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result(s) for
"Chandler, Rob"
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Snowbound mystery
A family, snowbound in a vacation cabin, discovers adventure in surrounding wild life, three children they find in the snow, and a search for a lost recipe.
Book
Genomics of lethal prostate cancer at diagnosis and castration resistance
The genomics of primary prostate cancer differ from those of metastatic castration-resistant prostate cancer (mCRPC). We studied genomic aberrations in primary prostate cancer biopsies from patients who developed mCRPC, also studying matching, same-patient, diagnostic, and mCRPC biopsies following treatment. We profiled 470 treatment-naive prostate cancer diagnostic biopsies and, for 61 cases, mCRPC biopsies, using targeted and low-pass whole-genome sequencing (n = 52). Descriptive statistics were used to summarize mutation and copy number profile. Prevalence was compared using Fisher's exact test. Survival correlations were studied using log-rank test. TP53 (27%) and PTEN (12%) and DDR gene defects (BRCA2 7%; CDK12 5%; ATM 4%) were commonly detected. TP53, BRCA2, and CDK12 mutations were markedly more common than described in the TCGA cohort. Patients with RB1 loss in the primary tumor had a worse prognosis. Among 61 men with matched hormone-naive and mCRPC biopsies, differences were identified in AR, TP53, RB1, and PI3K/AKT mutational status between same-patient samples. In conclusion, the genomics of diagnostic prostatic biopsies acquired from men who develop mCRPC differ from those of the nonlethal primary prostatic cancers. RB1/TP53/AR aberrations are enriched in later stages, but the prevalence of DDR defects in diagnostic samples is similar to mCRPC.
Journal Article
Life: Letters: Going down in flames
* \"Avcen, a London-based aviation company, is developing the Jetpod, a five-seater flying taxi, that, presumably, will be programmed so as to be unable to fly 'south of the river' late at night.\" The Jetpod will have unrestricted direct access into the centre of London in a straight line. You only had to enquire to get your facts right.
Newspaper Article
Structure-based protein function prediction using graph convolutional networks
The rapid increase in the number of proteins in sequence databases and the diversity of their functions challenge computational approaches for automated function prediction. Here, we introduce DeepFRI, a Graph Convolutional Network for predicting protein functions by leveraging sequence features extracted from a protein language model and protein structures. It outperforms current leading methods and sequence-based Convolutional Neural Networks and scales to the size of current sequence repositories. Augmenting the training set of experimental structures with homology models allows us to significantly expand the number of predictable functions. DeepFRI has significant de-noising capability, with only a minor drop in performance when experimental structures are replaced by protein models. Class activation mapping allows function predictions at an unprecedented resolution, allowing site-specific annotations at the residue-level in an automated manner. We show the utility and high performance of our method by annotating structures from the PDB and SWISS-MODEL, making several new confident function predictions. DeepFRI is available as a webserver at
https://beta.deepfri.flatironinstitute.org/
.
The rapid increase in the number of proteins in sequence databases and the diversity of their functions challenge computational approaches for automated function prediction. Here, the authors introduce DeepFRI, a Graph Convolutional Network for predicting protein functions by leveraging sequence features extracted from a protein language model and protein structures.
Journal Article
Sequence-structure-function relationships in the microbial protein universe
For the past half-century, structural biologists relied on the notion that similar protein sequences give rise to similar structures and functions. While this assumption has driven research to explore certain parts of the protein universe, it disregards spaces that don’t rely on this assumption. Here we explore areas of the protein universe where similar protein functions can be achieved by different sequences and different structures. We predict ~200,000 structures for diverse protein sequences from 1,003 representative genomes across the microbial tree of life and annotate them functionally on a per-residue basis. Structure prediction is accomplished using the World Community Grid, a large-scale citizen science initiative. The resulting database of structural models is complementary to the AlphaFold database, with regards to domains of life as well as sequence diversity and sequence length. We identify 148 novel folds and describe examples where we map specific functions to structural motifs. We also show that the structural space is continuous and largely saturated, highlighting the need for a shift in focus across all branches of biology, from obtaining structures to putting them into context and from sequence-based to sequence-structure-function based meta-omics analyses.
Advances in protein structure prediction have led to a significant influx of protein structure data. Here the authors exploit this data to offer an unbiased overview of complex sequence-structure-function relationships in the protein universe. This work opens up new uses for 3D structure data repositories in meta-omics and other fields of biology.
Journal Article
Further interceptions of the Neotropical fungus gnat Sciophila fractinervis Edwards, 1940 (Diptera, Mycetophilidae) in Britain with comments and observations on its biology and spread
From 2020 onwards, several specimens of the Neotropical fungus gnat
Sciophila fractinervis
(Edwards, 1940) have been intercepted by Fera Science Ltd. on or near plant material in the United Kingdom originating from nurseries and glasshouses at four separate locations: Preston, Lancashire; Chichester, West Sussex; East Riding of Yorkshire; and Middlesbrough, North Yorkshire, as well as a single interception from the Netherlands. Gnat interceptions were associated with a wide range of plant species:
Ficus benjamina
,
Ficus elastica
, Dracaena reflexa var. angustifolia,
Origanum vulgare
,
Rosmarinus officinalis
,
Thymus vulgaris
,
Impatiens hawkeri
(
Impatiens
New Guinea hybrids),
Chrysanthemum
, as well as
Fragaria vesca
(var.
Lusa
). The species does not appear to be doing any damage to affected plants with growing conditions likely promoting multiplication under protection. The larvae likely feed on spores (generally saprophytic) adhering to webs they erect on the soil and around the base of plants with spores likely originating from the growing medium and plants. Their spread is likely facilitated by movement of the growing medium or plant material where pupae are suspended in the lower stem or leaf axils.
An account of the various interceptions is provided, as well as images of the different life-stages with a brief discussion of
Sciophila cincticornis
Edwards, 1940, its relationship with
Sciophila fractinervis
and further evidence of instability in vein R
2+3
in the
Sciophila
genus.
Journal Article
Establishing the effectiveness of technology-enabled dementia education for health and social care practitioners: a systematic review
Background
Dementia prevalence is increasing globally and yet evidence suggest that gaps exist in dementia-specific knowledge among health and social care practitioners. Technological modes of educational delivery may be as effective as traditional education and can provide practitioners with increased accessibility to dementia training. Benefits of digitally based dementia education have been established including pedagogical strategies that influence dementia knowledge and care attitudes. This review aimed to appraise and synthesise contemporary experimental evidence that evaluated technology-enabled dementia education for health and social care practitioners. Outcomes based on Kirkpatrick’s Model were learner satisfaction; knowledge, skills, and attitudes; behaviours; and results.
Methods
MEDLINE, CINAHL, and Web of Science were among 8 bibliographic databases searched from January 2005 until February 2020. Keywords included dementia and education (and terms for technological modes of education, learning, or training). We included experimental and quasi-experimental studies. Medical Education Research Study Quality Instrument established the overall quality of included studies and pragmatic application of Mixed Methods Appraisal Tool established individual study quality and highlighted methodological features of educational research. Narrative synthesis was conducted as heterogeneous outcome data precluded meta-analysis.
Results
We identified 21 relevant studies: 16 evaluated online dementia education and 5 evaluated computer-based approaches. Most studies used before-after designs and study quality was moderate overall. Most studies reported knowledge-based outcomes with statistically significant findings favouring the training interventions. Positive effects were also observed in studies measuring skills and attitudinal change. Fewer studies reported significant findings for behavioural change and results due to training. Case-based instruction was a frequently described instructional strategy in online dementia education and videos were common information delivery modes. CD-ROM training and simulation activities were described in computer-based dementia education.
Discussion
Future emphasis must be placed on teaching and learning methods within technology-enabled dementia education which should be role relevant and incorporate active and interactive learning strategies. Future evaluations will require contextually relevant research methodologies with capacity to address challenges presented by these complex educational programmes and multi-component characteristics.
Systematic review registration
This systematic review is based on a protocol registered with PROSPERO (
CRD42018115378
).
Journal Article
Environmental Impact on Vascular Development Predicted by High-Throughput Screening
Background: Understanding health risks to embryonic development from exposure to environmental chemicals is a significant challenge given the diverse chemical landscape and paucity of data for most of these compounds. High-throughput screening (HTS) in the U.S. Environmental Protection Agency (EPA) ToxCast™ project provides vast data on an expanding chemical library currently consisting of >1,000 unique compounds across >500 in vitro assays in phase I (complete) and Phase II (under way). This public data set can be used to evaluate concentration-dependent effects on many diverse biological targets and build predictive models of prototypical toxicity pathways that can aid decision making for assessments of human developmental health and disease. Objective: We mined the ToxCast phase I data set to identify signatures for potential chemical disruption of blood vessel formation and remodeling. Methods: ToxCast phase I screened 309 chemicals using 467 HTS assays across nine assay technology platforms. The assays measured direct interactions between chemicals and molecular targets (receptors, enzymes), as well as downstream effects on reporter gene activity or cellular consequences. We ranked the chemicals according to individual vascular bioactivity score and visualized the ranking using ToxPi (Toxicological Priority Index) profiles. Results: Targets in inflammatory chemokine signaling, the vascular endothelial growth factor pathway, and the plasminogen-activating system were strongly perturbed by some chemicals, and we found positive correlations with developmental effects from the U. S. EPA ToxRefDB (Toxicological Reference Database) in vivo database containing prenatal rat and rabbit guideline studies. We observed distinctly different correlative patterns for chemicals with effects in rabbits versus rats, despite derivation oí in vitro signatures based on human cells and cell-free biochemical targets, implying conservation but potentially differential contributions of developmental pathways among species. Follow-up analysis with antiangiogenic thalidomide analogs and additional in vitro vascular targets showed in vitro activity consistent with the most active environmental chemicals tested here. Conclusions: We predicted that blood vessel development is a target for environmental chemicals acting as putative vascular disruptor compounds (pVDCs) and identified potential species differences in sensitive vascular developmental pathways.
Journal Article
Methods for Authenticating Participants in Fully Web-Based Mobile App Trials from the iReach Project: Cross-sectional Study
Mobile health apps are important interventions that increase the scale and reach of prevention services, including HIV testing and prevention counseling, pre-exposure prophylaxis, condom distribution, and education, of which all are required to decrease HIV incidence rates. The use of these web-based apps as well as fully web-based intervention trials can be challenged by the need to remove fraudulent or duplicate entries and authenticate unique trial participants before randomization to protect the integrity of the sample and trial results. It is critical to ensure that the data collected through this modality are valid and reliable.
The aim of this study is to discuss the electronic and manual authentication strategies for the iReach randomized controlled trial that were used to monitor and prevent fraudulent enrollment.
iReach is a randomized controlled trial that focused on same-sex attracted, cisgender males (people assigned male at birth who identify as men) aged 13-18 years in the United States and on enrolling people of color and those in rural communities. The data were evaluated by identifying possible duplications in enrollment, identifying potentially fraudulent or ineligible participants through inconsistencies in the data collected at screening and survey data, and reviewing baseline completion times to avoid enrolling bots and those who did not complete the baseline questionnaire. Electronic systems flagged questionable enrollment. Additional manual reviews included the verification of age, IP addresses, email addresses, social media accounts, and completion times for surveys.
The electronic and manual strategies, including the integration of social media profiles, resulted in the identification and prevention of 624 cases of potential fraudulent, duplicative, or ineligible enrollment. A total of 79% (493/624) of the potentially fraudulent or ineligible cases were identified through electronic strategies, thereby reducing the burden of manual authentication for most cases. A case study with a scenario, resolution, and authentication strategy response was included.
As web-based trials are becoming more common, methods for handling suspicious enrollments that compromise data quality have become increasingly important for inclusion in protocols.
RR2-10.2196/10174.
Journal Article