. Antimicrobial susceptibility testing reveals reduced susceptibility to azithromycin and other antibiotics in Legionella pneumophila serogroup 1 isolates from Portugal
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Minetti, Corrado, Barton, Rachael, Farley, Caitlin, Spiller, Owen Brad, Rodrigues, Raquel, and Gonçalves, Paulo
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- 2024
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37. Cosmological Distance Measurement of 12 Nearby Supernovae IIP with ROTSE-IIIB
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Dhungana, Govinda, Kehoe, Robert, Staten, Ryan, Vinko, Jozsef, Wheeler, J. Craig, Akerlof, Carl W., Doss, David, Farrente, Farley V., Gibson, Coyne A., Lasker, James, Marion, G. H., Pandey, Shashi Bhushan, Quimby, Robert, Rykoff, Eli, Smith, Donald A., Yuan, Fang, and Zheng, WeiKang
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Astrophysics - High Energy Astrophysical Phenomena ,Astrophysics - Cosmology and Nongalactic Astrophysics - Abstract
We present cosmological analysis of 12 nearby ($z<0.06$) Type IIP supernovae (SNe IIP) observed with the ROTSE-IIIb telescope. To achieve precise photometry, we present a new image differencing technique that is implemented for the first time on the ROTSE SN photometry pipeline. With this method, we find up to a 20\% increase in the detection efficiency and significant reduction in residual RMS scatter of the SN lightcurves when compared to the previous pipeline performance. We use the published optical spectra and broadband photometry of well studied SNe IIP to establish temporal models for ejecta velocity and photospheric temperature evolution for our SNe IIP population. This study yields measurements that are competitive to other methods even when the data are limited to a single epoch during the photospheric phase of SNe IIP. Using the fully reduced ROTSE photometry and optical spectra, we apply these models to the respective photometric epochs for each SN in the ROTSE IIP sample. This facilitates the use of the Expanding Photosphere Method (EPM) to obtain distance estimates to their respective host galaxies. We then perform cosmological parameter fitting using these EPM distances from which we measure the Hubble constant to be $72.9^{+5.7}_{-4.3}~{\rm kms^{-1}~Mpc^{-1}}$, which is consistent with the standard $\Lambda CDM$ model values derived using other independent techniques., Comment: 19 pages, 13 figures
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- 2023
38. Low-Dose Sorafenib Promotes Cancer Stem Cell Expansion and Accelerated Tumor Progression in Soft Tissue Sarcomas
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Cruz, Sylvia M, Iranpur, Khurshid R, Judge, Sean J, Ames, Erik, Sturgill, Ian R, Farley, Lauren E, Darrow, Morgan A, Crowley, Jiwon Sarah, Monjazeb, Arta M, Murphy, William J, and Canter, Robert J
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Biochemistry and Cell Biology ,Biological Sciences ,Medicinal and Biomolecular Chemistry ,Chemical Sciences ,Microbiology ,Stem Cell Research ,Clinical Research ,Stem Cell Research - Nonembryonic - Human ,Rare Diseases ,Cancer ,Humans ,Sorafenib ,Tyrosine Kinase Inhibitors ,Aldehyde Dehydrogenase ,Protein Kinase Inhibitors ,Sarcoma ,Neoplastic Stem Cells ,Cell Line ,Tumor ,cancer stem cells ,sorafenib ,ALDH ,sarcoma ,survival ,Survival ,Other Chemical Sciences ,Genetics ,Other Biological Sciences ,Chemical Physics ,Biochemistry and cell biology ,Medicinal and biomolecular chemistry - Abstract
The cancer stem cell (CSC) hypothesis postulates that heterogeneous human cancers harbor a population of stem-like cells which are resistant to cytotoxic therapies, thus providing a reservoir of relapse following conventional therapies like chemotherapy and radiation (RT). CSCs have been observed in multiple human cancers, and their presence has been correlated with worse clinical outcomes. Here, we sought to evaluate the impact of drug dosing of the multi-tyrosine kinase inhibitor, sorafenib, on CSC and non-CSCs in soft tissue sarcoma (STS) models, hypothesizing differential effects of sorafenib based on dose and target cell population. In vitro, human cancer cell lines and primary STS from surgical specimens were exposed to escalating doses of sorafenib to determine cell viability and expression of CSC marker aldehyde dehydrogenase (ALDH). In vivo, ALDHbright CSCs were isolated, exposed to sorafenib, and xenograft growth and survival analyses were performed. We observed that sarcoma CSCs appear to paradoxically respond to the tyrosine kinase inhibitor sorafenib at low doses with increased proliferation and stem-like function of CSCs, whereas anti-viability effects dominated at higher doses. Importantly, STS patients receiving neoadjuvant sorafenib and RT on a clinical trial (NCT00864032) showed increased CSCs post therapy, and higher ALDH scores post therapy were associated with worse metastasis-free survival. These data suggest that low-dose sorafenib may promote the CSC phenotype in STS with clinically significant effects, including increased tumor growth and higher rates of metastasis formation in sarcoma patients.
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- 2024
39. Examining the diagnostic value of the mnemonic discrimination task for classification of cognitive status and amyloid-beta burden
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Kim, Soyun, Adams, Jenna N, Chappel-Farley, Miranda G, Keator, David, Janecek, John, Taylor, Lisa, Mikhail, Abanoub, Hollearn, Martina, McMillan, Liv, Rapp, Paul, and Yassa, Michael A
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Biological Psychology ,Cognitive and Computational Psychology ,Psychology ,Neurosciences ,Aging ,Acquired Cognitive Impairment ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,Brain Disorders ,Alzheimer's Disease ,Neurodegenerative ,Basic Behavioral and Social Science ,Behavioral and Social Science ,4.1 Discovery and preclinical testing of markers and technologies ,Neurological ,Humans ,Alzheimer Disease ,Amyloid beta-Peptides ,Cognition ,Cognitive Dysfunction ,Memory ,Episodic ,Positron-Emission Tomography ,Mnemonic discrimination tasks ,Alzheimer's disease ,Mild cognitive impairment ,Amyloid-beta pathology ,Random forest classification ,Pattern separation ,Cognitive Sciences ,Experimental Psychology ,Biological psychology ,Cognitive and computational psychology - Abstract
Alzheimer's disease (AD) is the most common type of dementia, characterized by early memory impairments and gradual worsening of daily functions. AD-related pathology, such as amyloid-beta (Aβ) plaques, begins to accumulate many years before the onset of clinical symptoms. Predicting risk for AD via related pathology is critical as the preclinical stage could serve as a therapeutic time window, allowing for early management of the disease and reducing health and economic costs. Current methods for detecting AD pathology, however, are often expensive and invasive, limiting wide and easy access to a clinical setting. A non-invasive, cost-efficient platform, such as computerized cognitive tests, could be potentially useful to identify at-risk individuals as early as possible. In this study, we examined the diagnostic value of an episodic memory task, the mnemonic discrimination task (MDT), for predicting risk of cognitive impairment or Aβ burden. We constructed a random forest classification algorithm, utilizing MDT performance metrics and various neuropsychological test scores as input features, and assessed model performance using area under the curve (AUC). Models based on MDT performance metrics achieved classification results with an AUC of 0.83 for cognitive status and an AUC of 0.64 for Aβ status. Our findings suggest that mnemonic discrimination function may be a useful predictor of progression to prodromal AD or increased risk of Aβ load, which could be a cost-efficient, noninvasive cognitive testing solution for potentially wide-scale assessment of AD pathological and cognitive risk.
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- 2023
40. Predictive analyses of regulatory sequences with EUGENe.
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Klie, Adam, Laub, David, Talwar, James, Stites, Hayden, Jores, Tobias, Solvason, Joe, Farley, Emma, and Carter, Hannah
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Genome ,Genomics ,Software ,Workflow - Abstract
Deep learning has become a popular tool to study cis-regulatory function. Yet efforts to design software for deep-learning analyses in regulatory genomics that are findable, accessible, interoperable and reusable (FAIR) have fallen short of fully meeting these criteria. Here we present elucidating the utility of genomic elements with neural nets (EUGENe), a FAIR toolkit for the analysis of genomic sequences with deep learning. EUGENe consists of a set of modules and subpackages for executing the key functionality of a genomics deep learning workflow: (1) extracting, transforming and loading sequence data from many common file formats; (2) instantiating, initializing and training diverse model architectures; and (3) evaluating and interpreting model behavior. We designed EUGENe as a simple, flexible and extensible interface for streamlining and customizing end-to-end deep-learning sequence analyses, and illustrate these principles through application of the toolkit to three predictive modeling tasks. We hope that EUGENe represents a springboard towards a collaborative ecosystem for deep-learning applications in genomics research.
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- 2023
41. Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling
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Nicole C. Shaw, Kevin Chen, Kathryn O. Farley, Mitchell Hedges, Catherine Forbes, Gareth Baynam, Timo Lassmann, and Vanessa S. Fear
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SETBP1 haploinsufficiency disorder ,iPSC ,Neural cell modelling ,CRISPR ,Variants of unknown significance ,Neurodevelopmental disorders ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background SETBP1 Haploinsufficiency Disorder (SETBP1-HD) is characterised by mild to moderate intellectual disability, speech and language impairment, mild motor developmental delay, behavioural issues, hypotonia, mild facial dysmorphisms, and vision impairment. Despite a clear link between SETBP1 mutations and neurodevelopmental disorders the precise role of SETBP1 in neural development remains elusive. We investigate the functional effects of three SETBP1 genetic variants including two pathogenic mutations p.Glu545Ter and SETBP1 p.Tyr1066Ter, resulting in removal of SKI and/or SET domains, and a point mutation p.Thr1387Met in the SET domain. Methods Genetic variants were introduced into induced pluripotent stem cells (iPSCs) and subsequently differentiated into neurons to model the disease. We measured changes in cellular differentiation, SETBP1 protein localisation, and gene expression changes. Results The data indicated a change in the WNT pathway, RNA polymerase II pathway and identified GATA2 as a central transcription factor in disease perturbation. In addition, the genetic variants altered the expression of gene sets related to neural forebrain development matching characteristics typical of the SETBP1-HD phenotype. Limitations The study investigates changes in cellular function in differentiation of iPSC to neural progenitor cells as a human model of SETBP1 HD disorder. Future studies may provide additional information relevant to disease on further neural cell specification, to derive mature neurons, neural forebrain cells, or brain organoids. Conclusions We developed a human SETBP1-HD model and identified perturbations to the WNT and POL2RA pathway, genes regulated by GATA2. Strikingly neural cells for both the SETBP1 truncation mutations and the single nucleotide variant displayed a SETBP1-HD-like phenotype.
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- 2024
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42. Juvenile responses to immune challenges are not carried through to subsequent life stages in an insect
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Farley W. S. Silva, Daniel L. Viol, and Simon L. Elliot
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Immune defence ,Reproduction ,Insects ,Resource allocation trade-offs ,Life history ,Medicine ,Science - Abstract
Abstract Environmental variability can significantly impact individual survival and reproduction. Meanwhile, high population densities can lead to resource scarcity and increased exposure to parasites and pathogens. Studies with insects can offer valuable insights into eco-immunology, allowing us to explore the connections between these variables. Here we use the moth Anticarsia gemmatalis to examine how increases in population density and immunological challenge during the larval stage shape its investment in immune defence and reproduction. Larvae reared at a high population density exhibited greater lytic activity against bacteria compared to those reared at low density, whilst bacterial challenge (i.e. bacteria-immersed needles) also increased lytic activity. There was no interaction between the variables population density and bacterial challenge, indicating that these are independent. Surprisingly, neither increase in lytic activity carried through to activity in prepupal haemolymph. Rearing of larvae at a high density delayed pupation and decreased pupal weight. The immunological stimulus did not significantly influence pupal development. Lower population density as a larva resulted in greater adult weight, but did not significantly influence lytic activity in the eggs or the number of eggs laid. Negative correlations were found between lytic activity in the eggs and the number of eggs, as well as between adult weight and the number of eggs. Overall, this study demonstrates that high population density and immune challenge trigger increased lytic activity in caterpillars, but this effect is transient, not persisting into later stages. The trade-offs observed, such as delayed pupation and reduced prepupal weights under high density, suggest a balancing act between immune investment and developmental aspects. The findings hint at a short-term adaptive response rather than a sustained strategy. The implications of delayed pupation and smaller adult moths could influence the moth's life history strategy, impacting its role in the ecosystem. Further research tracking larval immune investment and subsequent reproductive success will unveil the evolutionary dynamics of this relationship in changing environments.
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- 2024
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43. Structural basis for CCR6 modulation by allosteric antagonists
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David Jonathan Wasilko, Brian S. Gerstenberger, Kathleen A. Farley, Wei Li, Jennifer Alley, Mark E. Schnute, Ray J. Unwalla, Jorge Victorino, Kimberly K. Crouse, Ru Ding, Parag V. Sahasrabudhe, Fabien Vincent, Richard K. Frisbie, Alpay Dermenci, Andrew Flick, Chulho Choi, Gary Chinigo, James J. Mousseau, John I. Trujillo, Philippe Nuhant, Prolay Mondal, Vincent Lombardo, Daniel Lamb, Barbara J. Hogan, Gurdeep Singh Minhas, Elena Segala, Christine Oswald, Ian W. Windsor, Seungil Han, Mathieu Rappas, Robert M. Cooke, Matthew F. Calabrese, Gabriel Berstein, Atli Thorarensen, and Huixian Wu
- Subjects
Science - Abstract
Abstract The CC chemokine receptor 6 (CCR6) is a potential target for chronic inflammatory diseases. Previously, we reported an active CCR6 structure in complex with its cognate chemokine CCL20, revealing the molecular basis of CCR6 activation. Here, we present two inactive CCR6 structures in ternary complexes with different allosteric antagonists, CCR6/SQA1/OXM1 and CCR6/SQA1/OXM2. The oxomorpholine analogues, OXM1 and OXM2 are highly selective CCR6 antagonists which bind to an extracellular pocket and disrupt the receptor activation network. An energetically favoured U-shaped conformation in solution that resembles the bound form is observed for the active analogues. SQA1 is a squaramide derivative with close-in analogues reported as antagonists of chemokine receptors including CCR6. SQA1 binds to an intracellular pocket which overlaps with the G protein site, stabilizing a closed pocket that is a hallmark of inactive GPCRs. Minimal communication between the two allosteric pockets is observed, in contrast to the prevalent allosteric cooperativity model of GPCRs. This work highlights the versatility of GPCR antagonism by small molecules, complementing previous knowledge of CCR6 activation, and sheds light on drug discovery targeting CCR6.
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- 2024
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44. Randomised controlled trial of a psychotherapeutic intervention to improve quality of life and other outcomes in people who repeatedly self-harm: FReSH START study protocol
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K. Farley, B. Copsey, A. Wright-Hughes, A. Farrin, C. Bojke, D. McMillan, C. D. Graham, R. Mattock, C. A. Brennan, C. Gates, A. Martin, A. Dowse, J. Horrocks, A. O. House, and E. A. Guthrie
- Subjects
Self-harm ,Suicide ,Talking therapies ,Mental health ,Medicine (General) ,R5-920 - Abstract
Abstract Background Self-harm is a major public health challenge, and repeated self-harm is common in those attending hospital following an episode. Evidence suggests psychological interventions could help people who self-harm, but few definitive studies have assessed their clinical and cost-effectiveness. Repeated self-harm is associated with poor quality of life, depression, suicide and increased health service costs which justify the development of psychotherapeutic interventions tailored for people with repeated self-harm. Methods FReSH START is a multicentre individually 1:1 randomised controlled trial evaluating the clinical and cost-effectiveness of standard care plus psychological therapy or standard care alone for adults (≥ 18 years) presenting at an emergency department (ED) with repeated self-harm. Recruiting 630 participants, it includes an internal pilot, economic evaluation and process evaluation. The intervention will be delivered by mental health staff working in acute settings, with experience of assessing and managing risk in people presenting to emergency services with self-harm. Staff will be trained and supervised to deliver one of three specially adapted therapies: psychodynamic interpersonal therapy, cognitive behavioural therapy or acceptance and commitment therapy. Participants allocated to the intervention will receive one of the adapted therapies according to therapist allocation for up to 6 months via 12 weekly, one to one, 45–50-min sessions. The primary outcome is quality of life measured by the Clinical Outcomes in Routine Evaluation Outcome Measure at 12 months post-randomisation. Secondary outcomes include suicidal intent, depression and cost-effectiveness. Data are collected using hospital attendance records and online/postal/telephone questionnaires at 6 and 12 months post-randomisation, with resource use additionally collected at 3 and 9 months. Discussion This protocol outlines a randomised controlled trial to investigate whether modified therapies are cost-effective and improve quality of life for people who repeatedly self-harm. Few interventions are proven to be deliverable in the NHS for this population. This study is strengthened by the involvement of qualified mental health workers experienced in managing risk as therapists. Trial registration Registered on August 03, 2021. IRAS number: 297939. ISRCTN: https://doi.org/10.1186/ISRCTN73357210 . REC reference: 21/EE/0145. Sponsor: University of Leeds.
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- 2024
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45. Burden of illness in Rett syndrome: initial evaluation of a disorder-specific caregiver survey
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Walter E. Kaufmann, Alan K. Percy, Jeffrey L. Neul, Jenny Downs, Helen Leonard, Paige Nues, Girish D. Sharma, Theresa E. Bartolotta, Gillian S. Townend, Leopold M. G. Curfs, Orietta Mariotti, Claude Buda, Heather M. O’Leary, Lindsay M. Oberman, Vanessa Vogel-Farley, Katherine V. Barnes, and Christopher U. Missling
- Subjects
Rett syndrome ,Quality of life ,Intellectual disability ,Caregiver ,Parent-proxy report ,Medicine - Abstract
Abstract Background Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder associated with multiple neurologic impairments. Previous studies have shown challenges to the quality of life of individuals with RTT and their caregivers. However, instruments applied to quantify disease burden have not adequately captured the impact of these impairments on affected individuals and their families. Consequently, an international collaboration of stakeholders aimed at evaluating Burden of Illness (BOI) in RTT was organized. Methods Based on literature reviews and qualitative interviews with parents of children and adults with RTT, a caregiver questionnaire was constructed to evaluate 22 problems (inclusive of core characteristics, functional impairments, and comorbidities) often experienced with RTT, rated mainly with a 5-level Likert scale. The questionnaire was administered anonymously online to an international sample of 756 caregivers (predominantly parents) of girls and women with RTT. Descriptive statistics were used to identify problems of high frequency and impact on affected individuals and caregivers. Chi-square tests characterized the relationship between problem severity and impact responses, while nonparametric ANOVAs of raw and z-score adjusted scores identified agreement between severity and impact on individual and caregiver. Secondary inferential tests were used to determine the roles of age, clinical type, and country of residence on BOI in RTT. Results There was variability in reported frequency of problems, with the most prevalent, severe and impactful being those related to the core features of RTT (i.e., communication and fine and gross motor impairments). Chi-square analyses demonstrated interdependence between severity and impact responses, while ANOVAs showed that many problems had disproportionately greater impact than severity, either on affected individuals (e.g., hand stereotypies) or their caregivers (e.g., sleep difficulties, seizures, pain, and behavioral abnormalities). With certain exceptions (e.g., breath-holding, seizures), age, clinical type, or country of residence did not influence these BOI profiles. Conclusions Our data demonstrate that core features and related impairments are particularly impactful in RTT. However, problems with mild severity can also have disproportionate impact on affected individuals and, particularly, on their caregivers. Future analyses will examine the role of factors such as treatment outcomes, healthcare services, and healthcare provider’s perspectives, in these BOI profiles.
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- 2024
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46. Roadmap for low-carbon ultra-low temperature storage in biobanking
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Matthew Graham, Gabrielle Samuel, and Martin Farley
- Subjects
Biobanking ,Sustainability ,Ultra-low temperature freezers ,Liquid nitrogen storage ,Carbon footprint ,Medicine - Abstract
Abstract Biobanks have become an integral part of health and bioscience research. However, the ultra-low temperature (ULT) storage methods that biobanks employ [ULT freezers and liquid nitrogen (LN2)] are associated with carbon emissions that contribute to anthropogenic climate change. This paper aims to provide a ‘Roadmap’ for reducing carbon emissions associated with ULT storage in biobanking. The Roadmap offers recommendations associated with nine areas of ULT storage practice: four relating to ULT freezers, three associated with LN2 storage, and two generalised discussions regarding biosample management and centralisation. For each practice, we describe (a) the best approaches to mitigate carbon emissions, (b) explore barriers associated with hindering their implementation, and (c) make a series of recommendations that can help biobank stakeholders overcome these barriers. The recommendations were the output of a one year, UK-based, multidisciplinary research project that involved a quantitative Carbon Footprinting Assessment of the emissions associated with 1 year of ULT storage (for both freezers and LN2) at four different case study sites; as well as two follow up stakeholder workshops to qualitatively explore UK biobank stakeholder perceptions, views, and experiences on how to consider such assessments within the broader social, political, financial, technical, and cultural contexts of biobanking.
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- 2024
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47. Produtividade de milho na presença de doses de N e de inoculação de Herbaspirillum seropedicae
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Farley Alexandre da Fonseca Breda, Gabriela Cavalcanti Alves, and Veronica Massena Reis
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Zea mays ,fixação biológica de nitrogênio ,inoculação de gramíneas ,promoção do crescimento. ,Agriculture (General) ,S1-972 - Abstract
Resumo: O objetivo deste trabalho foi avaliar o efeito de nitrogênio e da inoculação de Herbaspirillum seropedicae sobre a produtividade de milho (Zea mays) e os teores de nutrientes nos grãos. Os híbridos simples BRS 1030 e BRS 1060 receberam inoculação da estirpe BR 11417, na presença ou não de doses de adubação nitrogenada, em Argissolo Vermelho-Amarelo distrófico, durante os períodos de entressafra (plantio em maio de 2012) e safra (plantio em outubro de 2012). Em cada época, os seguintes tratamentos foram avaliados: controle absoluto, sem adubação nitrogenada nem inoculação; controle com inoculação; doses de 50 e 100 kg ha-1 de N, sem inoculação; e dose de 50 kg ha-1 de N mais inoculação. BRS 1030 produziu 1.157 kg ha-1 a mais de grãos que BRS 1060, na análise conjunta dos dois cultivos. Para o primeiro genótipo, a dose de 50 kg ha-1 de N, com inoculação, incrementou em 2% a produtividade na entressafra e em 4,5% na safra. A inoculação de H. seropedicae, estirpe BR 11417, favorece o acúmulo de P nos grãos, mas tem efeito positivo sobre a produtividade somente em combinação com doses de N mineral, o que indica que seu efeito é mais destacado na promoção do crescimento do milho do que na fixação biológica de N.
- Published
- 2016
- Full Text
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48. An Exploration of Individual, Job, and Organizational Characteristics Associated with District Research Leaders' Knowledge Brokering Work
- Author
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Shewchuk, Samantha and Farley-Ripple, Elizabeth
- Abstract
The role of district research leaders (DRLs) in central offices has emerged as a strategy for improving the creation, flow, and use of research knowledge in decision-making. However, there is limited information about the responsibilities, opportunities, and challenges inherent in these roles. This exploratory qualitative study features document analysis to examine the individual backgrounds, job demands, and organizational contexts of DRLs. The result of this study suggest that multiple pathways to the DRL role exist, but few include formal training in knowledge brokering. Further findings suggest that DRL jobs are complex and entail diverse tasks, but share a focus on research leadership and coordination, identifying and obtaining relevant research information, and facilitating evidence -informed change. Moreover, organizational contexts varied in supportiveness for knowledge brokering work. Overall, there was limited evidence of alignment across individual, job, and organizational characteristics, signaling an opportunity to better define and support those in DRL roles.
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- 2022
49. Survey of Evidence in Education for Schools (SEE-S) Descriptive Report. Executive Summary
- Author
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University of Delaware, Center for Research Use in Education (CRUE), Farley-Ripple, Elizabeth, Van Horne, Sam, Tilley, Kati, Shewchuk, Samantha, May, Henry, Micklos, Deborah Amsden, and Blackman, Horatio
- Abstract
This is the executive summary for the report, "Survey of Evidence in Education for Schools (SEE-S) Descriptive Report." In the United States, increased pressure through accountability policy and through the production and dissemination of scientifically based research are intended to create conditions for improving research use. Concurrently, researchers, education agencies, and funders have mounted efforts to strengthen relationships between research and educational practice to improve decisions about and outcomes for children. Accompanying these efforts is a need to understand, at scale, educational decision-making, and the role of research in it. To date, studies of research use in the United States have tended to focus on various stakeholders' research use (e.g., Biddle & Saha, 2002; Dagenais et al., 2012), case studies of schools or districts (e.g., Asen et al., 2013; Finnigan et al., 2013), or case studies of specific education policies or practices (e.g., Hopkins et al., 2019; Scott et al., 2017). The purpose of the report is to broadly portray research use in U.S. schools at scale to better understand where we are as an educational system in the more than forty-year journey to improve the role of research in education policy and practice. [For the full report, see ED628007. For the technical report, see ED628010.]
- Published
- 2022
50. Survey of Evidence in Education for Schools (SEE-S) Technical Report
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University of Delaware, Center for Research Use in Education (CRUE), May, Henry, Blackman, Horatio, Van Horne, Sam, Tilley, Katherine, Farley-Ripple, Elizabeth N., Shewchuk, Samantha, Agboh, Darren, and Micklos, Deborah Amsden
- Abstract
In this technical report, the Center for Research Use in Education (CRUE) presents the methodological design of a large-scale quantitative investigation of research use by school-based practitioners through the "Survey of Evidence in Education for Schools (SEE-S)." It documents the major technical aspects of the development of SEE-S, including item development, sample selection, and reliability and validity assessment. Descriptive statistics for data collected during the survey field trial are also detailed in this report. Through the development and validation of multiple survey measures, this study aims to deepen the fields' understanding of the actions and activities that educators are involved in concerning the use of evidence in decision-making. [For the descriptive report, see ED628007. For the executive summary, see ED628009.]
- Published
- 2022
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