Applications of Optical Control of Oligonucleotide and Protein Function

Optical regulation using light as an external trigger was applied to the control of biological processes with high spatio-temporal resolution. Photoremovable caging groups were site-specifically incorporated onto oligonucleotides and proteins to optically regulate their function in biological environments, typically for the photochemical control of gene expression. These caging group modifications enabled both OFF → ON and ON → OFF optochemical switches for important chemical biology tools. Oligonucleotides containing caging group modifications were synthesized to regulate nucleic acid function with light. Specifically, photocaged triplex-forming oligonucleotides were developed to optochemically control transcription in cell culture. Light-activated antagomirs were designed for the optical inhibition of miR-21 and miR-122 function in the regulation of endogenous microRNA activity. This technology was then applied to the study of miR-22 and miR-124 function in cortical neuron migration during cerebral corticogenesis. Splice-switching oligonucleotides were engineered to optically control mRNA splicing pathways in both human cells and zebrafish. The optical control of plasmid-based gene expression was demonstrated with a caged promoter, and applied to the photochemical activation of transcription in a live animal model. The caging of oligonucleotides was also applied to DNA computation in the production of optically controlled logic gates and amplification cycles, providing spatio-temporal control over hybridization cascades to add new functionality to DNA computation modules. These studies in DNA computation led to the development of novel biosensors for logic gate-based detection of specific micro RNA signatures in live cells. In addition, proteins were optically controlled through the site-specific installation of caging groups on amino acid side chains that are essential for protein function using unnatural amino acid mutagenesis in mammalian cells with an expanded genetic code. A caged lysine analogue was incorporated into T7 RNA polymerase to photochemically regulate transcription in the development of a light-activated synthetic gene network and light-triggered RNA interference. A light-activated Cas9 endonuclease was engineered through the installation of a caged lysine analogue to optically control CRISPR/Cas9 editing of both exogenous and endogenous genes. Lastly, a system for the incorporation of unnatural amino acids in zebrafish was studied in efforts to produce the first vertebrate species with an expanded genetic code

A pragmatic approach to resolving technological unfairness: The case of Nike’s Vaporfly & Alphafly running footwear

Background Technology is often introduced into sport to facilitate it or to improve human performance within it. On occasion, some forms of novel technology require regulation or prevention entirely to ensure that a sport remains fair and accessible. Recently, the Nike Vaporfly and Alphafly shoes have received some concerns over their appropriateness for use in competitive distance running. Methods This paper evaluates the use of these shoes against an existing framework for sports technology discourse and adopts a pragmatic approach to attempt to resolve them. Results It is proposed that the three concerns regarding cost, access and coercion cannot be ruled out but likely remain short term issues. As a result, it is proposed that these running shoes are acceptable forms of technology but that ongoing vigilance will be required as such technologies develop further in the future. Conclusions The Nike Vaporfly/Alphafly shoes do push the perceived acceptability of running shoes to the limits of the current sports regulations. However, the alleged gains have not manifested themselves to a level that could be considered excessive when reviewing historical performances or when evaluated against a set of well-cited criteria. The sport will need to adopt a stance of ongoing vigilance as such technologies continue to develop or be optimised in the future

Violent Recidivism: A Long-Time Follow-Up Study of Mentally Disordered Offenders

Background: In this prospective study, mentally disordered perpetrators of severe violent and/or sexual crimes were followed through official registers for 59 (range 8 to 73) months. The relapse rate in criminality was assessed, compared between offenders sentenced to prison versus forensic psychiatric care, and the predictive ability of various risk factors (criminological, clinical, and of structured assessment instruments) was investigated. Method: One hundred perpetrators were consecutively assessed between 1998 and 2001 by a clinical battery of established instruments covering DSM-IV diagnoses, psychosocial background factors, and structured assessment instruments (HCR-20, PCL-R, and life-time aggression (LHA)). Follow-up data was collected from official registers for: (i) recidivistic crimes, (ii) crimes during ongoing sanction. Results: Twenty subjects relapsed in violent criminality during ongoing sanctions (n = 6) or after discharge/parole (n = 14). Individuals in forensic psychiatric care spent significantly more time at liberty after discharge compared to those in prison, but showed significantly fewer relapses. Criminological (age at first conviction), and clinical (conduct disorder and substance abuse/dependence) risk factors, as well as scores on structured assessment instruments, were moderately associated with violent recidivism. Logistic regression analyses showed that the predictive ability of criminological risk factors versus clinical risk factors combined with scores from assessment instruments was comparable, with each set of variables managing to correctly classify about 80% of all individuals, but the only predictors that remained significant in multiple models were criminological (age at first conviction, and a history of substance abuse among primary relatives). Conclusions: Only one in five relapsed into serious criminality, with significantly more relapses among subjects sentenced to prison as compared to forensic psychiatric care. Criminological risk factors tended to be the best predictors of violent relapses, while few synergies were seen when the risk factors were combined. Overall, the predictive validity of common risk factors for violent criminality was rather weak

The Persisting Burden of Intracerebral Haemorrhage: Can Effective Treatments Be Found?

Colin Josephson, Rustam Al-Shahi Salman, and colleagues discuss the effectiveness of treatments for intracerebral haemorrhage

Gender and Age Interact to Affect Early Outcome after Intracerebral Hemorrhage

BackgroundIntracerebral hemorrhage (ICH) is a common and devastating form of cerebrovascular disease. In ICH, gender differences in outcomes remain relatively understudied but have been examined in other neurological emergencies. Further, a potential effect of age and gender on outcomes after ICH has not been explored. This study was designed to test the hypothesis that age and gender interact to modify neurological outcomes after ICH.MethodsAdult patients admitted with spontaneous primary supratentorial ICH from July 2007 through April 2010 were assessed via retrospective analysis of an existing stroke database at Duke University. Univariate analysis of collected variables was used to compare gender and outcome. Unfavorable outcome was defined as discharge to hospice or death. Using multivariate regression, the combined effect of age and gender on outcome after ICH was analyzed. ResultsIn this study population, women were younger (61.1+14.5 versus 65.8+17.3 years, p=0.03) and more likely to have a history of substance abuse (35% versus 8.9%, p<0.0001) compared to men. Multivariable models demonstrated that advancing age had a greater effect on predicting discharge outcome in women compared to men (p=0.02). For younger patients, female sex was protective; however, at ages greater than 60 years, female sex was a risk factor for discharge to hospice or death.ConclusionWhile independently associated with discharge to hospice or death after ICH, the interaction effect between gender and age demonstrated significantly stronger correlation with early outcome after ICH in a single center cohort. Prospective study is required to verify these findings