Publications by authors named "Steven Henderson"

23 Publications

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Representative cancer-associated U2AF2 mutations alter RNA interactions and splicing.

J Biol Chem 2020 12 5;295(50):17148-17157. Epub 2020 Oct 5.

Center for RNA Biology, Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA. Electronic address:

High-throughput sequencing of hematologic malignancies and other cancers has revealed recurrent mis-sense mutations of genes encoding pre-mRNA splicing factors. The essential splicing factor U2AF2 recognizes a polypyrimidine-tract splice-site signal and initiates spliceosome assembly. Here, we investigate representative, acquired mutations, namely N196K or G301D amino acid substitutions associated with leukemia or solid tumors, respectively. We determined crystal structures of the wild-type (WT) compared with N196K- or G301D-substituted U2AF2 proteins, each bound to a prototypical polypyrimidine tract, at 1.5, 1.4, or 1.7 Å resolutions. The N196K residue appears to stabilize the open conformation of U2AF2 with an inter-RNA recognition motif hydrogen bond, in agreement with an increased apparent RNA-binding affinity of the N196K-substituted protein. The G301D residue remains in a similar position as the WT residue, where unfavorable proximity to the RNA phosphodiester could explain the decreased RNA-binding affinity of the G301D-substituted protein. We found that expression of the G301D-substituted U2AF2 protein reduces splicing of a minigene transcript carrying prototypical splice sites. We further show that expression of either N196K- or G301D-substituted U2AF2 can subtly alter splicing of representative endogenous transcripts, despite the presence of endogenous, WT U2AF2 such as would be present in cancer cells. Altogether, our results demonstrate that acquired mutations such as N196K and G301D are capable of dysregulating gene expression for neoplastic transformation.
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http://dx.doi.org/10.1074/jbc.RA120.015339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863893PMC
December 2020

Efficient CRISPR/Cas9-Mediated Knockout of an Endogenous Gene in T1 Progeny of Apomictic Enables New Strategies for Apomixis Gene Identification.

Genes (Basel) 2020 09 10;11(9). Epub 2020 Sep 10.

Commonwealth Scientific and Industrial Research Organisation (CSIRO) Agriculture and Food, Glen Osmond, SA 5064, Australia.

Most subgenus species are self-incompatible. Some undergo facultative apomixis where most seeds form asexually with a maternal genotype. Most embryo sacs develop by mitosis, without meiosis and seeds form without fertilization. Apomixis is controlled by dominant loci where recombination is suppressed. Loci deletion by γ-irradiation results in reversion to sexual reproduction. Targeted mutagenesis of genes at identified loci would facilitate causal gene identification. In this study, the efficacy of CRISPR/Cas9 editing was examined in apomictic by targeting mutations in the endogenous () gene using -mediated leaf disk transformation. In three experiments, the expected albino dwarf-lethal phenotype, characteristic of knockout, was evident in 11% of T0 plants, 31.4% were sectorial albino chimeras, and the remainder were green. The chimeric plants flowered. Germinated T1 seeds derived from apomictic reproduction in two chimeric plants were phenotyped and sequenced to identify gene edits. Up to 86% of seeds produced albino seedlings with complete knockout. This was attributed to continuing Cas9-mediated editing in chimeric plants during apomictic seed formation preventing segregation from the target. This successful demonstration of efficient CRISPR/Cas9 gene editing in apomictic , enabled development of the discussed strategies for future identification of causal apomixis genes.
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http://dx.doi.org/10.3390/genes11091064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563859PMC
September 2020

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Authors:
Derek C Angus Lennie Derde Farah Al-Beidh Djillali Annane Yaseen Arabi Abigail Beane Wilma van Bentum-Puijk Lindsay Berry Zahra Bhimani Marc Bonten Charlotte Bradbury Frank Brunkhorst Meredith Buxton Adrian Buzgau Allen C Cheng Menno de Jong Michelle Detry Lise Estcourt Mark Fitzgerald Herman Goossens Cameron Green Rashan Haniffa Alisa M Higgins Christopher Horvat Sebastiaan J Hullegie Peter Kruger Francois Lamontagne Patrick R Lawler Kelsey Linstrum Edward Litton Elizabeth Lorenzi John Marshall Daniel McAuley Anna McGlothin Shay McGuinness Bryan McVerry Stephanie Montgomery Paul Mouncey Srinivas Murthy Alistair Nichol Rachael Parke Jane Parker Kathryn Rowan Ashish Sanil Marlene Santos Christina Saunders Christopher Seymour Anne Turner Frank van de Veerdonk Balasubramanian Venkatesh Ryan Zarychanski Scott Berry Roger J Lewis Colin McArthur Steven A Webb Anthony C Gordon Farah Al-Beidh Derek Angus Djillali Annane Yaseen Arabi Wilma van Bentum-Puijk Scott Berry Abigail Beane Zahra Bhimani Marc Bonten Charlotte Bradbury Frank Brunkhorst Meredith Buxton Allen Cheng Menno De Jong Lennie Derde Lise Estcourt Herman Goossens Anthony Gordon Cameron Green Rashan Haniffa Francois Lamontagne Patrick Lawler Edward Litton John Marshall Colin McArthur Daniel McAuley Shay McGuinness Bryan McVerry Stephanie Montgomery Paul Mouncey Srinivas Murthy Alistair Nichol Rachael Parke Kathryn Rowan Christopher Seymour Anne Turner Frank van de Veerdonk Steve Webb Ryan Zarychanski Lewis Campbell Andrew Forbes David Gattas Stephane Heritier Lisa Higgins Peter Kruger Sandra Peake Jeffrey Presneill Ian Seppelt Tony Trapani Paul Young Sean Bagshaw Nick Daneman Niall Ferguson Cheryl Misak Marlene Santos Sebastiaan Hullegie Mathias Pletz Gernot Rohde Kathy Rowan Brian Alexander Kim Basile Timothy Girard Christopher Horvat David Huang Kelsey Linstrum Jennifer Vates Richard Beasley Robert Fowler Steve McGloughlin Susan Morpeth David Paterson Bala Venkatesh Tim Uyeki Kenneth Baillie Eamon Duffy Rob Fowler Thomas Hills Katrina Orr Asad Patanwala Steve Tong Mihai Netea Shilesh Bihari Marc Carrier Dean Fergusson Ewan Goligher Ghady Haidar Beverley Hunt Anand Kumar Mike Laffan Patrick Lawless Sylvain Lother Peter McCallum Saskia Middeldopr Zoe McQuilten Matthew Neal John Pasi Roger Schutgens Simon Stanworth Alexis Turgeon Alexandra Weissman Neill Adhikari Matthew Anstey Emily Brant Angelique de Man Francois Lamonagne Marie-Helene Masse Andrew Udy Donald Arnold Phillipe Begin Richard Charlewood Michael Chasse Mark Coyne Jamie Cooper James Daly Iain Gosbell Heli Harvala-Simmonds Tom Hills Sheila MacLennan David Menon John McDyer Nicole Pridee David Roberts Manu Shankar-Hari Helen Thomas Alan Tinmouth Darrell Triulzi Tim Walsh Erica Wood Carolyn Calfee Cecilia O’Kane Murali Shyamsundar Pratik Sinha Taylor Thompson Ian Young Shailesh Bihari Carol Hodgson John Laffey Danny McAuley Neil Orford Ary Neto Michelle Detry Mark Fitzgerald Roger Lewis Anna McGlothlin Ashish Sanil Christina 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JAMA 2020 10;324(13):1317-1329

Division of Anaesthetics, Pain Medicine and Intensive Care Medicine, Department of Surgery and Cancer, Imperial College London and Imperial College Healthcare NHS Trust, London, United Kingdom.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited.

Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19.

Design, Setting, And Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.

Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).

Main Outcomes And Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).

Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.

Conclusions And Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.

Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.
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http://dx.doi.org/10.1001/jama.2020.17022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489418PMC
October 2020

SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species.

Cell 2019 04;177(3):622-638.e22

Department of Biology, University of Rochester, Rochester, NY 14627, USA. Electronic address:

DNA repair has been hypothesized to be a longevity determinant, but the evidence for it is based largely on accelerated aging phenotypes of DNA repair mutants. Here, using a panel of 18 rodent species with diverse lifespans, we show that more robust DNA double-strand break (DSB) repair, but not nucleotide excision repair (NER), coevolves with longevity. Evolution of NER, unlike DSB, is shaped primarily by sunlight exposure. We further show that the capacity of the SIRT6 protein to promote DSB repair accounts for a major part of the variation in DSB repair efficacy between short- and long-lived species. We dissected the molecular differences between a weak (mouse) and a strong (beaver) SIRT6 protein and identified five amino acid residues that are fully responsible for their differential activities. Our findings demonstrate that DSB repair and SIRT6 have been optimized during the evolution of longevity, which provides new targets for anti-aging interventions.
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http://dx.doi.org/10.1016/j.cell.2019.03.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499390PMC
April 2019

Assembled genomic and tissue-specific transcriptomic data resources for two genetically distinct lines of Cowpea ( (L.) Walp).

Gates Open Res 2018 18;2. Epub 2018 Jun 18.

CSIRO Agriculture and Food, Urrbrae, SA, 5064, Australia.

Cowpea ( (L.) Walp) is an important legume crop for food security in areas of low-input and smallholder farming throughout Africa and Asia. Genetic improvements are required to increase yield and resilience to biotic and abiotic stress and to enhance cowpea crop performance. An integrated cowpea genomic and gene expression data resource has the potential to greatly accelerate breeding and the delivery of novel genetic traits for cowpea. Extensive genomic resources for cowpea have been absent from the public domain; however, a recent early release reference genome for IT97K-499-35 (  v1.0, NSF, UCR, USAID, DOE-JGI, http://phytozome.jgi.doe.gov/) has now been established in a collaboration between the Joint Genome Institute (JGI) and University California (UC) Riverside. Here we release supporting genomic and transcriptomic data for two transformable cowpea varieties, IT97K-499-35 and IT86D-1010. The transcriptome resource includes six tissue-specific datasets for each variety, with particular emphasis on reproductive tissues that extend and support the v1.0 reference. Annotations have been included in our resource to allow direct mapping to the v1.0 cowpea reference. The resource described here is supported by downloadable raw and assembled sequence data.
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http://dx.doi.org/10.12688/gatesopenres.12777.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841572PMC
June 2018

The Stopit! programme to reduce bullying and undermining behaviour in hospitals.

J Health Organ Manag 2018 May 10;32(3):428-443. Epub 2018 Apr 10.

School of Sport, Health and Social Science, Southampton Solent University , Southampton, UK.

Purpose The impact of bullying and undermining behaviours on the National Health Service on costs, patient safety and retention of staff was well understood even before the Illing report, published in 2013, that reviewed the efficacy of training interventions designed to reduce bullying and harassment in the outputs. The purpose of this paper is to provide an example of a good programme well evaluated. Design/methodology/approach The methodology follows a broad realist approach, by specifying the underlying programme assumptions and intention of the designers. Three months after the event, Q-sort methodology was employed to group participants into one of three contexts - mechanism - output groups. Interviews were then undertaken with members of two of these groups, to evaluate how the programme had influenced each. Findings Q-sort identified a typology of three beneficiaries from the Stopit! workshops, characterised as professionals, colleagues and victims. Each group had acted upon different parts of the programme, depending chiefly upon their current and past experiences of bullying in hospitals. Research limitations/implications The paper demonstrates the effectiveness of using Q-sort method to identify relevant CMOs in a realist evaluation framework. Practical implications The paper considers the effectiveness of the programme to reduce bullying, rather than teach victims to cope, and how it may be strengthened based upon the research findings and Illing recommendations. Social implications Workplace bullying is invariably implicated in scandals concerning poor hospital practice, poor patient outcomes and staff illness. All too frequently, the sector responds by offering training in resilience, which though helpful, places the onus on the victim to cope rather than the employer to reduce or eliminate the practice. This paper documents and evaluates an attempt to change workplace practices to directly address bullying and undermining. Originality/value The paper describes a new programme broadly consistent with Illing report endorsements. Second, it illustrates a novel evaluation method that highlights rigorously the contexts, mechanisms and outcomes at the pilot stage of an intervention identifies contexts and mechanisms via factor analysis using Q-sort methodology.
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http://dx.doi.org/10.1108/JHOM-02-2018-0047DOI Listing
May 2018

Genetic analyses of the inheritance and expressivity of autonomous endosperm formation in Hieracium with different modes of embryo sac and seed formation.

Ann Bot 2017 04;119(6):1001-1010

Background And Aims: Apomixis, or asexual seed formation, in polyploid Hieracium subgenus Pilosella species results in clonal progeny with a maternal genotype. An aposporous embryo sac forms mitotically from a somatic cell, without prior meiosis, while embryo and endosperm formation is fertilization independent (autonomous). The latter two developmental components are tightly linked in Hieracium . Recently, two plants, AutE196 and AutE24, were identified from two different crosses. Both form embryo sacs via the sexual route by undergoing meiosis, and embryo development requires fertilization; however, 18 % of embryo sacs can undergo autonomous endosperm (AutE) formation. This study investigated the qualitative and quantitative inheritance of the AutE trait and factors influencing phenotype expressivity. An additional focus was to identify the linkage group bearing the AutE locus in AutE196.

Methods: Crosses and cytology were used to examine the inheritance of AutE from AutE24 and AutE196, and to reintroduce apomictic components into AutE plants, thereby changing the ploidy of developing embryo sacs and increasing the dosage of AutE loci. Markers from a Hieracium apomict linkage map were examined within a backcrossed AutE196 mapping population to identify the linkage group containing the AutE196 locus.

Key Results: Qualitative autonomous endosperm in the AutE24 line was conferred by a single dominant locus, and the trait was transmitted through male and female gametes in AutE196 and AutE24. Expressivity of the trait did not significantly increase when AutE loci from AutE196 and AutE24 were both present in the progeny, within embryo sacs formed via apospory, or sexually derived embryo sacs with increased ploidy. It remains unclear if these are identical loci.

Conclusions: The qualitative trait of autonomous endosperm formation is conferred by single dominant loci in AutE196 and AutE24. High expressivity of autonomous endosperm formation observed in apomicts requires additional genetic factors. Potential candidates may be signals arising from fertilization-independent embryo formation.
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http://dx.doi.org/10.1093/aob/mcw262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5604576PMC
April 2017

Generation of an integrated Hieracium genomic and transcriptomic resource enables exploration of small RNA pathways during apomixis initiation.

BMC Biol 2016 10 6;14(1):86. Epub 2016 Oct 6.

Commonwealth Scientific and Industrial Research Organisation Agriculture and Food, Private Bag 2, Glen Osmond, South Australia, 5064, Australia.

Background: Application of apomixis, or asexual seed formation, in crop breeding would allow rapid fixation of complex traits, economizing improved crop delivery. Identification of apomixis genes is confounded by the polyploid nature, high genome complexity and lack of genomic sequence integration with reproductive tissue transcriptomes in most apomicts.

Results: A genomic and transcriptomic resource was developed for Hieracium subgenus Pilosella (Asteraceae) which incorporates characterized sexual, apomictic and mutant apomict plants exhibiting reversion to sexual reproduction. Apomicts develop additional female gametogenic cells that suppress the sexual pathway in ovules. Disrupting small RNA pathways in sexual Arabidopsis also induces extra female gametogenic cells; therefore, the resource was used to examine if changes in small RNA pathways correlate with apomixis initiation. An initial characterization of small RNA pathway genes within Hieracium was undertaken, and ovary-expressed ARGONAUTE genes were identified and cloned. Comparisons of whole ovary transcriptomes from mutant apomicts, relative to the parental apomict, revealed that differentially expressed genes were enriched for processes involved in small RNA biogenesis and chromatin silencing. Small RNA profiles within mutant ovaries did not reveal large-scale alterations in composition or length distributions; however, a small number of differentially expressed, putative small RNA targets were identified.

Conclusions: The established Hieracium resource represents a substantial contribution towards the investigation of early sexual and apomictic female gamete development, and the generation of new candidate genes and markers. Observed changes in small RNA targets and biogenesis pathways within sexual and apomictic ovaries will underlie future functional research into apomixis initiation in Hieracium.
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http://dx.doi.org/10.1186/s12915-016-0311-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054587PMC
October 2016

Specialty courts: Who's in and are they working?

Psychol Serv 2016 08;13(3):246-253

Lubbock & Crosby County Community Supervision and Corrections Department.

The effectiveness of specialty courts has been well established in the literature; however, previous studies have not taken into account referral biases that may exist based on offenders' race, socioeconomic status (SES), attorney status, and so forth. The current study hypothesized that (a) Participants who are racially diverse, of lower SES, and represented by privately retained attorneys would be referred less frequently to specialty courts, and (b) Participants in specialty courts would evidence reductions in missed court appointments and failed urinary analyses (UAs) compared with peers not enrolled in specialty courts. Participants (N = 274) were probationers who were involved in 1 of 3 specialty court programs (i.e., drug, driving while intoxicated [DWI], or reentry courts) or a matched sample of probationers not in specialty court services. Results indicated that, in general and with few exceptions, specialty courts did not have differential referral rates based on offender demographics including race, ethnicity, SES, or attorney status (court appointed vs. privately retained). Results examining the effectiveness of the specialty courts were mixed. Participants in the in-prison treatment program reentry court missed a greater proportion of scheduled court meetings than did their matched sample counterparts; however, the other specialty court programs did not significantly differ from their matched-sample counterparts. Participants in the DWI court had a significantly smaller proportion of UA failures to total UAs than did their matched sample peers; however, the drug court and reentry court programs did not significantly differ from their matched sample counterparts. Implications, future directions, and limitations are discussed. (PsycINFO Database Record
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http://dx.doi.org/10.1037/ser0000085DOI Listing
August 2016

Consultants as victims of bullying and undermining: a survey of Royal College of Obstetricians and Gynaecologists consultant experiences.

BMJ Open 2016 06 20;6(6):e011462. Epub 2016 Jun 20.

Royal College of Obstetricians and Gynaecologists, London, UK.

Objective: To explore incidents of bullying and undermining among obstetrics and gynaecology (O&G) consultants in the UK, to add another dimension to previous research and assist in providing a more holistic understanding of the problem in medicine.

Design: Questionnaire survey.

Setting: Royal College of Obstetricians and Gynaecologists (RCOG).

Participants: O&G consultant members/fellows of the RCOG working in the UK.

Main Outcome Measures: Measures included a typology of 4 bullying and undermining consequences from major to coping.

Results: There was a 28% (664) response rate of whom 44% (229) responded that they had been persistently bullied or undermined. Victims responded that bullying and undermining is carried out by those senior or at least close in the hierarchy. Of the 278 consultants who answered the question on 'frequency of occurrence', 50% stated that bullying and undermining occurs on half, or more, of all encounters with perpetrators and two-thirds reported that it had lasted more than 3 years. The reported impact on professional and personal life spans a wide spectrum from suicidal ideation, depression and sleep disturbance, and a loss of confidence. Over half reported problems that could compromise patient care. When victims were asked if the problem was being addressed, 73% of those that responded stated that it was not.

Conclusions: Significant numbers of consultants in O&G in the UK are victims of bullying and undermining behaviour that puts their own health and patient care at risk. New interventions to tackle the problem, rather than its consequences, are required urgently, together with greater commitment to supporting such interventions.
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http://dx.doi.org/10.1136/bmjopen-2016-011462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916587PMC
June 2016

An extended U2AF(65)-RNA-binding domain recognizes the 3' splice site signal.

Nat Commun 2016 Mar 8;7:10950. Epub 2016 Mar 8.

Center for RNA Biology and Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.

How the essential pre-mRNA splicing factor U2AF(65) recognizes the polypyrimidine (Py) signals of the major class of 3' splice sites in human gene transcripts remains incompletely understood. We determined four structures of an extended U2AF(65)-RNA-binding domain bound to Py-tract oligonucleotides at resolutions between 2.0 and 1.5 Å. These structures together with RNA binding and splicing assays reveal unforeseen roles for U2AF(65) inter-domain residues in recognizing a contiguous, nine-nucleotide Py tract. The U2AF(65) linker residues between the dual RNA recognition motifs (RRMs) recognize the central nucleotide, whereas the N- and C-terminal RRM extensions recognize the 3' terminus and third nucleotide. Single-molecule FRET experiments suggest that conformational selection and induced fit of the U2AF(65) RRMs are complementary mechanisms for Py-tract association. Altogether, these results advance the mechanistic understanding of molecular recognition for a major class of splice site signals.
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http://dx.doi.org/10.1038/ncomms10950DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786784PMC
March 2016

A brief peripheral motion contrast threshold test predicts older drivers' hazardous behaviors in simulated driving.

Accid Anal Prev 2015 May 23;78:1-7. Epub 2015 Feb 23.

Systems Technology Incorporated, Hawthorne, CA, USA.

Our research group has previously demonstrated that the peripheral motion contrast threshold (PMCT) test predicts older drivers' self-report accident risk, as well as simulated driving performance. However, the PMCT is too lengthy to be a part of a battery of tests to assess fitness to drive. Therefore, we have developed a new version of this test, which takes under two minutes to administer. We assessed the motion contrast thresholds of 24 younger drivers (19-32) and 25 older drivers (65-83) with both the PMCT-10min and the PMCT-2min test and investigated if thresholds were associated with measures of simulated driving performance. Younger participants had significantly lower motion contrast thresholds than older participants and there were no significant correlations between younger participants' thresholds and any measures of driving performance. The PMCT-10min and the PMCT-2min thresholds of older drivers' predicted simulated crash risk, as well as the minimum distance of approach to all hazards. This suggests that our tests of motion processing can help predict the risk of collision or near collision in older drivers. Thresholds were also correlated with the total lane deviation time, suggesting a deficiency in processing of peripheral flow and delayed detection of adjacent cars. The PMCT-2min is an improved version of a previously validated test, and it has the potential to help assess older drivers' fitness to drive.
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http://dx.doi.org/10.1016/j.aap.2015.01.020DOI Listing
May 2015

A reference genetic linkage map of apomictic Hieracium species based on expressed markers derived from developing ovule transcripts.

Ann Bot 2015 Mar 22;115(4):567-80. Epub 2014 Dec 22.

Kazusa DNA Research Institute, 2-6-7 Kazusa-Kamatari, Kisarazu, Chiba 292-0818, Japan and Commonwealth Scientific and Industrial Research Organization (CSIRO), Agriculture Flagship, Waite Campus, Hartley Grove, Urrbrae, South Australia 5064, Australia

Background And Aims: Apomixis in plants generates clonal progeny with a maternal genotype through asexual seed formation. Hieracium subgenus Pilosella (Asteraceae) contains polyploid, highly heterozygous apomictic and sexual species. Within apomictic Hieracium, dominant genetic loci independently regulate the qualitative developmental components of apomixis. In H. praealtum, LOSS OF APOMEIOSIS (LOA) enables formation of embryo sacs without meiosis and LOSS OF PARTHENOGENESIS (LOP) enables fertilization-independent seed formation. A locus required for fertilization-independent endosperm formation (AutE) has been identified in H. piloselloides. Additional quantitative loci appear to influence the penetrance of the qualitative loci, although the controlling genes remain unknown. This study aimed to develop the first genetic linkage maps for sexual and apomictic Hieracium species using simple sequence repeat (SSR) markers derived from expressed transcripts within the developing ovaries.

Methods: RNA from microdissected Hieracium ovule cell types and ovaries was sequenced and SSRs were identified. Two different F1 mapping populations were created to overcome difficulties associated with genome complexity and asexual reproduction. SSR markers were analysed within each mapping population to generate draft linkage maps for apomictic and sexual Hieracium species.

Key Results: A collection of 14 684 Hieracium expressed SSR markers were developed and linkage maps were constructed for Hieracium species using a subset of the SSR markers. Both the LOA and LOP loci were successfully assigned to linkage groups; however, AutE could not be mapped using the current populations. Comparisons with lettuce (Lactuca sativa) revealed partial macrosynteny between the two Asteraceae species.

Conclusions: A collection of SSR markers and draft linkage maps were developed for two apomictic and one sexual Hieracium species. These maps will support cloning of controlling genes at LOA and LOP loci in Hieracium and should also assist with identification of quantitative loci that affect the expressivity of apomixis. Future work will focus on mapping AutE using alternative populations.
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http://dx.doi.org/10.1093/aob/mcu249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343286PMC
March 2015

A young patient with visual disturbance. Multiple sclerosis.

Authors:
Steven Henderson

Eur J Intern Med 2014 Jul 29;25(6):e69-70. Epub 2014 May 29.

Institute of Neurological Sciences, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TF, UK. Electronic address:

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http://dx.doi.org/10.1016/j.ejim.2014.05.007DOI Listing
July 2014

The LOSS OF APOMEIOSIS (LOA) locus in Hieracium praealtum can function independently of the associated large-scale repetitive chromosomal structure.

New Phytol 2014 Feb 1;201(3):973-81. Epub 2013 Nov 1.

Laboratory of Plant Molecular Genetics, Division of Natural Science, Osaka Kyoiku University, Kashiwara, Osaka, 582-8582, Japan.

Apomixis or asexual seed formation in Hieracium praealtum (Asteraceae) is controlled by two independent dominant loci. One of these, the LOSS OF APOMEIOSIS (LOA) locus, controls apomixis initiation, mitotic embryo sac formation (apospory) and suppression of the sexual pathway. The LOA locus is found near the end of a hemizygous chromosome surrounded by extensive repeats extending along the chromosome arm. Similar apomixis-carrying chromosome structures have been found in some apomictic grasses, suggesting that the extensive repetitive sequences may be functionally relevant to apomixis. Fluorescence in situ hybridization (FISH) was used to examine chromosomes of apomeiosis deletion mutants and rare recombinants in the critical LOA region arising from a cross between sexual Hieracium pilosella and apomictic H. praealtum. The combined analyses of aposporous and nonaposporous recombinant progeny and chromosomal karyotypes were used to determine that the functional LOA locus can be genetically separated from the very extensive repeat regions found on the LOA-carrying chromosome. The large-scale repetitive sequences associated with the LOA locus in H. praealtum are not essential for apospory or suppression of sexual megasporogenesis (female meiosis).
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http://dx.doi.org/10.1111/nph.12574DOI Listing
February 2014

Genetic separation of autonomous endosperm formation (AutE) from the two other components of apomixis in Hieracium.

Plant Reprod 2013 Jun 8;26(2):113-23. Epub 2013 Mar 8.

Commonwealth Scientific and Industrial Research Organization (CSIRO) Plant Industry, Waite Campus, P.O. Box 350, Glen Osmond, SA, 5064, Australia.

In apomictic Hieracium subgenus Pilosella species, embryo sacs develop in ovules without meiosis. Embryo and endosperm formation then occur without fertilization, producing seeds with a maternal genotype encased in a fruit (achene). Genetic analyses in H. praealtum indicate a dominant locus (LOA) controls meiotic avoidance, and another dominant locus (LOP) controls both fertilization-independent embryogenesis and endosperm formation. While cytologically examining developmental events in ovules of progeny from crosses between different wild-type and mutant Hieracium apomicts, and a sexual Hieracium species, we identified two plants, AutE196 and AutE24, which have lost the capacity for meiotic avoidance and fertilization-independent embryo formation. AutE196 and AutE24 exhibit autonomous endosperm formation and set parthenocarpic, seedless achenes at a penetrance of 18 %. Viable seed form after pollination. Cytological examination of 102 progeny from a backcross of AutE196 with sexual H. pilosella showed that autonomous endosperm formation is a heritable, dominant, qualitative trait, detected in 51 % of progeny. Variation in quantitative trait penetrance indicates other factors influence its expression. The correlation between autonomous endosperm development and mature parthenocarpic achene formation suggests the former is sufficient to trigger fruit maturation in Hieracium. The developmental component of autonomous endosperm formation is therefore genetically separable from those controlling meiotic avoidance and autonomous embryogenesis in Hieracium and has been denoted as AutE. We postulate that tight linkage of AutE and genes controlling autonomous embryogenesis at the LOP locus in H. praealtum may explain why inheritance of autonomous seed formation is typically observed as a single component.
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http://dx.doi.org/10.1007/s00497-013-0214-yDOI Listing
June 2013

Near peripheral motion contrast threshold predicts older drivers' simulator performance.

Accid Anal Prev 2013 Jan 23;50:103-9. Epub 2012 Apr 23.

Transportation Safety Board of Canada, Place du Centre, 200 Promenade du Portage, 4th Floor, Gatineau, Quebec, Canada K1A 1K8.

Our group has previously demonstrated that peripheral motion contrast threshold (PMCT) is significantly associated with self-reported accident risk of older drivers (questionnaire assessment), and with Useful Field of View(®) subtest 2 (UFOV2). It has not been shown, however, that PMCT is significantly associated with driving performance. Using the method of descending limits (spatial two-alternative forced choice) we assessed motion contrast thresholds of 28 young participants (25-45), and 21 older drivers (63-86) for 0.4 cycle/degree drifting Gabor stimuli at 15° eccentricity and examined whether it was related to performance on a simulated on-road test and to a measure of visual attention (UFOV(®) subtests 2 and 3). Peripheral motion contrast thresholds (PMCT) of younger participants were significantly lower than older participants. PMCT and UFOV2 significantly predicted driving examiners' scores of older drivers' simulator performance, as well as number of crashes. Within the older group, PMCT correlated significantly with UFOV2, UFOV3, and age. Within the younger group, PMCT was not significantly related to either UFOV(®) scores or age. Partial correlations showed that: substantial association between PMCT and UFOV2 was not age-related (within the older driver group); PMCT and UFOV2 tapped a common visual function; and PMCT assessed a component not captured by UFOV2. PMCT is potentially a useful assessment tool for predicting accident risk of older drivers, and for informing efforts to develop effective countermeasures to remediate this functional deficit as much as possible.
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http://dx.doi.org/10.1016/j.aap.2012.03.035DOI Listing
January 2013

Exploring the benefits of augmented reality documentation for maintenance and repair.

IEEE Trans Vis Comput Graph 2011 Oct;17(10):1355-68

Department of Computer Science, Computer Graphics and User Interfaces Lab, Columbia University, 500 W. 120th St., 450 CS Building, New York, NY 10027, USA.

We explore the development of an experimental augmented reality application that provides benefits to professional mechanics performing maintenance and repair tasks in a field setting. We developed a prototype that supports military mechanics conducting routine maintenance tasks inside an armored vehicle turret, and evaluated it with a user study. Our prototype uses a tracked headworn display to augment a mechanic's natural view with text, labels, arrows, and animated sequences designed to facilitate task comprehension, localization, and execution. A within-subject controlled user study examined professional military mechanics using our system to complete 18 common tasks under field conditions. These tasks included installing and removing fasteners and indicator lights, and connecting cables, all within the cramped interior of an armored personnel carrier turret. An augmented reality condition was tested against two baseline conditions: the same headworn display providing untracked text and graphics and a fixed flat panel display representing an improved version of the laptop-based documentation currently employed in practice. The augmented reality condition allowed mechanics to locate tasks more quickly than when using either baseline, and in some instances, resulted in less overall head movement. A qualitative survey showed that mechanics found the augmented reality condition intuitive and satisfying for the tested sequence of tasks.
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http://dx.doi.org/10.1109/TVCG.2010.245DOI Listing
October 2011

Near peripheral motion detection threshold correlates with self-reported failures of attention in younger and older drivers.

Accid Anal Prev 2010 Jul 16;42(4):1189-94. Epub 2010 Feb 16.

Transportation Safety Board of Canada, Place du Centre, Gatineau, Quebec, Canada K1A 1K8.

Motion contrast thresholds for 0.4cycle/degree drifting Gabor stimuli were assessed at 15 degrees eccentricity in the right and left visual fields for 16 younger drivers (ages 24-42), and 15 older drivers (ages 65-84), using a temporal two-alternative forced choice staircase procedure. Two self-report questionnaires that assess failures of attention while driving-the Driver Perception Questionnaire (DPQ5), and an abridged Aging Driver Questionnaire (ADQ15)-were administered. The three UFOV((R)) subtests of attention and processing speed were also administered. Mean peripheral motion contrast threshold (PMCT) of older drivers was significantly higher than that of younger drivers. When controlling for age, PMCT thresholds correlated significantly with both DPQ5 and ADQ15 while the UFOV((R)) subtests were found not to correlate with PMCT results. The potential value of the PMCT as an assessment of drivers' hazard detection capacity is discussed.
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http://dx.doi.org/10.1016/j.aap.2010.01.009DOI Listing
July 2010

Opportunistic tangible user interfaces for augmented reality.

IEEE Trans Vis Comput Graph 2010 Jan-Feb;16(1):4-16

Department of Computer Science, Columbia University, New York, NY 10027-7002, USA.

Opportunistic Controls are a class of user interaction techniques that we have developed for augmented reality (AR) applications to support gesturing on, and receiving feedback from, otherwise unused affordances already present in the domain environment. By leveraging characteristics of these affordances to provide passive haptics that ease gesture input, Opportunistic Controls simplify gesture recognition, and provide tangible feedback to the user. In this approach, 3D widgets are tightly coupled with affordances to provide visual feedback and hints about the functionality of the control. For example, a set of buttons can be mapped to existing tactile features on domain objects. We describe examples of Opportunistic Controls that we have designed and implemented using optical marker tracking, combined with appearance-based gesture recognition. We present the results of two user studies. In the first, participants performed a simulated maintenance inspection of an aircraft engine using a set of virtual buttons implemented both as Opportunistic Controls and using simpler passive haptics. Opportunistic Controls allowed participants to complete their tasks significantly faster and were preferred over the baseline technique. In the second, participants proposed and demonstrated user interfaces incorporating Opportunistic Controls for two domains, allowing us to gain additional insights into how user interfaces featuring Opportunistic Controls might be designed.
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http://dx.doi.org/10.1109/TVCG.2009.91DOI Listing
March 2010

Proteomic analysis of butyrate effects and loss of butyrate sensitivity in HT29 colorectal cancer cells.

J Proteome Res 2009 Mar;8(3):1220-7

CSIRO Preventative Health Flagship, Australia, CSIRO, Human Nutrition, Adelaide, Australia, CSIRO, Division of Molecular and Health Technologies, Adelaide, Australia.

Butyrate, a fermentation product of the large bowel microflora, is potentially protective against the development of colorectal cancer. In vitro, butyrate has been shown to induce apoptosis and inhibit proliferation in numerous cancer cell lines, including colorectal cancer. Although these tumor suppressing properties of butyrate are well-documented in experimental systems, the mechanisms underlying the induction of these effects are not fully understood. Understanding these mechanisms in cancer cells, as well as the pathways involved in a cell's ability to overcome them and progress toward malignancy, is vital to determine therapeutic approaches for disease management. We have developed a colorectal cancer cell line (HT29-BR) that is less responsive to the apoptotic effects of butyrate through sustained exposure of HT29 cells to 5 mM butyrate and have used proteomics to investigate the mechanisms involved in the development of butyrate insensitivity. Proteomic analysis identified a number of cellular processes in HT29 and HT29-BR cells influenced by butyrate including remodeling of the actin cytoskeleton, inhibition of protein biosynthesis and dysregulation of the cell stress response. We describe novel roles for butyrate in the induction of its tumor suppressing effects and outline potential cellular pathways involved in the development of butyrate insensitivity in the HT29-BR cell population.
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http://dx.doi.org/10.1021/pr8009929DOI Listing
March 2009

The relationship of cognitive retraining to neurological patients' work and school status.

Brain Inj 2007 Oct;21(11):1097-107

Catholic Healthcare West, Barrow Neurological Institute, Centre for Transitional Neurorehabilitation, Phoenix, AZ, USA.

Primary Objective: To explore the relationship of cognitive retraining performance to discharge productivity status.

Methods And Procedures: One hundred and one brain-injured patients from a holistic milieu-oriented work/school re-entry programme.

Experimental Interventions: Initial, last, mean and best cognitive retraining scores; cognitive retraining behavioural checklist ratings; and working alliance scores.

Main Outcomes And Results: Most (82.2%) of the sample returned to paid work or school. Better performance on two cognitive retraining tasks addressing information processing speed, visual scanning, visuospatial skills and memory were associated with return to the same level of work/school with and without modifications. Selected process variables related to the patients' behavioural approach to cognitive retraining tasks (e.g. their use of compensations, organizational and abstraction skills, procedural skills and unassisted task recall) were associated with better work/school outcomes. Patients' positive working alliance ratings related to their behavioural approach to cognitive retraining tasks. This highlights the importance of combining interventions targeting both the therapeutic interactive process and skill remediation to maximize work/school reintegration.

Conclusions: Cognitive Retraining exercises that incorporate both process variables and metacognitive skills, as well as a better working alliance with patients, positively related to return to work and school at the time of discharge from a holistic milieu-oriented programme.
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http://dx.doi.org/10.1080/02699050701687342DOI Listing
October 2007

Psychosocial outcomes 1-7 years after comprehensive milieu-oriented neurorehabilitation: the role of pre-injury status.

Brain Inj 2006 Jun;20(6):601-12

Catholic Healthcare West, Barrow Neurological Institute, Center for Transitional Neurorehabilitation, Phoenix, AZ 85013, USA.

Primary Objective: To explore pre-injury variables related to post-discharge psychosocial status and identify factors related to work and driving outcomes.

Methods And Procedures: Ninety-three brain-injured patients attended a holistic milieu-oriented neurorehabilitation program and were contacted 1-7 years post-discharge.

Experimental Interventions: Questionnaire data addressing pre-injury and post-injury work, driving, income, marital status and living situation.

Main Outcomes And Results: 74.3% were involved in competitive work and/or school with 86.0% productive at follow-up. Post-injury income decreased significantly compared with pre-injury levels. Pre-injury relationship status did not differ significantly from post-injury; 81.1% remaining in a stable relationship or married at follow-up. Pre-injury and post-injury accident rates were related; 73.1% drove at follow-up. Higher education, non-right hemispheric injury, shorter treatment length and return to work related to driving. Younger age, higher education, non-right hemispheric injury and driving post-injury related to positive work status.

Conclusions: Pre-injury psychosocial data provide an important context for understanding post-discharge outcome after brain injury. Holistic milieu-oriented rehabilitation facilitates long-term successful work, driving and relationship stability.
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http://dx.doi.org/10.1080/02699050600744301DOI Listing
June 2006