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1.
Nat Methods ; 19(10): 1295-1305, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36064771

RESUMO

Adaptive immunity relies on T lymphocytes that use αß T cell receptors (TCRs) to discriminate among peptides presented by major histocompatibility complex molecules (pMHCs). Identifying pMHCs capable of inducing robust T cell responses will not only enable a deeper understanding of the mechanisms governing immune responses but could also have broad applications in diagnosis and treatment. T cell recognition of sparse antigenic pMHCs in vivo relies on biomechanical forces. However, in vitro screening methods test potential pMHCs without force and often at high (nonphysiological) pMHC densities and thus fail to predict potent agonists in vivo. Here, we present a technology termed BATTLES (biomechanically assisted T cell triggering for large-scale exogenous-pMHC screening) that uses biomechanical force to initiate T cell triggering for peptides and cells in parallel. BATTLES displays candidate pMHCs on spectrally encoded beads composed of a thermo-responsive polymer capable of applying shear loads to T cells, facilitating exploration of the force- and sequence-dependent landscape of T cell responses. BATTLES can be used to explore basic T cell mechanobiology and T cell-based immunotherapies.


Assuntos
Ativação Linfocitária , Receptores de Antígenos de Linfócitos T , Peptídeos/química , Polímeros , Linfócitos T
2.
Virol J ; 20(1): 90, 2023 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-37149667

RESUMO

Insufficient tracking of virus introduction, spread, and new lineage emergence for the human monkeypox (mpox) virus 1 (hMPXV1) outbreak of 2022 hindered epidemiological studies and public health response. hMPXV1 mutations accumulated unexpectedly faster than predicted. Thus, new variants with altered pathogenicity could emerge and spread without early detection. Whole genome sequencing addresses this gap when implemented but requires widely accessible and standardized methodologies to be effective both regionally and globally. Here we developed a rapid nanopore whole genome sequencing method complete with working protocols, from DNA extraction to phylogenetic analysis tools. Using this method, we sequenced 84 complete hMPXV1 genomes from Illinois, a Midwestern region of the United States, spanning the first few months of the outbreak. The resulting five-fold increase in hMPXV1 genomes from this region established two previously unnamed global lineages, several mutational profiles not seen elsewhere, multiple separate introductions of the virus into the region, and the likely emergence and spread of new lineages from within this region. These results demonstrate that a dearth of genomic sequencing of hMPXV1 slowed our understanding and response to the mpox outbreak. This accessible nanopore sequencing approach makes near real-time mpox tracking and rapid lineage discovery straightforward and creates a blueprint for how to deploy nanopore sequencing for genomic surveillance of diverse viruses and future outbreaks.


Assuntos
Mpox , Sequenciamento por Nanoporos , Humanos , Filogenia , Sequenciamento Completo do Genoma/métodos , Surtos de Doenças
3.
Inj Prev ; 29(1): 79-84, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36376056

RESUMO

This article examines how 'framing' is used to resist a proposal to remove rugby tackling from UK schools. It focuses on rugby tackling for UK school children, which is often a compulsory part of many schools' curricula. Specifically, we explore the importance of framing in how the problem is described in various academic publications, how ideas about risk are articulated and how advocates themselves are represented. We show how the corporate interests of rugby governing bodies can become entangled with distortions about injury prevention. These distortions (or framing practices) include omitting arguments, conflating arguments, changing the argument, misrepresenting advocacy positions and skewing advocate identities. Next, the article demonstrates how a combination of recent advocacy, political interventions, research and cultural shifts appears to be changing perceptions about the risks associated with rugby tackling for children in school settings. In conclusion, we argue that while framing can be a useful strategy for policy advocates, there is value in paying attention to how framing is used by different stakeholder groups.


Assuntos
Rugby , Instituições Acadêmicas , Criança , Humanos
4.
Brain Inj ; 37(6): 478-484, 2023 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-36843269

RESUMO

PRIMARY OBJECTIVE: To investigate the effect of home and away game travel on risk of concussion across different levels of rugby union. RESEARCH DESIGN: Exploration study across school, university, and professional rugby teams. METHODS AND PROCEDURES: Retrospective analysis of concussion incidence and symptomology of surveillance data and prospective data collection for potential concussions via surveys. Data was collected from school rugby teams (n = 344 matches, over 2 years), a university rugby (n = 6 matches), and a professional rugby team (n = 64 matches, over two seasons). MAIN OUTCOMES AND RESULTS: School level rugby had an increased prevalence of concussions in away matches (p = 0.02). Likewise, there was a significant increase (p < 0.05) in concussions at away matches in university rugby. In addition, the professional rug by team had significant differences in recovery times and symptoms with away fixtures, including longer recovery times (p < 0.01), more initial symptoms (p < 0.01), as well as greater and more severe symptoms at 48 hours (p < 0.05). CONCLUSIONS: This research highlights an increased prevalence of concussion in school and university-aged rugby players away from home, as well as increased symptoms, symptom severity, and recovery times in professional rugby players.


Assuntos
Traumatismos em Atletas , Concussão Encefálica , Futebol Americano , Humanos , Idoso , Traumatismos em Atletas/complicações , Estudos Retrospectivos , Concussão Encefálica/diagnóstico , Incidência
5.
Adapt Behav ; 31(1): 3-19, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36618906

RESUMO

We present three new diagnostic prediction problems inspired by classical-conditioning experiments to facilitate research in online prediction learning. Experiments in classical conditioning show that animals such as rabbits, pigeons, and dogs can make long temporal associations that enable multi-step prediction. To replicate this remarkable ability, an agent must construct an internal state representation that summarizes its interaction history. Recurrent neural networks can automatically construct state and learn temporal associations. However, the current training methods are prohibitively expensive for online prediction-continual learning on every time step-which is the focus of this paper. Our proposed problems test the learning capabilities that animals readily exhibit and highlight the limitations of the current recurrent learning methods. While the proposed problems are nontrivial, they are still amenable to extensive testing and analysis in the small-compute regime, thereby enabling researchers to study issues in isolation, ultimately accelerating progress towards scalable online representation learning methods.

6.
Plant Cell Physiol ; 61(7): 1335-1347, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32379869

RESUMO

Alpha-linolenic acid (ALA, 18:3Δ9,12,15) and γ-linolenic acid \ (GLA, 18:3Δ6,9,12) are important trienoic fatty acids, which are beneficial for human health in their own right, or as precursors for the biosynthesis of long-chain polyunsaturated fatty acids. ALA and GLA in seed oil are synthesized from linoleic acid (LA, 18:2Δ9,12) by the microsomal ω-3 fatty acid desaturase (FAD3) and Δ6 desaturase (D6D), respectively. Cotton (Gossypium hirsutum L.) seed oil composition was modified by transforming with an FAD3 gene from Brassica napus and a D6D gene from Echium plantagineum, resulting in approximately 30% ALA and 20% GLA, respectively. The total oil content in transgenic seeds remained unaltered relative to parental seeds. Despite the use of a seed-specific promoter for transgene expression, low levels of GLA and increased levels of ALA were found in non-seed cotton tissues. At low temperature, the germinating cottonseeds containing the linolenic acid isomers elongated faster than the untransformed controls. ALA-producing lines also showed higher photosynthetic rates at cooler temperature and better fiber quality compared to both untransformed controls and GLA-producing lines. The oxidative stability of the novel cottonseed oils was assessed, providing guidance for potential food, pharmaceutical and industrial applications of these oils.


Assuntos
Fibra de Algodão , Óleo de Sementes de Algodão/metabolismo , Germinação/genética , Gossypium/genética , Fotossíntese/genética , Sementes/crescimento & desenvolvimento , Ácido alfa-Linolênico/metabolismo , Ácido gama-Linolênico/metabolismo , Brassica napus/genética , Resposta ao Choque Frio , Fibra de Algodão/normas , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Engenharia Genética , Gossypium/metabolismo , Plantas Geneticamente Modificadas , Sementes/metabolismo , Ácido alfa-Linolênico/genética , Ácido gama-Linolênico/genética
7.
Br J Sports Med ; 51(15): 1113-1117, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28701366

RESUMO

In a paper published in BJSM (June 2016), World Rugby employees Ross Tucker and Martin Raftery and a third coauthor Evert Verhagen took issue with the recent call to ban tackling in school rugby in the UK and Ireland. That call (to ban tackling) was supported by a systematic review published in BJSM Tucker et al claim that: (1) the mechanisms and risk factors for injury along with the incidence and severity of injury in youth rugby union have not been thoroughly identified or understood; (2) rugby players are at no greater risk of injury than other sports people, (3) this is particularly the case for children under 15 years and (4) removing the opportunity to learn the tackle from school pupils might increase rates of injuries. They conclude that a ban 'may be unnecessary and may also lead to unintended consequences such as an increase in the risk of injury later in participation.' Here we aim to rebut the case by Tucker et al We share new research that extends the findings of our original systematic review and meta-analysis. A cautionary approach requires the removal of the tackle from school rugby as the quickest and most effective method of reducing high injury rates in youth rugby, a public health priority.


Assuntos
Traumatismos em Atletas/prevenção & controle , Futebol Americano/lesões , Adolescente , Traumatismos em Atletas/etiologia , Concussão Encefálica/etiologia , Concussão Encefálica/prevenção & controle , Criança , Humanos , Irlanda , Metanálise como Assunto , Medição de Risco , Fatores de Risco , Reino Unido
9.
Nat Methods ; 8(7): 581-6, 2011 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-21602799

RESUMO

Heterogeneity in cell populations poses a major obstacle to understanding complex biological processes. Here we present a microfluidic platform containing thousands of nanoliter-scale chambers suitable for live-cell imaging studies of clonal cultures of nonadherent cells with precise control of the conditions, capabilities for in situ immunostaining and recovery of viable cells. We show that this platform mimics conventional cultures in reproducing the responses of various types of primitive mouse hematopoietic cells with retention of their functional properties, as demonstrated by subsequent in vitro and in vivo (transplantation) assays of recovered cells. The automated medium exchange of this system made it possible to define when Steel factor stimulation is first required by adult hematopoietic stem cells in vitro as the point of exit from quiescence. This technology will offer many new avenues to interrogate otherwise inaccessible mechanisms governing mammalian cell growth and fate decisions.


Assuntos
Técnicas de Cultura de Células/métodos , Células-Tronco Hematopoéticas/citologia , Técnicas Analíticas Microfluídicas/métodos , Análise Serial de Tecidos , Adulto , Técnicas de Cultura de Células/instrumentação , Proliferação de Células , Ensaios de Triagem em Larga Escala , Humanos , Técnicas Analíticas Microfluídicas/instrumentação
10.
Proc Natl Acad Sci U S A ; 108(34): 13999-4004, 2011 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-21808033

RESUMO

A long-sought milestone in microfluidics research has been the development of integrated technology for scalable analysis of transcription in single cells. Here we present a fully integrated microfluidic device capable of performing high-precision RT-qPCR measurements of gene expression from hundreds of single cells per run. Our device executes all steps of single-cell processing, including cell capture, cell lysis, reverse transcription, and quantitative PCR. In addition to higher throughput and reduced cost, we show that nanoliter volume processing reduced measurement noise, increased sensitivity, and provided single nucleotide specificity. We apply this technology to 3,300 single-cell measurements of (i) miRNA expression in K562 cells, (ii) coregulation of a miRNA and one of its target transcripts during differentiation in embryonic stem cells, and (iii) single nucleotide variant detection in primary lobular breast cancer cells. The core functionality established here provides the foundation from which a variety of on-chip single-cell transcription analyses will be developed.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Microfluídica/métodos , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Análise de Célula Única/métodos , Linhagem Celular , Regulação da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes
12.
Mol Ther Nucleic Acids ; 35(2): 102206, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38803421

RESUMO

Huntington's disease (HD) is an incurable neurodegenerative disorder caused by genetic expansion of a CAG repeat sequence in one allele of the huntingtin (HTT) gene. Reducing expression of the mutant HTT (mutHTT) protein has remained a clear therapeutic goal, but reduction of wild-type HTT (wtHTT) is undesirable, as it compromises gene function and potential therapeutic efficacy. One promising allele-selective approach involves targeting the CAG repeat expansion with steric binding small RNAs bearing central mismatches. However, successful genetic encoding requires consistent placement of mismatches to the target within the small RNA guide sequence, which involves 5' processing precision by cellular enzymes. Here, we used small RNA sequencing (RNA-seq) to monitor the processing precision of a limited set of CAG repeat-targeted small RNAs expressed from multiple scaffold contexts. Small RNA-seq identified expression constructs with high-guide strand 5' processing precision and promising allele-selective inhibition of mutHTT. Transcriptome-wide mRNA-seq also identified an allele-selective small RNA with a favorable off-target profile. These results support continued investigation and optimization of genetically encoded repeat-targeted small RNAs for allele-selective HD gene therapy and underscore the value of sequencing methods to balance specificity with allele selectivity during the design and selection process.

15.
Behav Sci (Basel) ; 12(12)2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36546993

RESUMO

The purpose of this study was to explore the understandings and perceptions of risk related to brain trauma amongst parents of children that play contact rugby. A qualitative approach was taken, using semi-structured interviews with 7 mothers and 27 fathers of children that participate in contact rugby. A thematic analysis of data suggests that parents used two primary cognitive strategies to process the risk they consented to with their children's participation in rugby; (1) minimalizing rugby risk to be equivalent to less injurious sports; and (2) elevating physical and social advantages above what they think other sports are capable of providing. From the findings it is suggested that parents who permit their children to play contact rugby are both aware of the high risks of injury in the sport, but simultaneously utilize two cognitive distortion techniques to rectify the dissonance caused between their choice to have their children play, and the salient number of concussions they observe. These results suggest that it will take properly informed consent, inclusive of concussion rates compared to other sports, in order to reduce cognitive distortion and effectively communicate risks associated with participation in contact rugby.

16.
Hum Gene Ther ; 33(15-16): 829-839, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35726380

RESUMO

Short hairpin RNAs, or short hairpin RNAs (shRNAs), are a proven tool for gene knockdown and a promising therapeutic approach for suppression of disease-associated genes. The efficient preparation of shRNA-expressing vectors can sometimes become a bottleneck due to the complexity of shRNA hairpin sequence and structure, especially for repetitive or high GC-content targets. Here, we present improved shRNA cloning and validation methods that enabled efficient and rapid cloning of several shRNAs targeting disease-associated repeat expansions, including GGGGCC, CAG, CTG, CCTG, and CGG into modified pLKO.1 vectors. Improvements included shRNA insert design and preparation, recombination-based cloning, and sequencing-based validation that included Sanger and nanopore long-read sequencing. This improved method should enable practical, efficient cloning of nearly any shRNA sequence.


Assuntos
Vetores Genéticos , Clonagem Molecular , Técnicas de Silenciamento de Genes , Vetores Genéticos/genética , RNA Interferente Pequeno/genética
17.
BMC Sports Sci Med Rehabil ; 14(1): 125, 2022 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-35818048

RESUMO

BACKGROUND: Concussion in sport is an ongoing global concern. The head injury assessment (HIA) by the field of play is acknowledged as the first step in recognising and identifying concussion. While previous systematic literature reviews have evaluated the sensitivity of side-line screening tools and assessment protocols, no systematic review has evaluated the research designs and assessments used in a field setting. This systematic review investigated existing screening and diagnostic tools used in research as part of the HIA protocol to identify concussion that are currently used in professional, semi-professional and amateur (club) sports settings. METHODS: A systematic searching of relevant databases was undertaken for peer-reviewed literature between 2015 and 2020. RESULTS: Twenty-six studies met the inclusion criteria. Studies were of moderate to good quality, reporting a variety of designs. The majority of studies were undertaken in professional/elite environments with medical doctors and allied health practitioners (e.g., physical therapists) involved in 88% of concussion assessments. While gender was reported in 24 of the 26 studies, the majority of participants were male (77%). There was also a variety of concussion assessments (n = 20) with the sports concussion assessment tool (SCAT) used in less than half of the included studies. CONCLUSION: The majority of studies investigating concussion HIAs are focused on professional/elite sport. With concussion an issue at all levels of sport, future research should be directed at non-elite sport. Further, for research purposes, the SCAT assessment should also be used more widely to allow for consistency across studies.

18.
Nat Nanotechnol ; 17(10): 1097-1103, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36163507

RESUMO

The ability to manipulate light and liquids on integrated optofluidics chips has spurred a myriad of important developments in biology, medicine, chemistry and display technologies. Here we show how the convergence of optofluidics and metasurface optics can lead to conceptually new platforms for the dynamic control of light fields. We first demonstrate metasurface building blocks that display an extreme sensitivity in their scattering properties to their dielectric environment. These blocks are then used to create metasurface-based flat optics inside microfluidic channels where liquids with different refractive indices can be directed to manipulate their optical behaviour. We demonstrate the intensity and spectral tuning of metasurface colour pixels as well as on-demand optical elements. We finally demonstrate automated control in an integrated meta-optofluidic platform to open up new display functions. Combined with large-scale microfluidic integration, our dynamic-metasurface flat-optics platform could open up the possibility of dynamic display, imaging, holography and sensing applications.


Assuntos
Dispositivos Ópticos , Óptica e Fotônica
19.
Front Sports Act Living ; 4: 784103, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35873207

RESUMO

Objective: To establish the extent to which Rugby Union was a compulsory physical education activity in state-funded secondary schools in England and to understand the views of Subject Leaders for Physical Education with respect to injury risk. Method: A cross-sectional research study using data obtained under the Freedom of Information Act (2000) from 288 state-funded secondary schools. Results: Rugby Union was delivered in 81% (n = 234 of 288) of state-funded secondary school physical education curricula, including 83% (n = 229 of 275) of state-funded secondary school boys' and 54% (n = 151 of 282) of girls' physical education curricular. Rugby Union was compulsory in 91% (n = 208 of 229) of state-funded secondary schools that delivered it as part of the boys' physical education curriculum and 54% (n = 82 of 151) of state-funded secondary schools that delivered contact Rugby Union as part of the girls' physical education curriculum. Subject Leaders for Physical Education also perceived Rugby Union to have the highest risk of harm of the activities they delivered in their school physical education curriculum. Conclusion: Notwithstanding discussions of appropriate measures (i.e., mandatory concussion training, Rugby Union specific qualifications and CPD) to reduce injury risk, it is recommended that Rugby Union should not be a compulsory activity given that it has a perceived high risk of injury and is an unnecessary risk for children in physical education.

20.
Front Neurol ; 13: 938163, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35937061

RESUMO

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with a history of repetitive head impacts (RHI). CTE was described in boxers as early as the 1920s and by the 1950s it was widely accepted that hits to the head caused some boxers to become "punch drunk." However, the recent discovery of CTE in American and Australian-rules football, soccer, rugby, ice hockey, and other sports has resulted in renewed debate on whether the relationship between RHI and CTE is causal. Identifying the strength of the evidential relationship between CTE and RHI has implications for public health and medico-legal issues. From a public health perspective, environmentally caused diseases can be mitigated or prevented. Medico-legally, millions of children are exposed to RHI through sports participation; this demographic is too young to legally consent to any potential long-term risks associated with this exposure. To better understand the strength of evidence underlying the possible causal relationship between RHI and CTE, we examined the medical literature through the Bradford Hill criteria for causation. The Bradford Hill criteria, first proposed in 1965 by Sir Austin Bradford Hill, provide a framework to determine if one can justifiably move from an observed association to a verdict of causation. The Bradford Hill criteria include nine viewpoints by which to evaluate human epidemiologic evidence to determine if causation can be deduced: strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy. We explored the question of causation by evaluating studies on CTE as it relates to RHI exposure. Through this lens, we found convincing evidence of a causal relationship between RHI and CTE, as well as an absence of evidence-based alternative explanations. By organizing the CTE literature through this framework, we hope to advance the global conversation on CTE mitigation efforts.

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