2,889 results on '"S Fraser"'
Search Results
2. Development of a clinical risk score for the prediction of Pneumocystis jirovecii pneumonia in hospitalised patients
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Benjamin Mappin-Kasirer, Olivier Del Corpo, Marc-Alexandre Gingras, Aaron Hass, Jimmy M. Hsu, Cecilia T. Costiniuk, Nicole Ezer, Richard S. Fraser, Todd C. Lee, and Emily G. McDonald
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Clinical risk score ,Fungal infections ,Infections in immunocompromised hosts ,Opportunistic infections ,Pneumocystis jirovecii pneumonia ,Pulmonary infections ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background The performance and availability of invasive and non-invasive investigations for the diagnosis of Pneumocystis jirovecii pneumonia (PCP) vary across clinical settings. Estimating the pre-test probability of PCP is essential to the optimal selection and interpretation of diagnostic tests, such as the 1,3-β-D-glucan assay (BDG), for the prioritization of bronchoscopy, and to guide empiric treatment decisions. We aimed to develop a multivariable risk score to estimate the pre-test probability of PCP. Methods The score was developed from a cohort of 626 individuals who underwent bronchoscopy for the purposes of identifying PCP in a Canadian tertiary-care centre, between 2015 and 2018. We conducted a nested case-control study of 57 cases and 228 unmatched controls. Demographic, clinical, laboratory, and radiological data were included in a multivariable logistic regression model to estimate adjusted odds ratios for PCP diagnosis. A clinical risk score was derived from the multivariable model and discrimination was assessed by estimating the score’s receiver operating characteristic curve. Results Participants had a median age of 60 years (interquartile range [IQR] 49–68) and 115 (40%) were female; 40 (14%) had HIV and 49 (17%) had a solid organ transplant (SOT). The risk score included prior SOT or HIV with CD4 ≤ 200/µL (+ 2), serum lactate dehydrogenase ≥ 265.5 IU/mL (+ 2), radiological pattern typical of PCP on chest x-ray (+ 2) or CT scan (+ 2.5), and PCP prophylaxis with trimethoprim-sulfamethoxazole (-3) or other antimicrobials (-2). The median score was 4 points (IQR, 2-4.5) corresponding to a 28% probability of PCP. The risk prediction model had good discrimination with a c-statistic of 0.79 (0.71–0.84). Given the operating characteristics of the BDG assay, scores ≤ 3 in patients without HIV, and ≤ 5.5 in those with HIV, paired with a negative BDG, would be expected to rule out PCP with 95% certainty. Conclusion We propose the PCP Score to estimate pre-test probability of PCP. Once validated, it should help clinicians determine which patients to refer for invasive investigations, when to rely on serological testing, and in whom to consider pre-emptive treatment.
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- 2024
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3. Human tumor suppressor protein Pdcd4 binds at the mRNA entry channel in the 40S small ribosomal subunit
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Jailson Brito Querido, Masaaki Sokabe, Irene Díaz-López, Yuliya Gordiyenko, Philipp Zuber, Yifei Du, Lucas Albacete-Albacete, V. Ramakrishnan, and Christopher S. Fraser
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Science - Abstract
Abstract Translation is regulated mainly in the initiation step, and its dysregulation is implicated in many human diseases. Several proteins have been found to regulate translational initiation, including Pdcd4 (programmed cell death gene 4). Pdcd4 is a tumor suppressor protein that prevents cell growth, invasion, and metastasis. It is downregulated in most tumor cells, while global translation in the cell is upregulated. To understand the mechanisms underlying translational control by Pdcd4, we used single-particle cryo-electron microscopy to determine the structure of human Pdcd4 bound to 40S small ribosomal subunit, including Pdcd4-40S and Pdcd4-40S-eIF4A-eIF3-eIF1 complexes. The structures reveal the binding site of Pdcd4 at the mRNA entry site in the 40S, where the C-terminal domain (CTD) interacts with eIF4A at the mRNA entry site, while the N-terminal domain (NTD) is inserted into the mRNA channel and decoding site. The structures, together with quantitative binding and in vitro translation assays, shed light on the critical role of the NTD for the recruitment of Pdcd4 to the ribosomal complex and suggest a model whereby Pdcd4 blocks the eIF4F-independent role of eIF4A during recruitment and scanning of the 5′ UTR of mRNA.
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- 2024
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4. Comprehensive encoding of conformational and compositional protein structural ensembles through the mmCIF data structure
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Stephanie A. Wankowicz and James S. Fraser
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biomolecules ,macromolecular ensembles ,ensemble–function predictions ,mmcif ,cryoem ,Crystallography ,QD901-999 - Abstract
In the folded state, biomolecules exchange between multiple conformational states crucial for their function. However, most structural models derived from experiments and computational predictions only encode a single state. To represent biomolecules accurately, we must move towards modeling and predicting structural ensembles. Information about structural ensembles exists within experimental data from X-ray crystallography and cryo-electron microscopy. Although new tools are available to detect conformational and compositional heterogeneity within these ensembles, the legacy PDB data structure does not robustly encapsulate this complexity. We propose modifications to the macromolecular crystallographic information file (mmCIF) to improve the representation and interrelation of conformational and compositional heterogeneity. These modifications will enable the capture of macromolecular ensembles in a human and machine-interpretable way, potentially catalyzing breakthroughs for ensemble–function predictions, analogous to the achievements of AlphaFold with single-structure prediction.
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- 2024
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5. Conserved regulatory motifs in the juxtamembrane domain and kinase N-lobe revealed through deep mutational scanning of the MET receptor tyrosine kinase domain
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Gabriella O Estevam, Edmond M Linossi, Christian B Macdonald, Carla A Espinoza, Jennifer M Michaud, Willow Coyote-Maestas, Eric A Collisson, Natalia Jura, and James S Fraser
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deep mutational scanning ,receptor tyrosine kinase ,cancer ,allostery ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
MET is a receptor tyrosine kinase (RTK) responsible for initiating signaling pathways involved in development and wound repair. MET activation relies on ligand binding to the extracellular receptor, which prompts dimerization, intracellular phosphorylation, and recruitment of associated signaling proteins. Mutations, which are predominantly observed clinically in the intracellular juxtamembrane and kinase domains, can disrupt typical MET regulatory mechanisms. Understanding how juxtamembrane variants, such as exon 14 skipping (METΔEx14), and rare kinase domain mutations can increase signaling, often leading to cancer, remains a challenge. Here, we perform a parallel deep mutational scan (DMS) of the MET intracellular kinase domain in two fusion protein backgrounds: wild-type and METΔEx14. Our comparative approach has revealed a critical hydrophobic interaction between a juxtamembrane segment and the kinase ⍺C-helix, pointing to potential differences in regulatory mechanisms between MET and other RTKs. Additionally, we have uncovered a β5 motif that acts as a structural pivot for the kinase domain in MET and other TAM family of kinases. We also describe a number of previously unknown activating mutations, aiding the effort to annotate driver, passenger, and drug resistance mutations in the MET kinase domain.
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- 2024
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6. Rosace: a robust deep mutational scanning analysis framework employing position and mean-variance shrinkage
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Jingyou Rao, Ruiqi Xin, Christian Macdonald, Matthew K. Howard, Gabriella O. Estevam, Sook Wah Yee, Mingsen Wang, James S. Fraser, Willow Coyote-Maestas, and Harold Pimentel
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Biology (General) ,QH301-705.5 ,Genetics ,QH426-470 - Abstract
Abstract Deep mutational scanning (DMS) measures the effects of thousands of genetic variants in a protein simultaneously. The small sample size renders classical statistical methods ineffective. For example, p-values cannot be correctly calibrated when treating variants independently. We propose Rosace, a Bayesian framework for analyzing growth-based DMS data. Rosace leverages amino acid position information to increase power and control the false discovery rate by sharing information across parameters via shrinkage. We also developed Rosette for simulating the distributional properties of DMS. We show that Rosace is robust to the violation of model assumptions and is more powerful than existing tools.
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- 2024
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7. Automated multiconformer model building for X-ray crystallography and cryo-EM
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Stephanie A Wankowicz, Ashraya Ravikumar, Shivani Sharma, Blake Riley, Akshay Raju, Daniel W Hogan, Jessica Flowers, Henry van den Bedem, Daniel A Keedy, and James S Fraser
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structural biology ,conformational heterogeneity ,cryo-EM ,protein dynamics ,X-ray crystallography ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
In their folded state, biomolecules exchange between multiple conformational states that are crucial for their function. Traditional structural biology methods, such as X-ray crystallography and cryogenic electron microscopy (cryo-EM), produce density maps that are ensemble averages, reflecting molecules in various conformations. Yet, most models derived from these maps explicitly represent only a single conformation, overlooking the complexity of biomolecular structures. To accurately reflect the diversity of biomolecular forms, there is a pressing need to shift toward modeling structural ensembles that mirror the experimental data. However, the challenge of distinguishing signal from noise complicates manual efforts to create these models. In response, we introduce the latest enhancements to qFit, an automated computational strategy designed to incorporate protein conformational heterogeneity into models built into density maps. These algorithmic improvements in qFit are substantiated by superior Rfree and geometry metrics across a wide range of proteins. Importantly, unlike more complex multicopy ensemble models, the multiconformer models produced by qFit can be manually modified in most major model building software (e.g., Coot) and fit can be further improved by refinement using standard pipelines (e.g., Phenix, Refmac, Buster). By reducing the barrier of creating multiconformer models, qFit can foster the development of new hypotheses about the relationship between macromolecular conformational dynamics and function.
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- 2024
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8. Disruption of dopamine D2/D3 system function impairs the human ability to understand the mental states of other people.
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Bianca A Schuster, Sophie Sowden, Alicia J Rybicki, Dagmar S Fraser, Clare Press, Lydia Hickman, Peter Holland, and Jennifer L Cook
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Biology (General) ,QH301-705.5 - Abstract
Difficulties in reasoning about others' mental states (i.e., mentalising/Theory of Mind) are highly prevalent among disorders featuring dopamine dysfunctions (e.g., Parkinson's disease) and significantly affect individuals' quality of life. However, due to multiple confounding factors inherent to existing patient studies, currently little is known about whether these sociocognitive symptoms originate from aberrant dopamine signalling or from psychosocial changes unrelated to dopamine. The present study, therefore, investigated the role of dopamine in modulating mentalising in a sample of healthy volunteers. We used a double-blind, placebo-controlled procedure to test the effect of the D2/D3 antagonist haloperidol on mental state attribution, using an adaptation of the Heider and Simmel (1944) animations task. On 2 separate days, once after receiving 2.5 mg haloperidol and once after receiving placebo, 33 healthy adult participants viewed and labelled short videos of 2 triangles depicting mental state (involving mentalistic interaction wherein 1 triangle intends to cause or act upon a particular mental state in the other, e.g., surprising) and non-mental state (involving reciprocal interaction without the intention to cause/act upon the other triangle's mental state, e.g., following) interactions. Using Bayesian mixed effects models, we observed that haloperidol decreased accuracy in labelling both mental and non-mental state animations. Our secondary analyses suggest that dopamine modulates inference from mental and non-mental state animations via independent mechanisms, pointing towards 2 putative pathways underlying the dopaminergic modulation of mental state attribution: action representation and a shared mechanism supporting mentalising and emotion recognition. We conclude that dopaminergic pathways impact Theory of Mind, at least indirectly. Our results have implications for the neurochemical basis of sociocognitive difficulties in patients with dopamine dysfunctions and generate new hypotheses about the specific dopamine-mediated mechanisms underlying social cognition.
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- 2024
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9. Structural characterization of ligand binding and pH-specific enzymatic activity of mouse Acidic Mammalian Chitinase
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Roberto Efraín Díaz, Andrew K Ecker, Galen J Correy, Pooja Asthana, Iris D Young, Bryan Faust, Michael C Thompson, Ian B Seiple, Steven Van Dyken, Richard M Locksley, and James S Fraser
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enzyme ,chitin ,lung ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Chitin is an abundant biopolymer and pathogen-associated molecular pattern that stimulates a host innate immune response. Mammals express chitin-binding and chitin-degrading proteins to remove chitin from the body. One of these proteins, Acidic Mammalian Chitinase (AMCase), is an enzyme known for its ability to function under acidic conditions in the stomach but is also active in tissues with more neutral pHs, such as the lung. Here, we used a combination of biochemical, structural, and computational modeling approaches to examine how the mouse homolog (mAMCase) can act in both acidic and neutral environments. We measured kinetic properties of mAMCase activity across a broad pH range, quantifying its unusual dual activity optima at pH 2 and 7. We also solved high-resolution crystal structures of mAMCase in complex with oligomeric GlcNAcn, the building block of chitin, where we identified extensive conformational ligand heterogeneity. Leveraging these data, we conducted molecular dynamics simulations that suggest how a key catalytic residue could be protonated via distinct mechanisms in each of the two environmental pH ranges. These results integrate structural, biochemical, and computational approaches to deliver a more complete understanding of the catalytic mechanism governing mAMCase activity at different pH. Engineering proteins with tunable pH optima may provide new opportunities to develop improved enzyme variants, including AMCase, for therapeutic purposes in chitin degradation.
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- 2024
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10. CONTINUOUS BIM ALIGNMENT FOR MIXED REALITY VISUALISATION
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M. Radanovic, K. Khoshelham, C. S. Fraser, and D. Acharya
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Technology ,Engineering (General). Civil engineering (General) ,TA1-2040 ,Applied optics. Photonics ,TA1501-1820 - Abstract
Several methods exist that can be used to perform initial alignment of Building information models (BIMs) to the real building for Mixed Reality (MR) applications, such as marker-based or markerless visual methods, but this alignment is susceptible to drift over time. The existing model-based methods that can be used to maintain this alignment have multiple limitations, such as the use of iterative processes and poor performance in environments with either too many or not enough lines. To address these issues, we propose an end-to-end trainable Convolutional Neural Network (CNN) that takes a real and synthetic BIM image pair as input to regress the 6 DoF relative camera pose difference between them directly. By correcting the relative pose error we are able to considerably improve the alignment of the BIM to the real building. Furthermore, the results of our experiments demonstrate good performance in a challenging environment and high resilience to domain shift between synthetic and real images. A high localisation accuracy of approximately 7.0 cm and 0.9° is achieved which indicates the method can be used to reduce the camera tracking drift for MR applications.
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- 2023
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11. Recommendations for accelerating open preprint peer review to improve the culture of science.
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Michele Avissar-Whiting, Frédérique Belliard, Stefano M Bertozzi, Amy Brand, Katherine Brown, Géraldine Clément-Stoneham, Stephanie Dawson, Gautam Dey, Daniel Ecer, Scott C Edmunds, Ashley Farley, Tara D Fischer, Maryrose Franko, James S Fraser, Kathryn Funk, Clarisse Ganier, Melissa Harrison, Anna Hatch, Haley Hazlett, Samantha Hindle, Daniel W Hook, Phil Hurst, Sophien Kamoun, Robert Kiley, Michael M Lacy, Marcel LaFlamme, Rebecca Lawrence, Thomas Lemberger, Maria Leptin, Elliott Lumb, Catriona J MacCallum, Christopher Steven Marcum, Gabriele Marinello, Alex Mendonça, Sara Monaco, Kleber Neves, Damian Pattinson, Jessica K Polka, Iratxe Puebla, Martyn Rittman, Stephen J Royle, Daniela Saderi, Richard Sever, Kathleen Shearer, John E Spiro, Bodo Stern, Dario Taraborelli, Ron Vale, Claudia G Vasquez, Ludo Waltman, Fiona M Watt, Zara Y Weinberg, and Mark Williams
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Biology (General) ,QH301-705.5 - 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
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12. It’s a competitive business
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Masaaki Sokabe and Christopher S Fraser
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translation ,ribosomes ,purified reconstituted systems ,molecular biology ,mRNA ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
A new in vitro system called Rec-Seq sheds light on how mRNA molecules compete for the machinery that translates their genetic sequence into proteins.
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- 2024
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13. Risk factors for ill health: How do we specify what is ‘modifiable’?
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Nisreen A. Alwan, Seb Stannard, Ann Berrington, Shantini Paranjothy, Rebecca B. Hoyle, Rhiannon K. Owen, and Simon D. S. Fraser
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Public aspects of medicine ,RA1-1270 - Published
- 2024
14. Digital determinants of health: Editorial.
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Hamish S Fraser, Alvin Marcelo, Mahima Kalla, Khumbo Kalua, Leo A Celi, and Jennifer Ziegler
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Computer applications to medicine. Medical informatics ,R858-859.7 - Published
- 2023
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15. Exploiting endogenous and therapy-induced apoptotic vulnerabilities in immunoglobulin light chain amyloidosis with BH3 mimetics
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Cameron S. Fraser, Johan K. E. Spetz, Xingping Qin, Adam Presser, Jonathan Choiniere, Chendi Li, Stacey Yu, Frances Blevins, Aaron N. Hata, Jeffrey W. Miller, Gary A. Bradshaw, Marian Kalocsay, Vaishali Sanchorawala, Shayna Sarosiek, and Kristopher A. Sarosiek
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Science - Abstract
Immunoglobulin light chain amyloidosis is a lethal hematologic disorder driven by clonal plasma cells producing abnormal light chains that damage healthy tissues. Fraser et al. show that BH3 mimetics, which inhibit pro-survival proteins BCL-2 or MCL-1, can effectively eliminate diseased cells.
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- 2022
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16. Characterization of Chinese Tallow Invasion in the Southern United States
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Mohammad M. Bataineh, Jacob S. Fraser, and Lauren S. Pile Knapp
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Triadica sebifera ,popcorn tree ,citizen science ,invasive plants ,Plant ecology ,QK900-989 - Abstract
Chinese tallow is a non-native invasive tree expanding in range and abundance throughout the southern United States. Several biogeographical studies mapping tallow distribution and examining key underlying environmental factors relied on the U.S. Forest Service Forest Inventory and Analysis (FIA) data, representing forestlands at scales of ~2400 ha. However, given that most invasive trees, like tallow, are cosmopolitan and dynamic in nature, FIA data fails to capture the extent and severity of the invasion especially outside areas classified as forestlands. To develop tallow maps that more adequately depict its distribution at finer spatial scales and to capture observations in non-forestlands, we combined verified citizen science observations with FIA data. Further, we described spatiotemporal patterns and compared citizen science to FIA and other previously published distribution maps. From our work, although tallow is prevalent in the south, Louisiana, Texas, and Mississippi were the most invaded states. Tallow was associated with flatwoods and prairie grasslands of the Gulf Coast. Annual extreme minimum temperatures of less than −12.2 °C (10 °F) represented the northern limit of naturalized tallow populations. Tallow’s northward and inland expansion was captured in citizen science and FIA data, indicating a tallow spread rate ranging from 5 to 20 km annually over the last decade. Systematic sampling, such as FIA, and citizen science data both have their own unique pitfalls. However, the use of citizen science data can complement invasive plant distribution mapping, especially when combined with data from established systematic monitoring networks. This approach provides for a more complete understanding of invasive tree extent and spatiotemporal dynamics across large landscapes.
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- 2024
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17. The dynamics of frailty development and progression in older adults in primary care in England (2006–2017): a retrospective cohort profile
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Carole Fogg, Simon D. S. Fraser, Paul Roderick, Simon de Lusignan, Andrew Clegg, Sally Brailsford, Abigail Barkham, Harnish P. Patel, Vivienne Windle, Scott Harris, Shihua Zhu, Tracey England, Dave Evenden, Francesca Lambert, Bronagh Walsh, and The Frailty Dynamics study team
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Frailty ,Cohort study ,Adults ,Trajectories ,Computer simulation modelling ,Primary care ,Geriatrics ,RC952-954.6 - Abstract
Abstract Background Frailty is a common condition in older adults and has a major impact on patient outcomes and service use. Information on the prevalence in middle-aged adults and the patterns of progression of frailty at an individual and population level is scarce. To address this, a cohort was defined from a large primary care database in England to describe the epidemiology of frailty and understand the dynamics of frailty within individuals and across the population. This article describes the structure of the dataset, cohort characteristics and planned analyses. Methods Retrospective cohort study using electronic health records. Participants were aged ≥50 years registered in practices contributing to the Oxford Royal College of General Practitioners Research and Surveillance Centre between 2006 to 2017. Data include GP practice details, patient sociodemographic and clinical characteristics, twice-yearly electronic Frailty Index (eFI), deaths, medication use and primary and secondary care health service use. Participants in each cohort year by age group, GP and patient characteristics at cohort entry are described. Results The cohort includes 2,177,656 patients, contributing 15,552,946 person-years, registered at 419 primary care practices in England. The mean age was 61 years, 52.1% of the cohort was female, and 77.6% lived in urban environments. Frailty increased with age, affecting 10% of adults aged 50–64 and 43.7% of adults aged ≥65. The prevalence of long-term conditions and specific frailty deficits increased with age, as did the eFI and the severity of frailty categories. Conclusion A comprehensive understanding of frailty dynamics will inform predictions of current and future care needs to facilitate timely planning of appropriate interventions, service configurations and workforce requirements. Analysis of this large, nationally representative cohort including participants aged ≥50 will capture earlier transitions to frailty and enable a detailed understanding of progression and impact. These results will inform novel simulation models which predict future health and service needs of older people living with frailty. Study registration Registered on www.clinicaltrials.gov October 25th 2019, NCT04139278 .
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- 2022
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18. Kinematics and observer-animator kinematic similarity predict mental state attribution from Heider–Simmel style animations
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Bianca A. Schuster, Dagmar S. Fraser, Jasper J. F. van den Bosch, Sophie Sowden, Andrew S. Gordon, Dongsung Huh, and Jennifer L. Cook
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Medicine ,Science - Abstract
Abstract The ability to ascribe mental states, such as beliefs or desires to oneself and other individuals forms an integral part of everyday social interaction. Animations tasks, in which observers watch videos of interacting triangles, have been extensively used to test mental state attribution in a variety of clinical populations. Compared to control participants, individuals with clinical conditions such as autism typically offer less appropriate mental state descriptions of such videos. Recent research suggests that stimulus kinematics and movement similarity (between the video and the observer) may contribute to mental state attribution difficulties. Here we present a novel adaptation of the animations task, suitable to track and compare animation generator and -observer kinematics. Using this task and a population-derived stimulus database, we confirmed the hypotheses that an animation’s jerk and jerk similarity between observer and animator significantly contribute to the correct identification of an animation. By employing random forest analysis to explore other stimulus characteristics, we reveal that other indices of movement similarity, including acceleration- and rotation-based similarity, also predict performance. Our results highlight the importance of movement similarity between observer and animator and raise new questions about reasons why some clinical populations exhibit difficulties with this task.
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- 2021
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19. Enterprise Risk Management: Today's Leading Research and Best Practices for Tomorrow's Executives
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John R. S. Fraser, Rob Quail, Betty Simkins, John R. S. Fraser, Rob Quail, Betty Simkins
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- 2021
20. Ligand binding remodels protein side-chain conformational heterogeneity
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Stephanie A Wankowicz, Saulo H de Oliveira, Daniel W Hogan, Henry van den Bedem, and James S Fraser
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ligand binding ,conformational entropy ,conformational ensembles ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
While protein conformational heterogeneity plays an important role in many aspects of biological function, including ligand binding, its impact has been difficult to quantify. Macromolecular X-ray diffraction is commonly interpreted with a static structure, but it can provide information on both the anharmonic and harmonic contributions to conformational heterogeneity. Here, through multiconformer modeling of time- and space-averaged electron density, we measure conformational heterogeneity of 743 stringently matched pairs of crystallographic datasets that reflect unbound/apo and ligand-bound/holo states. When comparing the conformational heterogeneity of side chains, we observe that when binding site residues become more rigid upon ligand binding, distant residues tend to become more flexible, especially in non-solvent-exposed regions. Among ligand properties, we observe increased protein flexibility as the number of hydrogen bonds decreases and relative hydrophobicity increases. Across a series of 13 inhibitor-bound structures of CDK2, we find that conformational heterogeneity is correlated with inhibitor features and identify how conformational changes propagate differences in conformational heterogeneity away from the binding site. Collectively, our findings agree with models emerging from nuclear magnetic resonance studies suggesting that residual side-chain entropy can modulate affinity and point to the need to integrate both static conformational changes and conformational heterogeneity in models of ligand binding.
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- 2022
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21. How accurate is the Isabel diagnostic decision support system with patients presenting with acute symptoms of heart disease?
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Katherine A. Brown and Hamish S. Fraser
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- 2021
22. Ensemble-based enzyme design can recapitulate the effects of laboratory directed evolution in silico
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Aron Broom, Rojo V. Rakotoharisoa, Michael C. Thompson, Niayesh Zarifi, Erin Nguyen, Nurzhan Mukhametzhanov, Lin Liu, James S. Fraser, and Roberto A. Chica
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Science - Abstract
Kemp eliminases are artificial enzymes that catalyze the concerted deprotonation and ring-opening of benzisoxazoles. Here, the authors use room-temperature X-ray crystallography to investigate changes to the conformational ensemble of the Kemp eliminase HG3 along a directed evolutionary trajectory, and develop an experimentally guided, ensemble-based computational enzyme design procedure.
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- 2020
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23. Radiographic features in investigated for Pneumocystis jirovecii pneumonia: a nested case-control study
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Jimmy M. Hsu, Aaron Hass, Marc-Alexandre Gingras, Jaron Chong, Cecilia Costiniuk, Nicole Ezer, Richard S. Fraser, Emily G. McDonald, and Todd C. Lee
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Pneumocysitis jirovecii ,PCP ,PJP ,Pneumonia ,Computed tomography ,Diagnosis ,Infectious and parasitic diseases ,RC109-216 - Abstract
Abstract Background Pneumocystis jirovecii pneumonia (PJP) can be challenging to diagnose, often requiring bronchoscopy. Since most patients suspected of PJP undergo imaging, we hypothesized that the findings of these studies could help estimate the probability of disease prior to invasive testing. Methods We created a cohort of patients who underwent bronchoscopy specifically to diagnose PJP and conducted a nested case-control study to compare the radiographic features between patients with (n = 72) and without (n = 288) pathologically proven PJP. We used multivariable logistic regression to identify radiographic features independently associated with PJP. Results Chest x-ray findings poorly predicted the diagnosis of PJP. However, multivariable analysis of CT scan findings found that “increased interstitial markings” (OR 4.3; 95%CI 2.2–8.2), “ground glass opacities” (OR 3.3; 95%CI 1.2–9.1) and the radiologist’s impression of PJP being “possible” (OR 2.0; 95%CI 1.0–4.1) or “likely” (OR 9.3; 95%CI 3.4–25.3) were independently associated with the final diagnosis (c-statistic 0.75). Conclusions Where there is clinical suspicion of PJP, the use of CT scan can help determine the probability of PJP. Identifying patients at low risk of PJP may enable better use of non-invasive testing to avoid bronchoscopy while higher probability patients could be prioritized.
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- 2020
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24. Ethnic minority disparities in progression and mortality of pre-dialysis chronic kidney disease: a systematic scoping review
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Hilda O. Hounkpatin, Simon D. S. Fraser, Rory Honney, Gavin Dreyer, Alison Brettle, and Paul J. Roderick
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Chronic kidney disease ,Epidemiology ,End stage renal disease ,Ethnicity ,Pre-dialysis ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Abstract Background There are a growing number of studies on ethnic differences in progression and mortality for pre-dialysis chronic kidney disease (CKD), but this literature has yet to be synthesised, particularly for studies on mortality. Methods This scoping review synthesized existing literature on ethnic differences in progression and mortality for adults with pre-dialysis CKD, explored factors contributing to these differences, and identified gaps in the literature. A comprehensive search strategy using search terms for ethnicity and CKD was taken to identify potentially relevant studies. Nine databases were searched from 1992 to June 2017, with an updated search in February 2020. Results 8059 articles were identified and screened. Fifty-five studies (2 systematic review, 7 non-systematic reviews, and 46 individual studies) were included in this review. Most were US studies and compared African-American/Afro-Caribbean and Caucasian populations, and fewer studies assessed outcomes for Hispanics and Asians. Most studies reported higher risk of CKD progression in Afro-Caribbean/African-Americans, Hispanics, and Asians, lower risk of mortality for Asians, and mixed findings on risk of mortality for Afro-Caribbean/African-Americans and Hispanics, compared to Caucasians. Biological factors such as hypertension, diabetes, and cardiovascular disease contributed to increased risk of progression for ethnic minorities but did not increase risk of mortality in these groups. Conclusions Higher rates of renal replacement therapy among ethnic minorities may be partly due to increased risk of progression and reduced mortality in these groups. The review identifies gaps in the literature and highlights a need for a more structured approach by researchers that would allow higher confidence in single studies and better harmonization of data across studies to advance our understanding of CKD progression and mortality.
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- 2020
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25. Identification of single-nucleotide variants associated with susceptibility to Salmonella in pigs using a genome-wide association approach
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Corinne H. Schut, Abdolvahab Farzan, Russell S. Fraser, Margaret H. Ainslie-Garcia, Robert M. Friendship, and Brandon N. Lillie
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Salmonella ,Swine ,Antibody response ,Shedding ,GWAS ,Single-nucleotide variant ,Veterinary medicine ,SF600-1100 - Abstract
Abstract Background Salmonella enterica serovars are a major cause of foodborne illness and have a substantial impact on global human health. In Canada, Salmonella is commonly found on swine farms and the increasing concern about drug use and antimicrobial resistance associated with Salmonella has promoted research into alternative control methods, including selecting for pig genotypes associated with resistance to Salmonella. The objective of this study was to identify single-nucleotide variants in the pig genome associated with Salmonella susceptibility using a genome-wide association approach. Repeated blood and fecal samples were collected from 809 pigs in 14 groups on farms and tonsils and lymph nodes were collected at slaughter. Sera were analyzed for Salmonella IgG antibodies by ELISA and feces and tissues were cultured for Salmonella. Pig DNA was genotyped using a custom 54 K single-nucleotide variant oligo array and logistic mixed-models used to identify SNVs associated with IgG seropositivity, shedding, and tissue colonization. Results Variants in/near PTPRJ (p = 0.0000066), ST6GALNAC3 (p = 0.0000099), and DCDC2C (n = 3, p
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- 2020
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26. Comparing serial X-ray crystallography and microcrystal electron diffraction (MicroED) as methods for routine structure determination from small macromolecular crystals
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Alexander M. Wolff, Iris D. Young, Raymond G. Sierra, Aaron S. Brewster, Michael W. Martynowycz, Eriko Nango, Michihiro Sugahara, Takanori Nakane, Kazutaka Ito, Andrew Aquila, Asmit Bhowmick, Justin T. Biel, Sergio Carbajo, Aina E. Cohen, Saul Cortez, Ana Gonzalez, Tomoya Hino, Dohyun Im, Jake D. Koralek, Minoru Kubo, Tomas S. Lazarou, Takashi Nomura, Shigeki Owada, Avi J. Samelson, Tomoyuki Tanaka, Rie Tanaka, Erin M. Thompson, Henry van den Bedem, Rahel A. Woldeyes, Fumiaki Yumoto, Wei Zhao, Kensuke Tono, Sebastien Boutet, So Iwata, Tamir Gonen, Nicholas K. Sauter, James S. Fraser, and Michael C. Thompson
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microcrystals ,batch crystallization ,serial crystallography ,microed ,Crystallography ,QD901-999 - Abstract
Innovative new crystallographic methods are facilitating structural studies from ever smaller crystals of biological macromolecules. In particular, serial X-ray crystallography and microcrystal electron diffraction (MicroED) have emerged as useful methods for obtaining structural information from crystals on the nanometre to micrometre scale. Despite the utility of these methods, their implementation can often be difficult, as they present many challenges that are not encountered in traditional macromolecular crystallography experiments. Here, XFEL serial crystallography experiments and MicroED experiments using batch-grown microcrystals of the enzyme cyclophilin A are described. The results provide a roadmap for researchers hoping to design macromolecular microcrystallography experiments, and they highlight the strengths and weaknesses of the two methods. Specifically, we focus on how the different physical conditions imposed by the sample-preparation and delivery methods required for each type of experiment affect the crystal structure of the enzyme.
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- 2020
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27. Impact of traffic, poverty and facility ownership on travel time to emergency care in Nairobi, Kenya
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Maya S. Fraser, Benjamin W. Wachira, Abraham D. Flaxman, Aaron Y. Lee, and Herbert C. Duber
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Medicine ,Medicine (General) ,R5-920 - Abstract
Background: In many low and middle-income countries (LMICs), timely access to emergency healthcare services is limited. In urban settings, traffic can have a significant impact on travel time, leading to life-threatening delays for time-sensitive injuries and medical emergencies. In this study, we examined travel times to hospitals in Nairobi, Kenya, one of the largest and most congested cities in the developing world. Methods: We used a network approach to estimate average minimum travel times to different types of hospitals (e.g. ownership and level of care) in Nairobi under both congested and uncongested traffic conditions. We also examined the correlation between travel time and socioeconomic status. Results: We estimate the average minimum travel time during uncongested traffic conditions to any level 4 health facility (primary hospitals) or above in Nairobi to be 4.5 min (IQR 2.5–6.1). Traffic added an average of 9.0 min (a 200% increase). In uncongested conditions, we estimate an average travel time of 7.9 min (IQR 5.1–10.4) to level 5 facilities (secondary hospitals) and 11.6 min (IQR 8.5–14.2) to Kenyatta National Hospital, the only level 6 facility (tertiary hospital) in the country. Traffic congestion added an average of 13.1 and 16.0 min (166% and 138% increase) to travel times to level 5 and level 6 facilities, respectively. For individuals living below the poverty line, we estimate that preferential use of public or faith-based facilities could increase travel time by as much as 65%. Conclusion: Average travel times to health facilities capable of providing emergency care in Nairobi are quite low, but traffic congestion double or triple estimated travel times. Furthermore, we estimate significant disparities in timely access to care for those individuals living under the poverty line who preferentially seek care in public or faith-based facilities. Keywords: Emergency care, Kenya, Traffic, Poverty
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- 2020
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28. Directed evolution of the rRNA methylating enzyme Cfr reveals molecular basis of antibiotic resistance
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Kaitlyn Tsai, Vanja Stojković, Lianet Noda-Garcia, Iris D Young, Alexander G Myasnikov, Jordan Kleinman, Ali Palla, Stephen N Floor, Adam Frost, James S Fraser, Dan S Tawfik, and Danica Galonić Fujimori
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Cfr ,directed evolution ,antibiotic resistance ,RNA modifications ,peptidyl transferase center ,cryoEM ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
Alteration of antibiotic binding sites through modification of ribosomal RNA (rRNA) is a common form of resistance to ribosome-targeting antibiotics. The rRNA-modifying enzyme Cfr methylates an adenosine nucleotide within the peptidyl transferase center, resulting in the C-8 methylation of A2503 (m8A2503). Acquisition of cfr results in resistance to eight classes of ribosome-targeting antibiotics. Despite the prevalence of this resistance mechanism, it is poorly understood whether and how bacteria modulate Cfr methylation to adapt to antibiotic pressure. Moreover, direct evidence for how m8A2503 alters antibiotic binding sites within the ribosome is lacking. In this study, we performed directed evolution of Cfr under antibiotic selection to generate Cfr variants that confer increased resistance by enhancing methylation of A2503 in cells. Increased rRNA methylation is achieved by improved expression and stability of Cfr through transcriptional and post-transcriptional mechanisms, which may be exploited by pathogens under antibiotic stress as suggested by natural isolates. Using a variant that achieves near-stoichiometric methylation of rRNA, we determined a 2.2 Å cryo-electron microscopy structure of the Cfr-modified ribosome. Our structure reveals the molecular basis for broad resistance to antibiotics and will inform the design of new antibiotics that overcome resistance mediated by Cfr.
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- 2022
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29. Equine Endocrinology
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François-René Bertin, Natalie S Fraser
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- 2020
30. Outcomes of gynecologic cancer surgery during the COVID-19 pandemic: an international, multicenter, prospective CovidSurg-Gynecologic Oncology Cancer study
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Nepogodiev, Dmitri, Siaw-Acheampong, Kwabena, Benson, Ruth A., Bywater, Edward, Chaudhry, Daoud, Dawson, Brett E., Evans, Jonathan P., Glasbey, James C., Gujjuri, Rohan R., Heritage, Emily, Jones, Conor S., Kamarajah, Sivesh K., Khatri, Chetan, Khaw, Rachel A., Keatley, James M., Knight, Andrew, Lawday, Samuel, Li, Elizabeth, Mann, Harvinder S., Marson, Ella J., McLean, Kenneth A., Mckay, Siobhan C., Mills, Emily C., Pellino, Gianluca, Picciochi, Maria, Taylor, Elliott H., Tiwari, Abhinav, Simoes, Joana FF., Trout, Isobel M., Venn, Mary L., Wilkin, Richard JW., Bhangu, Aneel, Abbott, Tom EF., Abukhalaf, Sadi, Adamina, Michel, Ademuyiwa, Adesoji O., Agarwal, Arnav, Akkulak, Murat, Alameer, Ehab, Alderson, Derek, Alakaloko, Felix, Albertsmeier, Markus, Alser, Osaid, Alshaar, Muhammad, Alshryda, Sattar, Arnaud, Alexis P., Augestad, Knut Magne, Ayasra, Faris, Azevedo, José, Bankhead-Kendall, Brittany K., Barlow, Emma, Beard, David, Blanco-Colino, Ruth, Brar, Amanpreet, Minaya-Bravo, Ana, Breen, Kerry A., Bretherton, Chris, Buarque, Igor Lima, Burke, Joshua, Caruana, Edward J., Chaar, Mohammad, Chakrabortee, Sohini, Christensen, Peter, Cox, Daniel, Cukier, Moises, Cunha, Miguel F., Davidson, Giana H., Desai, Anant, Di Saverio, Salomone, Drake, Thomas M., Edwards, John G., Elhadi, Muhammed, Emile, Sameh, Farik, Shebani, Fiore, Marco, Fitzgerald, J Edward, Ford, Samuel, Garmanova, Tatiana, Gallo, Gaetano, Ghosh, Dhruva, Ataíde Gomes, Gustavo Mendonça, Grecinos, Gustavo, Griffiths, Ewen A., Gruendl, Magdalena, Halkias, Constantine, Harrison, Ewen M., Hisham, Intisar, Hutchinson, Peter J., Hwang, Shelley, Isik, Arda, Jenkinson, Michael D., Jonker, Pascal, MA Kaafarani, Haytham, Keller, Debby, Kolias, Angelos, Kruijff, Schelto, Lawani, Ismail, Lederhuber, Hans, Leventoglu, Sezai, Litvin, Andrey, Loehrer, Andrew, Löffler, Markus W., Lorena, Maria Aguilera, Modolo, Maria Marta, Major, Piotr, Martin, Janet, Mashbari, Hassan N., Mazingi, Dennis, Metallidis, Symeon, Mohan, Helen M., Moore, Rachel, Moszkowicz, David, Moug, Susan, Ng-Kamstra, Joshua S., Maimbo, Mayaba, Negoi, Ionut, Niquen, Milagros, Ntirenganya, Faustin, Olivos, Maricarmen, Oussama, Kacimi, Outani, Oumaima, Parreno-Sacdalanm, Marie Dione, Pata, Francesco, Perez Rivera, Carlos Jose, Pinkney, Thomas D., van der Plas, Willemijn, Pockney, Peter, Qureshi, Ahmad, Radenkovic, Dejan, Ramos-De la Medina, Antonio, Richards, Toby, Roberts, Keith, Roslani, April C., Rutegård, Martin, Segura-Sampedro, Juan José, Santos, Irène, Satoi, Sohei, Sayyed, Raza, Schache, Andrew, Schnitzbauer, Andreas A., Seyi-Olajide, Justina O., Sharma, Neil, Shaw, Catherine A., Shaw, Richard, Shu, Sebastian, Soreide, Kjetil, Spinelli, Antonino, Stewart, Grant D., Sund, Malin, Sundar, Sudha, Tabiri, Stephen, Townend, Philip, Tsoulfas, Georgios, van Ramshorst, Gabrielle H., Vidya, Raghavan, Vimalachandran, Dale, Warren, Oliver J., Wedderburn, Duane, Wright, Naomi, Booth, Lesley, Barker, Neil, Cooke, Shirley, Doré, Suzanne, Horwood, Nigel, Runigamugabo, Emmy, Weir, Carrie Tierney, Dajti I, Albania, C, Allemand, LA, Boccalatte, M, Figari, M, Lamm, J, Larrañaga, C, Marchitelli, F, Noll, D, Odetto, M, Perrotta, J, Saadi, L, Zamora, Ballester, A.M., KE, Tapper, N, Zeff, JI, Valenzuela, C, Alurralde, J, Anastasio, Perez de Nucci A, Apas, EL, Caram, D, Eskinazi, JP, Mendoza, M, Usandivaras, R, Badra, A, Esteban, JS, García, PM, García, JI, Gerchunoff, Lucchini, S.M., NIgra, M.A., L, Vargas, T, Hovhannisyan, A, Stepanyan, CE, Vasey, EGR, Watson, C, Ip, J, Kealey, CSH, Lim, S, Sengupta, S, Ward, E, Wong, T, Gould, R, Gourlay, B, Griffiths, S, Gananadha, M, McLaren, J, Cecire, N, Joshi, S, Salindera, A, Sutherland, JH, Ahn, G, Charlton, S, Chen, N, Gauri, R, Hayhurst, S, Jang, F, Jia, C, Mulligan, W, Yang, G, Ye, H, Zhang, M, Ballal, D, Gibson, D, Hayne, H, McMillan, J, Moss, MJ, Pugliese, T, Richards, YTN, Seow, A, Thian, P, Viswambaram, UG, Vo, J, Bennetts, T, Bright, Brooke-Smith, M., R, Fong, B, Gricks, L, Huang, YH, Lam, A, Nathan, Ong, B.S., E, Ooi, M, Szpytma, D, Watson, K, Bagraith, S, Caird, E, Chan, C, Dawson, D, Ho, N, Hui, S, Izwan, E, Jeyarajan, S, Jordan, R, Liang, A, Lim, GJ, Nolan, A, Oar, D, Parker, H, Puhalla, A, Quennell, L, Rutherford, C, Sommerville, P, Townend, Papen M, Von, M, Wullschleger, AC, Dawson, A, Drane, A, Blatt, D, Cope, N, Egoroff, M, Fenton, J, Gani, N, Lott, P, Pockney, N, Shugg, M, Elliott, D, Phung, D, Phan, D, Townend, C, Bong, J, Gundara, A, Frankel, S, Bowman, GR, Guerra, N, Gerns, S, McGeorge, A, Riddell, M, Roberts, N, Rukin, J, Bolt, K, Buddingh, Dudi-Venkata, N.N., S, Jog, HM, Kroon, T, Sammour, R, Smith, C, Stranz, M, Batstone, K, Lah, W, McGahan, D, Mitchell, A, Morton, A, Pearce, G, Sheahan, B, Swinson, A, Waldron, P, Walker, N, Alam, S, Banting, L, Chong, P, Choong, S, Clatworthy, D, Foley, A, Fox, MW, Hii, B, Knowles, J, Mack, M, Read, A, Rowcroft, G, Wright, EWY, Lun, M, Lanner, J, Burtscher, Trivik-Barrientos, F., I, Königsrainer, M, Bauer, C, Freyschlag, M, Kafka, F, Messner, D, Öfner, I, Tsibulak, S, Holawe, M, Zimmermann, K, Emmanuel, M, Grechenig, R, Gruber, M, Harald, L, Öhlberger, J, Presl, A, Wimmer, İ, Namazov, E, Samadov, D, Barker, R, Boyce, S, Corbin, A, Doyle, A, Eastmond, R, Gill, A, Haynes, S, Millar, M, O’Shea, G, Padmore, N, Paquette, E, Phillips, John S, St., K, Walkes, J, Abeloos, Backer T, De, Ceulaer J, De, C, Dick, Diez-Fraile, A., P, Lamoral, C, Spaas, W, Ceelen, P, Pattyn, D, Van de putte, Nieuwenhove Y, Van, Ramshorst G, Van, Willaert, W., Bazzett-Matabele, L., SP, Chiyapo, Ramogola-Masire, D., G, Ramontshonyana, A, Seiphetlheng, P, Vuylsteke, EA, Abdallah, Júnior S, Aguiar, G, Baiocchi, GB, Carvalho, FJF, Coimbra, LP, Kowalski, F, Makdissi, N, Marques, T, Marques, Santos S, Soares Dos, Gonçalves B, Tirapelli, JG, Vartanian, Reis R, Dos, P, Camara, Lima RK, De, Giustina E, Della, PV, Hoffmann, A, Gatti, C, Nardi, R, Oliva, L, Nacif, Ferro C, Carvalho, Ataíde G, Gomes Mendonça, Buarque I, Lima, A, Lira dos Santos Leite, Pol-Fachin, L., Bezerra T, Santos, Ramos da Silva A, Maylson, de Araújo Silvestre D, Windson, Barros A, Vieira, L, Campbell, Cicco R, De, I, Cecconello, P, Gregorio, Lima L, Pontual, Junior U, Ribeiro, FR, Takeda, RM, Terra, Teixeira M, Faccini, Kulcsar, M.A.V., LL, Matos, KS, Nunes, G, Laporte, M, Salem, Awada J, Barakat, TR, Ijichi, NJ, Kim, A, Marreiro, B, Muller, R, Nunes, B, Bodanese, ER, Eidt, JC, Isoton, Vieira da Cunha M, Lemos, de Sampaio L, Regina, C, Vendrame, M, Zeni, JA, Zortéa, MR, Zortéa, M, Sokolov, B, Kidane, S, Srinathan, A, Munro, L, Helyer, D, McKeen, M, Boutros, NG, Caminsky, G, Ghitulescu, G, Jamjoum, J, Moon, J, Pelletier, T, Vanounou, S, Wong, D, Cheng, SD, MacNeil, J, Martin, S, Dumitra, A, Kouyoumdjian, S, Schmid, J, Spicer, A, Agarwal, A, Brar, J, Dada, A, Dare, U, Hameed, F, Osman, B, Johnston, C, Russell, G, Groot, A, Persad, H, Pham, M, Wood, M, Ko, L, Rajendran, S, Demyttenaere, R, Garfinkle, C, Brown, A, Karimuddin, N, Lee, J, Liu, Kia T, Madani, Phang, P.T., M, Raval, K, Tom, Abou-Khalil, J., A, Martel, C, Nessim, J, Stevenson, Riyami S, Al, K, Bali, D, Bigam, K, Dajani, A, Dell, MM, Modolo, Nieto P, Ramirez, R, Sepulveda, A, Molero, A, Bolbaran, I, Ruiz, F, Heredia, F, Bellolio, N, Besser, E, Grasset, JO, Guaman, M, Inzunza, MJ, Irarrázaval, C, Jarry, Martinic M, Quintana, Altamirano C, Riquoir, Manqui CA, Romero, Esquide M, Ruiz, Añazco C, Vargas, A, Almeciga, A, Fletcher, A, Merchan, T, Quijano, D, Sanabria, Arias-Amézquita, F., C, Cétares, Murgueitio N, Cortes, Gomez-Mayorga, J.L., Herrera-Almario, G., J, Rodriguez, P, Iglesias, LO, Puentes, JA, Calvache, Orozco-Chamorro, C.M., DA, Rojas, Sánchez-Gómez, A., M, Abadia, J, Acosta, Aristizabal J, Angel, A, Bonilla, L, Caicedo, Quiroz PH, Calderon, Bonilla S, Cervera, S, Diaz, H, Facundo, Mora M, Garcia, O, Guevara, L, Guzman, Mora DR, Herrera, Ramirez LJ, Jimenez, C, Lehmann, E, Manrique, I, Mariño, M, Medina, Morales RE, Pinilla, A, Puerto, Horta J, Puerto, M, Quintero, Ferro M, Rey, A, Saénz, D, Santana, W, Serrano, O, Suescun, Sanchez LM, Trujillo, Cuasquen BG, Velasquez, Quevedo J , Bogota, Mendoza, G, Bačić, D, Karlović, D, Kršul, M, Zelić, I, Luksic, M, Mamic, I, Bacic, B, Bakmaz, I, Ćoza, E, Dijan, Z, Katusic, J, Mihanovic, D, Morović, I, Rakvin, H, Almezghwi, K, Arslan, H, Besim, A, Özant, N, Özçay, K, Frantzeskou, N, Gouvas, G, Kokkinos, P, Papatheodorou, I, Pozotou, O, Stavrinidou, A, Yiallourou, L, Martinek, M, Skrovina, M, Straka, I, Szubota, M, Peteja, J, Žatecký, V, Javurkova, J, Klat, S, Antony, T, Avlund, KD, Berg, M, Borre, P, Christensen, MC, Elkjær, A, Ernst, SK, Fensman, M, Haldrup, JL, Harbjerg, LH, Iversen, Jensen, P.T., TD, Jeppesen, DW, Kjaer, HØ, Kristensen, N, Lund, Axelsen S, Maigaard, M, Mekhael, N, Mikic, EB, Ostenfeld, AL, Ebbehøj, P, Krarup, N, Schlesinger, H, Smith, S, Batista, A, Crespo, PJ, Díaz, R, Rivas, Rodriguez-Abreu, J., N, Tactuk, Kassas M, El, W, Omar, A, Tawheed, M, Talaat, A, Abdelsamed, AY, Azzam, 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Emile, B, Refky, S, Abd-elsalam, H, Badr, M, Elbahnasawy, M, Elzoghby, M, Essa, Badr S, Gamal, A, Ghoneim, O, Hamad, M, Hamada, M, Hammad, A, Hawila, Morsy, M.S., S, Salman, S, Sarsik, K, Bekele, JH, Kauppila, E, Sarjanoja, O, Helminen, H, Huhta, C, Beyrne, L, Jouffret, L, Lugans, Marie-Macron, L., E, Chouillard, Simone B, De, F, Fredon, A, Roux, J, Bettoni, S, Dakpé, B, Devauchelle, N, Lavagen, S, Testelin, S, Boucher, R, Breheret, A, Gueutier, A, Kahn, Kün-Darbois, J., A, Barrabe, Z, Lakkis, A, Louvrier, S, Manfredelli, P, Mathieu, A, Chebaro, V, Drubay, M, El amrani, C, Eveno, K, Lecolle, G, Legault, L, Martin, G, Piessen, FR, Pruvot, S, Truant, P, Zerbib, Q, Ballouhey, B, Barrat, L, Fourcade, J, Laloze, H, Salle, A, Taibi, J, Tricard, J, Usseglio, D, Bergeat, A, Merdrignac, Roy B, Le, LO, Perotto, A, Scalabre, H, Gornes, C, Vaysse, K, Vergriete, A, Aimé, A, Ezanno, B, Malgras, AP, Arnaud, E, Fustec, V, Lavoue, C, Tesson, P, Bouche, S, Tzedakis, E, Cotte, O, Glehen, J, Lifante, L, Bendjemar, H, Braham, L, Charre, Arbi N, El, L, Morel-chevillet, A, Police, V, Villefranque, E, Volpin, A, D’Urso, E, Felli, D, Mutter, P, Pessaux, B, Seeliger, Y, Barbé, J, Bardet, E, Barret, R, Berry, G, Boddaert, S, Bonnet, E, Brian, N, Cathala, X, Cathelineau, C, Denet, D, Fuks, D, Gossot, M, Grigoroiu, A, Laforest, Levy-Zauberman, Y., Louis-Sylvestre, C., P, Macek, A, Mombet, A, Moumen, G, Pourcher, F, Rozet, Salas R, Sanchez, A, Seguin-givelet, E, Tribillon, V, Crenn, Vergie S, De, E, Duchalais, F, Espitalier, C, Ferron, H, Fragnaud, O, Malard, N, Regenet, J, Rigaud, Y, Varenne, D, Waast, U, Bork, M, Distler, J, Fritzmann, J, Kirchberg, C, Praetorius, C, Riediger, J, Weitz, T, Welsch, P, Wimberger, K, Beyer, C, Kamphues, J, Lauscher, FN, Loch, C, Schineis, M, Albertsmeier, M, Angele, A, Kappenberger, H, Niess, T, Schiergens, J, Werner, R, Becker, J, Jonescheit, J, Doerner, R, Seiberth, I, Pergolini, D, Reim, J, Herzberg, H, Honarpisheh, T, Strate, C, Boeker, I, Hakami, J, Mall, 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Nikolaou, A, Poddar, V, Pronisceva, V, Reddy, N, Williams, L, Alakandy, P, Bhattathiri, J, Brown, M, Canty, E, Day, A, Geddes, A, Grivas, S, Hassan, S, Lammy, P, Littlechild, C, Maseland, C, Mathieson, J, McCaul, J, McMahon, R, O’Kane, George E, St., N, Suttner, W, Taylor, E, Tilling, W, English, S, Kaul, AH, Khan, F, Khan, A, Mansuri, S, Mukherjee, M, Sarigul, KL, Tan, P, Vulliamy, A, Woodham, YH, Yang, A, Adiamah, H, Brewer, A, Chowdhury, D, Humes, J, Jackman, A, Koh, Lewis-Lloyd, C., A, Navarro, O, Oyende, J, Reilly, R, Vohra, D, Worku, P, Cool, G, Cribb, K, Shepherd, C, Bisset, S, Moug, R, Chadha, N, Elson, R, Galleano, G, Faulkner, A, Langone, Z, Panayi, P, Saleh, F, Tuminello, C, Underwood, G, Brixton, L, Findlay, T, Klatte, A, Majkowska, J, Manson, R, Potter, Al-Khyatt, W., A, Bhalla, Z, Chia, P, Daliya, A, Goyal, E, Grimley, A, Hamad, FL, Malcolm, JCK, Ng, A, Phillips, E, Theophilidou, S, Williams, J, Bowden, N, Campain, I, Daniels, G, Fowler, J, John, L, Massey, F, McDermott, J, McGrath, A, McLennan, M, Ng, J, Pascoe, N, Rajaretnam, N, Angamuthu, S, Bulathsinhala, S, Chowdhury, B, Davidson, G, Fusai, J, Gilliland, C, Hart, Salinas C, Hidalgo, J, Knowles, N, Machairas, R, Mirnezami, T, Pissanou, JM, Pollok, DA, Raptis, F, Soggiu, H, Tzerbinis, M, Varcada, S, Xyda, A, Beamish, E, Davies, R, Foulkes, D, Magowan, H, Nassa, R, Ooi, C, Price, L, Smith, F, Solari, A, Tang, G, Williams, Kahar NN, Abd, Al-Tamimi, Y., A, Bacon, N, Beasley, J, Catto, LH, Chan, D, Chew, M, Crank, N, Ilenkovan, M, Macdonald, B, Narice, O, Rominiyi, S, Saad, S, Sinha, A, Thompson, I, Varley, P, Brennan, T, Drake, EM, Harrison, G, Linder, J, Mayes, R, McGregor, R, Pasricha, RJE, Skipworth, V, Zamvar, P, Hawkin, T, Raymond, O, Ryska, R, Baron, D, Dunne, S, Gahunia, C, Halloran, N, Howes, R, McKinney, F, McNicol, K, Rajput, J, Russ, R, Sutton, P, Szatmary, JR, Tan, P, Whelan, A, Anzak, A, Banerjee, O, Fuwa, F, Hughes, Jayasinghe, J.D., C, Knowles, HM, Kocher, Silva I, Leal, FS, Ledesma, A, Minicozzi, L, Navaratne, P, Patki, R, Rahman, R, Ramamoorthy, C, Sohrabi, C, Tanabalan, M, Thaha, B, Thakur, M, Venn, V, Yip, R, Baumber, J, Parry, S, Evans, L, Jeys, G, Morris, M, Parry, N, Ahmadi, G, Aresu, Barrett-Brown, Z.M., A, Coonar, Yates H, Durio, D, Gearon, J, Hogan, M, King, A, Peryt, IS, Pradeep, M, Adishesh, R, Atherton, K, Baxter, M, Brocklehurst, M, Chaudhury, N, Krishnamohan, J, McAleer, G, Owens, E, Parkin, P, Patkar, I, Phang, A, Aladeojebi, M, Ali, B, Barmayehvar, A, Gaunt, M, Gowda, E, Halliday, M, Kitchen, F, Mansour, P, Nanjaiah, D, Zakai, Abbassi-Ghadi, N., H, Assalaarachchi, A, Currie, M, Flavin, A, Frampton, M, Hague, C, Hammer, J, Hopper, J, Horsnell, S, Humphries, A, Kamocka, TK, Madhuri, S, Preston, P, Singh, J, Stebbing, A, Tailor, D, Walker, E, Coomber, S, Jaunoo, L, Kennedy, A, Airey, J, Bunni, R, Crowley, K, Fairhurst, J, Frost, R, George, S, Lee, S, Mitchell, J, Phull, S, Richards, F, Aljanadi, A, Campbell, A, Glass, I, Hraishawi, M, Jones, C, McIlmunn, S, McIntosh, P, Mhandu, C, O’Donnell, R, Turkington, Al-Ishaq, Z., S, Bhasin, AS, Bodla, A, Burahee, A, Crichton, El-Ghobashy, A., R, Fossett, N, Pigadas, E, Rahman, D, Snee, R, Vidya, N, Yassin, D, Fountain, Hasan, M.T., K, Karabatsou, R, Laurente, O, Pathmanaban, C, Barlow, D, Ding, J, Foster, L, Longstaff, Brett-Miller, C., FE, Buruiana, A, Al-mukhtar, J, Edwards, A, Giblin, C, Kelty, M, Lee, G, Lye, T, Newman, A, Sharkey, C, Steele, Shah N, Sureshkumar, E, Whitehall, J, Blair, A, Lakhiani, Parry-Smith, W., B, Sahu, R, Athwal, A, Baker, L, Jones, C, Konstantinou, S, Ramcharan, J, Vatish, R, Wilkin, A, Alzetani, K, Amer, A, Badran, HV, Colvin, M, Ethunandan, GK, Sekhon, Z, Shakoor, H, Shields, R, Singh, T, Talbot, F, Wensley, S, Lawday, A, Lyons, S, Newman, E, Chung, R, Hagger, A, Hainsworth, I, Hunt, A, Karim, H, Owen, A, Ramwell, G, Santhirakumaran, J, Smelt, C, Tan, P, Vaughan, K, Williams, C, Baker, A, Davies, J, Gossage, M, Kelly, W, Knight, S, Bromage, J, Hall, V, Kaushik, M, Rudic, N, Vallabh, Y, Zhang, G, Harris, G, James, C, Kang, DJ, Lin, AD, Rajgor, T, Royle, R, Scurrah, B, Steel, LJ, Watson, D, Choi, R, Hutchison, V, Luoma, HJ, Marcus, R, May, A, Menon, B, Pramodana, L, Webber, A, Hayes, R, Jones, G, Sivarajah, M, Smith, A, Smrke, D, Strauss, FAM, Abouelela, IA, Aneke, P, Asaad, B, Brown, J, Collis, S, Duff, A, Khan, F, Moura, M, Taylor, B, Wadham, H, Warburton, T, Elmoslemany, Jenkinson, M.D., CP, Millward, R, Zakaria, S, Mccluney, C, Parmar, S, Shah, J, Allison, Babar, M.S., J, Bowen, B, Collard, S, Goodrum, K, Lau, M, Sargent, R, Scott, E, Thomas, H, Whitmore, D, Balasubramaniam, B, Jayasankar, S, Kapoor, A, Ramachandran, C, Semple, A, Elhamshary, SMB, Imam, K, Kapriniotis, V, Kasivisvanathan, J, Lindsay, Rakhshani-Moghadam, S., N, Beech, M, Chand, L, Green, N, Kalavrezos, H, Kiconco, R, McEwen, C, Schilling, D, Sinha, J, Pereca, S, Chopra, D, Egbeare, R, Thomas, S, Arumugam, B, Ibrahim, K, Khan, T, Combellack, G, Hill, S, Jones, M, Kornaszewska, M, Mohammed, G, Tahhan, V, Valtzoglou, N, Blencowe, P, Eskander, K, Gash, L, Gourbault, M, Hanna, TA, Maccabe, B, Main, J, Olivier, C, Newton, S, Roswadowski, N, Ryan, E, Teh, D, West, H, Al-omishy, M, Baig, H, Bates, Taranto G, Di, K, Dickson, N, Dunne, C, Gill, D, Howe, D, Jeevan, A, Khajuria, Martin-Ucar, A., K, McEvoy, P, Naredla, S, Robertson, M, Sait, DR, Sarma, S, Shanbhag, T, Shortland, S, Simmonds, J, Skillman, N, Tewari, G, Walton, Akhtar, M.A., A, Brunt, J, McIntyre, K, Milne, MM, Rashid, A, Sgrò, KE, Stewart, A, Turnbull, Abou-Foul, A.K., G, Gossedge, S, O’Donnell, F, Oldfield, S, Thomson, Gonzalez M, Aguilar, S, Talukder, C, Boyle, D, Fernando, K, Gallagher, A, Laird, D, Tham, M, Bath, P, Basnyat, H, Davis, P, Montauban, A, Shrestha, K, Agarwal, T, Arif, C, Magee, T, Nambirajan, S, Powell, R, Vinayagam, I, Flindall, A, Hanson, V, Mahendran, S, Green, M, Lim, L, MacDonald, V, Miu, L, Onos, K, Sheridan, R, Young, F, Alam, O, Griffiths, C, Houlden, VS, Kolli, AK, Lala, S, Leeson, R, Peevor, Z, Seymour, E, Consorti, R, Gonzalez, R, Grolman, Kwan-Feinberg, R., T, Liu, O, Merzlikin, Francisco, San, A, Brown, Z, Cooper, S, Hirji, J, Jolissaint, D, Mahvi, B, Okafor, CP, Raut, V, Roxo, A, Salim, S, Bessen, L, Chen, L, Dagrosa, K, Fay, C, Fleischer, R, Hasson, E, Henderson, M, Leech, A, Loehrer, C, Markey, J, Paydarfar, K, Rosenkranz, K, Telma, N, Tocci, Wilkinson-Ryan, I., M, Bokenkamp, K, Brown, D, Fleming, C, Heron, C, Hill, H, Kay, E, Leede, K, McElhinney, KA, Olson, EC, Osterberg, C, Riley, P, Srikanth, J, Barbour, D, Blazer, GA, DiLalla, O, Fayanju, ES, Hwang, R, Kahmke, H, Kazaure, A, Lazarides, W, Lee, M, Lidsky, C, Menendez, D, Moris, J, Plichta, MC, Pradhan, L, Puscas, HE, Rice, D, Rocke, L, Rosenberger, R, Scheri, Smith, B.D., Stang, M.T., L, Tolnitch, K, Turnage, J, Visgauss, FS, Walton, T, Watts, S, Zani, J, Farma, K, Cardona, MC, Russell, J, Clark, D, Kwon, N, Goel, J, Kronenfeld, B, Bigelow, E, Etchill, Gabre-Kidan, A., H, Jenny, A, Kent, MR, Ladd, C, Long, H, Malapati, A, Margalit, S, Rapaport, J, Rose, K, Stevens, L, Tsai, D, Vervoort, P, Yesantharao, A, Dehal, D, Klaristenfeld, K, Huynh, H, Kaafarani, L, Naar, M, Qadan, L, Brown, I, Ganly, JE, Mullinax, N, Alpert, C, Gillezeau, Miles DDS MD, F.A.C.S.B.A., E, Taioli, DE, Cha, E, Gleeson, C, Horn, U, Sarpel, N, Gusani, J, Hazelton, J, Maines, JS, Oh, A, Ssentongo, P, Ssentongo, A, Bhama, K, Colling, M, Najarian, M, Azam, A, Choudhry, W, Marx, Y, Abedin, G, Arzumanov, R, Chokshi, S, Gabrilovich, N, Glass, E, Kalyoussef, Parvin-Nejad, F.P., D, Roden, J, Stein, Suarez-Ligon, A., G, Tsui, K, Zhao, J, Fleming, A, Fuson, J, Gigliotti, A, Ovaitt, Y, Ying, MK, Abel, V, Andaya, K, Bigay, Boeck, M.A., H, Chern, C, Corvera, El-Sayed, I., A, Glencer, P, Ha, Hamilton, B.C.S., C, Heaton, K, Hirose, Jablons, D.M., KS, Kirkwood, LZ, Kornblith, JR, Kratz, RH, Lee, PN, Miller, EK, Nakakura, Nunez-Garcia, B., RJ, O’Donnell, D, Ozgediz, P, Park, B, Robinson, A, Sarin, B, Sheu, MG, Varma, KC, Wai, R, Wustrack, MJ, Xu, M, Zimel, D, CA) Beswick, J, Goddard, J, Manor, J, Song, Springs/Loveland, Denver/Colorado, A, Cioci, W, Pavlis, K, Rakoczy, G, Ruiz, R, Saberi, T, Fullmer, C, Gaskill, N, Gross, K, Kiong, CL, Roland, SN, Zafar, M, Abdallah, A, Abouassi, E, Aigbivbalu, M, Almasri, J, Eid, B, George, G, Kulkarni, H, Marwan, M, Mehdi, Andrés M, San, J, Sundaresan, SG, Aoun, VS, Ban, HH, Batjer, K, Bosler, J, Caruso, B, Sumer, D, Abbott, A, Acher, T, Aiken, J, Barrett, E, Foley, PB, Schwartz, AT, Hawkins, A, Maiga, NM, Ruzgar, M, Sion, S, Ullrich, J, Laufer, S, Scasso, Al-Naggar, H., Al-Shehari, M., A, Almassaudi, M, Alsayadi, R, Alsayadi, M, Nahshal, S, Shream, S, AL-Ameri, M, Aldawbali, Fotopoulou, Christina, Khan, Tabassum, Bracinik, Juraj, Glasbey, James, Abu-Rustum, Nadeem, Chiva, Luis, Fagotti, Anna, Fujiwara, Keiichi, Ghebre, Rahel, Gutelkin, Murat, Konney, Thomas O., Ng, Joseph, Pareja, Rene, Kottayasamy Seenivasagam, Rajkumar, Sehouli, Jalid, Surappa, Shylasree T.S., and Leung, Elaine
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- 2022
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31. ORACLE reveals a bright future to fight bacteria
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Willow Coyote-Maestas and James S Fraser
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bacteriophage ,phage ,virus engineering ,deep mutational scanning ,synthetic biology ,tail fiber ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
A new way to alter the genome of bacteriophages helps produce large libraries of variants, allowing these bacteria-killing viruses to be designed to target species harmful to human health.
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- 2021
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32. Evaluating the performance of a general diagnostic decision support system on case data from urgent cardiology admissions.
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Hamish S. Fraser
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- 2019
33. Change in treatment burden among people with multimorbidity: Protocol of a follow up survey and development of efficient measurement tools for primary care.
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Hilda O Hounkpatin, Paul Roderick, James E Morris, Scott Harris, Forbes Watson, Hajira Dambha-Miller, Helen Roberts, Bronagh Walsh, Dianna Smith, Simon D S Fraser, and ARC Wessex Treatment Burden Group
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Medicine ,Science - Abstract
BackgroundTreatment burden is the effort required of patients to look after their health and the impact this has on their functioning and wellbeing. It is likely treatment burden changes over time as circumstances change for patients and health services. However, there are a lack of population-level studies of treatment burden change and factors associated with this change over time. Furthermore, there are currently no practical screening tools for treatment burden in time-pressured clinical settings or at population level.Methods and analysisThis is a three-year follow-up of a cross-sectional survey of 723 people with multimorbidity (defined as three or more long-term conditions; LTCs) registered at GP practices in in Dorset, England. The survey will repeat collection of information on treatment burden (using the 10-item Multimorbidity Treatment Burden Questionnaire (MTBQ) and a novel single-item screening tool), sociodemographics, medications, LTCs, health literacy and financial resource, as at baseline. Descriptive statistics will be used to compare change in treatment burden since the baseline survey in 2019 and associations of treatment burden change will be assessed using regression methods. Diagnostic test accuracy metrics will be used to evaluate the single-item treatment burden screening tool using the MTBQ as the gold-standard. Routine primary care data (including demographics, medications, LTCs, and healthcare usage data) will be extracted from medical records for consenting participants. A forward-stepwise, likelihood-ratio logistic regression model building approach will be employed in order to assess the utility of routine data metrics in quantifying treatment burden in comparison to self-reported treatment burden using the MTBQ.ImpactTo the authors' knowledge, this will be the first study investigating longitudinal aspects of treatment burden. Findings will improve understanding of the extent to which treatment burden changes over time for people with multimorbidity and factors contributing to this change, as well as allowing better identification of people at risk of high treatment burden.
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- 2021
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34. Molecular-dynamics simulation methods for macromolecular crystallography
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David C. Wych, Phillip C. Aoto, Lily Vu, Alexander M. Wolff, David L. Mobley, James S. Fraser, Susan S. Taylor, and Michael E. Wall
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protein kinases ,Crystallography ,Protein Conformation ,1.1 Normal biological development and functioning ,conformational ensembles ,Biophysics ,Proteins ,Molecular Dynamics Simulation ,Biological Sciences ,1.4 Methodologies and measurements ,molecular-dynamics simulations ,water structure ,Underpinning research ,Structural Biology ,Physical Sciences ,Chemical Sciences ,Solvents ,X-Ray ,Generic health relevance - Abstract
To assess the potential benefits of molecular-dynamics (MD) simulations for macromolecular crystallography (MX), we performed room-temperature X-ray diffraction studies of the catalytic subunit of mouse protein kinase A (PKA-C). We then performed crystalline MD simulations of PKA-C, computed simulated electron densities from the water, protein, and ion components of the MD simulations, and carefully compared them to the initial crystal structure. The results led to the development of an MD-MX analysis procedure and several associated methods: 1) density comparison to evaluate consistency between the MD and the initial crystal structure model; 2) water building to generate alternative solvent models; and 3) protein remodeling to improve the crystal structure where interpretation of density is unclear. This procedure produced a revised structure of PKA with a new ordered water model and a modified protein structure. The revisions yield new insights into PKA mechanisms, including: a sensitivity of the His294 conformation to protonation state, with potential consequences for regulation of substrate binding; a remodeling of the Lys217 side chain along with a bound phosphate; an alternative conformation for Lys213 associated with binding to the regulatory subunit; and an alternative conformation for catalytic base Asp166 and nearby waters, suggesting a mechanism of progression of the phosphotransfer reaction via changes in Mg2+ coordination. Based on the benefits seen applying these methods to PKA, we recommend incorporating our MD-MX procedure into MX studies, to decide among ambiguous interpretations of electron density that occur, inevitably, as part of standard model refinement.
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- 2023
35. Long-Term Effects of Fertilizer Application and Irrigation on Soils Under Pasture Land Use
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A. Eger, B. A. Stevenson, B. Theng, P. Rhodes, S. Fraser, V. Penny, and O. R. Burge
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Soil Science ,Plant Science ,Agronomy and Crop Science - Published
- 2022
36. Environmental Policy Convergence in Canada’s Fossil Fuel Provinces? Regulatory Streamlining, Impediments, and Drift
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V. Carter, Angela, S. Fraser, Gail, and Zalik, Anna
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- 2017
37. Dual RNA-Seq characterization of host and pathogen gene expression in liver cells infected with Crimean-Congo Hemorrhagic Fever Virus.
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Robert A Kozak, Russell S Fraser, Mia J Biondi, Anna Majer, Sarah J Medina, Bryan D Griffin, Darwyn Kobasa, Patrick J Stapleton, Chantel Urfano, Giorgi Babuadze, Kym Antonation, Lisa Fernando, Stephanie Booth, Brandon N Lillie, and Gary P Kobinger
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Arctic medicine. Tropical medicine ,RC955-962 ,Public aspects of medicine ,RA1-1270 - Abstract
Crimean-Congo hemorrhagic fever virus (CCHFV) is a tick-borne virus that can cause a hemorrhagic fever in humans, with a case fatality rate of up to 40%. Cases of CCHFV have been reported in Africa, Asia, and southern Europe; and recently, due to the expanding range of its vector, autochthonous cases have been reported in Spain. Although it was discovered over 70 years ago, our understanding of the pathogenesis of this virus remains limited. We used RNA-Seq in two human liver cell lines (HepG2 and Huh7) infected with CCHFV (strain IbAr10200), to examine kinetic changes in host expression and viral replication simultaneously at 1 and 3 days post infection. Through this, numerous host pathways were identified that were modulated by the virus including: antiviral response and endothelial cell leakage. Notably, the genes encoding DDX60, a cytosolic component of the RIG-I signalling pathway and OAS2 were both shown to be dysregulated. Interestingly, PTPRR was induced in Huh7 cells but not HepG2 cells. This has been associated with the TLR9 signalling cascade, and polymorphisms in TLR9 have been associated with poor outcomes in patients. Additionally, we performed whole-genome sequencing on CCHFV to assess viral diversity over time, and its relationship to the host response. As a result, we have demonstrated that through next-generation mRNA deep-sequencing it is possible to not only examine mRNA gene expression, but also to examine viral quasispecies and typing of the infecting strain. This demonstrates a proof-of-principle that CCHFV specimens can be analyzed to identify both the virus and host biomarkers that may have implications for prognosis.
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- 2020
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38. Rescue of conformational dynamics in enzyme catalysis by directed evolution
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Renee Otten, Lin Liu, Lillian R. Kenner, Michael W. Clarkson, David Mavor, Dan S. Tawfik, Dorothee Kern, and James S. Fraser
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Science - Abstract
A key challenge in the field of protein design and evolution is to understand the mechanisms by which directed evolution is improving enzymes. Here the authors combine different biophysical methods and give mechanistic insights into how directed evolution increases the catalytic efficiency of human peptidyl-prolyl cis/trans isomerase CypA.
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- 2018
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39. Incidence, Risk Factors, and Outcomes of Rhegmatogenous Retinal Detachment after Intravitreal Injections of Anti-VEGF for Retinal Diseases
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Pierre-Henry Gabrielle, Vuong Nguyen, Louis Arnould, Francesco Viola, Javier Zarranz-Ventura, Daniel Barthelmes, Catherine Creuzot-Garcher, Mark Gillies, D. Squirrell, J. Gilhotra, C. Brooijmans, O. Tigchelaar-Besling, A. Cohn, F. Chen, A. McGeorge, S. Welch, N. Jaross, P. Peters, R. Barry, I. McLean, T. Guillaumie, A. Miri, J. Korobelnik, P. Gabrielle, M. Weber, B. Walid, S. Tick, S. Valen, A. Field, S. Wickremasinghe, C. Dayajeewa, J. Wells, R. Essex, A. Dunlop, K. Michalova, C. Ng, S. Young, G. MIMOUN, C. Generic, R. Guymer, P. Carnota, C. Torres Borrego, R. Dolz Marco, R. Gallego-Pinazo, J. Pareja Esteban, A. García Layana, M. Saenz-de-Viteri, J. Uzzan, R. Ferrier, J. Ah-Chan, L. Chow, H. Steiner, A. Amini, G. Clark, N. Wittles, P. Windle, J. Vingerling, C. Clement, M. Gillies, A. Hunt, P. Beaumont, L. Cottee, K. Lee, H. Mack, Z. Louw, J. Lusthaus, J. Chen, J. Landers, K. Billing, N. Saha, S. Lake, D. Qatarneh, R. Phillips, M. Perks, K. Banon, M. Guarro, G. Londoño, C. Rethati, L. Sararols, J. Suarez, F. Viola, S. Lan Oei, S. Fraser-Bell, R. Montejano Milner, C. Arruabarrena, E. Chong, S. Lal, A. Higueras, F. Ascaso, A. Boned Murillo, M. Díaz, G. Perez Rivases, S. Alforja Castiella, C. Bernal-Morales, R. Casaroli-Marano, M. Figueras-Roca, J. Izquierdo-Serra, A. Moll Udina, A. Parrado-Carrillo, J. Zarranz-Ventura, j. escobar, F. Lavid, M. Alvarez Gil, P. Catalán Muñoz, M. Tena Sempere, L. Cerri, F. RICCI, L. Broc Iturralde, P. Campos Figueroa, S. Gómez Sánchez, X. Valldeperas, F. Vilaplana, E. Carreño, N. Munoz Sanz, N. Ventura Abreu, M. Asencio Duran, P. Calvo, J. Sanchez, E. Almazan Alonso, I. Flores-Moreno, M. Garcia Zamora, E. Ciancas, J. Gonzalez-Lopez, M. de la Fuente, M. Rodriguez Maqueda, E. Cobos, D. Lorenzo, L. Cordoves, m. Acebes, S. Aparicio-Sanchis, A. Fernández Hortelano, J. Zarallo-Gallardo, C. Azrak, A. Piñero Sánchez, P. Almuina-Varela, L. García García, E. Salinas Martínez, M. Castilla Marti, A. Campo Gesto, M. Rodriguez Núñez, G. Furness, T. Ponsioen, G. Wilson, L. Manning, I. McAllister, Tim Isaacs, A. Invernizzi, L. Castelnovo, G. Michel, B. Wolff, J. Arnold, H. Cass, D. Chan, T. Tan, L. OToole, K. Tang, C. Chung, H. Beylerian, V. DAIEN, G. Banerjee, M. Morgan, I. Reddie, J. Ongkosuwito, F. Verbraak, R. Schlingemann, s. piermarocchi, A. Thompson, J. Game, C. Thompson, R. Chalasani, M. Chilov, A. Fung, S. Nothling, R. Chong, A. Hunyor, C. Younan, R. Barnes, D. Sharp, A. Vincent, N. Murray, S. Ah-Moye, C. Hennings, H. Mehta, P. Monaco, G. Cheung, N. Karia, D. Louis, S. Every, P. Lockie, M. van Hecke, J. van Lith-Verhoeven, J. Wong, J. Grigg, P. Hinchcliffe, D. Barthelmes, E. Diaz De Durana Santa Coloma, G. Garay-Aramburu, S. Vujosevic, H. Brosa Morros, M. Daniell, A. Harper, L. Lim, J. ODay, D. Velazquez Villoria, C. Hooper, N. Klaassen-Broekema, and R. Smit
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Ophthalmology - Published
- 2022
40. Of problems and opportunities—How to treat and how to not treat crystallographic fragment screening data
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Manfred S. Weiss, Jan Wollenhaupt, Galen J. Correy, James S. Fraser, Andreas Heine, Gerhard Klebe, Tobias Krojer, Marjolein Thunissen, Nicholas M. Pearce, Organic Chemistry, and AIMMS
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Crystallography ,fragment-screening ,Biophysics ,Proteins ,Computation Theory and Mathematics ,conformational heterogeneity ,PanDDA ,group depositions ,Crystallography, X-Ray ,Ligands ,Biochemistry ,compositional heterogeneity ,X-Ray ,Biochemistry and Cell Biology ,compositional heterogeneity, conformational heterogeneity, fragment screening, groupdepositions, low occupancy ligands, PanDDA ,Other Information and Computing Sciences ,Molecular Biology ,low-occupancy ligands - Abstract
In their recent commentary in Protein Science, Jaskolski et al. analyzed three randomly picked diffraction data sets from fragment-screening group depositions from the PDB and, based on that, they claimed that such data are principally problematic. We demonstrate here that if such data are treated properly, none of the proclaimed criticisms persist.
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- 2022
41. Investigations into the chemical and cellular mechanisms of drug hypersensitivity
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Gordon, S. Fraser
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615 ,Drug reactions - Published
- 2002
42. Separability of targets in urban areas using features from full-waveform LiDARA data.
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Mohsen Azadbakht, Clive S. Fraser, and Chunsun Zhang
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- 2015
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43. Parkinson’s medications do not affect movement smoothness in fine motor control: Limitations of medication and importance of measurement
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Lydia J. Hickman, Dagmar S. Fraser, and Jennifer L. Cook
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- 2023
44. Using a linked database for epidemiology across the primary and secondary care divide: acute kidney injury
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M. Johnson, H. Hounkpatin, S. Fraser, D. Culliford, M. Uniacke, and P. Roderick
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Acute kidney injury ,Epidemiology ,NHS AKI algorithm ,Linked data ,Computer applications to medicine. Medical informatics ,R858-859.7 - Abstract
Abstract Background NHS England has mandated the use in hospital laboratories of an automated early warning algorithm to create a consistent method for the detection of acute kidney injury (AKI). It generates an ‘alert’ based on changes in serum creatinine level to notify attending clinicians of a possible incident case of the condition, and to provide an assessment of its severity. We aimed to explore the feasibility of secondary data analysis to reproduce the algorithm outside of the hospital laboratory, and to describe the epidemiology of AKI across primary and secondary care within a region. Methods Using the Hampshire Health Record Analytical database, a patient-anonymised database linking primary care, secondary care and hospital laboratory data, we applied the algorithm to one year (1st January-31st December 2014) of retrospective longitudinal data. We developed database queries to modularise the collection of data from various sectors of the local health system, recreate the functions of the algorithm and undertake data cleaning. Results Of a regional population of 642,337 patients, 176,113 (27.4%) had two or more serum creatinine test results available, with testing more common amongst older age groups. We identified 5361 (or 0.8%) with incident AKI indicated by the algorithm, generating a total of 13,845 individual AKI alerts. A cross-sectional assessment of each patient’s first alert found that more than two-thirds of cases originated in the community, of which nearly half did not lead to a hospital admission. Conclusion It is possible to reproduce the algorithm using linked primary care, secondary care and hospital laboratory data, although data completeness, data quality and technical issues must be overcome. Linked data is essential to follow the significant proportion of people with AKI who transition from primary to secondary care, and can be used to assess clinical outcomes and the impact of interventions across the health system. This study emphasises that the development of data systems bridging across different sectors of the health and social care system can provide benefits for researchers, clinicians, healthcare providers and commissioners.
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- 2017
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45. Hydrogen–Deuterium Exchange of Lipoxygenase Uncovers a Relationship between Distal, Solvent Exposed Protein Motions and the Thermal Activation Barrier for Catalytic Proton-Coupled Electron Tunneling
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Adam R. Offenbacher, Shenshen Hu, Erin M. Poss, Cody A. M. Carr, Alexander D. Scouras, Daniil M. Prigozhin, Anthony T. Iavarone, Ali Palla, Tom Alber, James S. Fraser, and Judith P. Klinman
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Chemistry ,QD1-999 - Published
- 2017
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46. Potentially effective therapy of heavy menstrual bleeding with an oestradiol-nomegestrol acetate oral contraceptive: a pilot study
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Edith Weisberg, Kevin McGeehan, Jane Hangan, and Ian S Fraser
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Survey ,Menstruation ,Heavy menstrual bleeding (HMB) ,Menstrual pain ,Quality of life (QoL) ,Medicine (General) ,R5-920 - Abstract
Abstract Background Heavy menstrual bleeding (HMB) exceeding 80 mL per cycle leads to considerable adverse impact on a woman’s iron metabolism, incidence of iron deficiency and anaemia, as well as her functioning in society. The objective of the study is to determine the potential efficacy of a Monophasic oestradiol-17β-nomegestrol acetate (E2/Nomac) combined oral contraceptive pill on measured menstrual blood loss as a pilot study in 12 women with objectively demonstrated HMB (>80 mL per cycle). The pilot study aimed to recruit 20 women. Method Consented women completed the HMB questionnaire. The blood was taken for haemoglobin, transferrin, iron saturation, TIBC, serum iron and ferritin. Women were given verbal and written detailed instructions for MBL collection for three control cycles and four treatment cycles. Results Forty-three women were enrolled, but 31 were ineligible and withdrawn (mainly for failure to meet eligibility criteria). Twelve women entered the treatment phase and commenced the E2/nomegestrol acetate (NOMAC) 24/4 combined pill treatment on the first day of their fourth cycle. All women with complete MBL measurements had >50% reduction in MBL on treatment (exact 95% confidence interval for proportion with MBL reduction >50%: 69 to 100%). The mean percent reduction in MBL between pretreatment and during treatment was 76.9%, and the median was 79% with a range of 53.7 to 100%. Conclusions This pilot study indicates that the E2/NOMAC COC will provide a useful potential option for treating HMB in women with FIGO classification AUB-E (primary endometrial causes) but requires a larger placebo-controlled study for confirmation.
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- 2017
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47. The strength of reproductive isolating barriers in seed plants: Insights from studies quantifying premating and postmating reproductive barriers over the past 15 years
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Kyle Christie, Linnea S. Fraser, and David B. Lowry
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Gene Flow ,Reproductive Isolation ,Genetic Speciation ,Reproduction ,Seeds ,Genetics ,Plants ,General Agricultural and Biological Sciences ,Ecology, Evolution, Behavior and Systematics - Abstract
Speciation is driven by the evolution of reproductive isolating barriers that reduce, and ultimately prevent, substantial gene flow between lineages. Despite its central role in evolutionary biology, the process can be difficult to study because it proceeds differently among groups and may occur over long timescales. Due to this complexity, we typically rely on generalizations of empirical data to describe and understand the process. Previous reviews of reproductive isolation (RI) in flowering plants have suggested that prezygotic or extrinsic barriers generally have a stronger effect on reducing gene flow compared to postzygotic or intrinsic barriers. Past conclusions have rested on relatively few empirical estimates of RI; however, RI data have become increasingly abundant over the past 15 years. We analyzed data from recent studies quantifying multiple pre- and postmating barriers in plants and compared the strengths of isolating barriers across 89 taxa pairs using standardized RI metrics. Individual prezygotic barriers were on average stronger than individual postzygotic barriers, and the total strength of prezygotic RI was approximately twice that of postzygotic RI. These findings corroborate that ecological divergence and extrinsic factors, as opposed to solely the accumulation of genetic incompatibilities, are important to speciation and the maintenance of species boundaries in plants. Despite an emphasis in the literature on asymmetric postmating and postzygotic RI, we found that prezygotic barriers acted equally asymmetrically. Overall, substantial variability in the strengths of 12 isolating barriers highlights the great diversity of mechanisms that contribute to plant diversification.
- Published
- 2022
48. Disaster recovery funding: Enhanced understanding for improved outcomes
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Ryan S. Fraser, MS, Tim Frazier, PhD, Tim Manning, MS, and Erik Wood, MS
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Emergency Medicine ,General Medicine ,Safety, Risk, Reliability and Quality ,Safety Research - Abstract
The complexities of post-disaster recovery funding present significant challenges to state and local communities, particularly with the increase in frequency and intensity of disasters triggered by climate change. This paper explores the disaster recovery funding process for which there is limited existing research. A concurrent triangulation method was utilized as the strategy of inquiry. This mixed methods approach consisted of a content review of the related literature, an analysis of the New Jersey (NJ) Transit damage from Hurricane Sandy, a case study examining NJ Transit’s unmet recovery need, and semistructured interviews with related officials. Findings suggest that improved interagency communication is required to better understand funding limitations and develop formal procedures for recovery. Despite progress, extensive gaps in disaster recovery funding remain. The analysis resulted in three key post-disaster recovery coordination findings: (1) there remains a lack of compatibility among the different federal grant programs; (2) there is an identified need for a single point of coordination to enhance the communication process; (3) a solution to recovery funding should include insurance and the private sector. Enhanced coordination mechanisms will result in improved outcomes for jurisdictions recovering from the overwhelming and cascading effects of disasters. These findings have both national and international implications.
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- 2022
49. eIF5B and eIF1A reorient initiator tRNA to allow ribosomal subunit joining
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Christopher P. Lapointe, Rosslyn Grosely, Masaaki Sokabe, Carlos Alvarado, Jinfan Wang, Elizabeth Montabana, Nancy Villa, Byung-Sik Shin, Thomas E. Dever, Christopher S. Fraser, Israel S. Fernández, and Joseph D. Puglisi
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RNA, Transfer, Met ,Multidisciplinary ,General Science & Technology ,1.1 Normal biological development and functioning ,Cryoelectron Microscopy ,Eukaryotic Initiation Factor-1 ,Article ,Single Molecule Imaging ,Transfer ,Underpinning research ,Met ,Ribosome Subunits ,Genetics ,Humans ,RNA ,Generic health relevance ,Eukaryotic Initiation Factors - Abstract
Translation initiation defines the identity and quantity of a synthesized protein. The process is dysregulated in many human diseases1,2. A key commitment step is when the ribosomal subunits join at a translation start site on a messenger RNA to form a functional ribosome. Here, we combined single-molecule spectroscopy and structural methods using an in vitro reconstituted system to examine how the human ribosomal subunits join. Single-molecule fluorescence revealed when theuniversally conserved eukaryotic initiation factors eIF1A and eIF5B associate with and depart from initiation complexes. Guided by single-molecule dynamics, we visualized initiation complexes that contained both eIF1A and eIF5B using single-particle cryo-electron microscopy. The resulting structure revealed how eukaryote-specific contacts between the two proteins remodel the initiation complex to orient the initiator aminoacyl-tRNA in a conformation compatible with ribosomal subunit joining. Collectively, our findings provide a quantitative and architectural framework for the molecular choreography orchestrated by eIF1A and eIF5B during translation initiation in humans.
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- 2022
50. Liquid-like and rigid-body motions in molecular-dynamics simulations of a crystalline protein
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David C. Wych, James S. Fraser, David L. Mobley, and Michael E. Wall
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Crystallography ,QD901-999 - Abstract
To gain insight into crystalline protein dynamics, we performed molecular-dynamics (MD) simulations of a periodic 2 × 2 × 2 supercell of staphylococcal nuclease. We used the resulting MD trajectories to simulate X-ray diffraction and to study collective motions. The agreement of simulated X-ray diffraction with the data is comparable to previous MD simulation studies. We studied collective motions by analyzing statistically the covariance of alpha-carbon position displacements. The covariance decreases exponentially with the distance between atoms, which is consistent with a liquidlike motions (LLM) model, in which the protein behaves like a soft material. To gain finer insight into the collective motions, we examined the covariance behavior within a protein molecule (intraprotein) and between different protein molecules (interprotein). The interprotein atom pairs, which dominate the overall statistics, exhibit LLM behavior; however, the intraprotein pairs exhibit behavior that is consistent with a superposition of LLM and rigid-body motions (RBM). Our results indicate that LLM behavior of global dynamics is present in MD simulations of a protein crystal. They also show that RBM behavior is detectable in the simulations but that it is subsumed by the LLM behavior. Finally, the results provide clues about how correlated motions of atom pairs both within and across proteins might manifest in diffraction data. Overall, our findings increase our understanding of the connection between molecular motions and diffraction data and therefore advance efforts to extract information about functionally important motions from crystallography experiments.
- Published
- 2019
- Full Text
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