Evaluation of canonical siRNA and Dicer substrate RNA for inhibition of hepatitis C virus genome replication - a comparative study

Hepatitis C virus (HCV) frequently establishes persistent infections in the liver, leading to the development of chronic hepatitis and, potentially, to liver cirrhosis and hepatocellular carcinoma at later stages. The objective of this study was to test the ability of five Dicer substrate siRNAs (DsiRNA) to inhibit HCV replication and to compare these molecules to canonical 21 nt siRNA. DsiRNA molecules were designed to target five distinct regions of the HCV genome - the 5′ UTR and the coding regions for NS3, NS4B, NS5A or NS5B. These molecules were transfected into Huh7.5 cells that stably harboured an HCV subgenomic replicon expressing a firefly luciferase/neoR reporter (SGR-Feo-JFH-1) and were also tested on HCVcc-infected cells. All of the DsiRNAs inhibited HCV replication in both the subgenomic system and HCVcc-infected cells. When DsiRNAs were transfected prior to infection with HCVcc, the inhibition levels reached 99.5%. When directly compared, canonical siRNA and DsiRNA exhibited similar potency of virus inhibition. Furthermore, both types of molecules exhibited similar dynamics of inhibition and frequencies of resistant mutants after 21 days of treatment. Thus, DsiRNA molecules are as potent as 21 nt siRNAs for the inhibition of HCV replication and may provide future approaches for HCV therapy if the emergence of resistant mutants can be addressed

Modelling capture efficiency of single-cell RNA-sequencing data improves inference of transcriptome-wide burst kinetics

MOTIVATION: Gene expression is characterised by stochastic bursts of transcription that occur at brief and random periods of promoter activity. The kinetics of gene expression burstiness differs across the genome and is dependent on the promoter sequence, among other factors. Single-cell RNA sequencing (scRNA-seq) has made it possible to quantify the cell-to-cell variability in transcription at a global genome-wide level. However, scRNA-seq data is prone to technical variability, including low and variable capture efficiency of transcripts from individual cells. RESULTS: Here, we propose a novel mathematical theory for the observed variability in scRNA-seq data. Our method captures burst kinetics and variability in both the cell size and capture efficiency, which allows us to propose several likelihood-based and simulation-based methods for the inference of burst kinetics from scRNA-seq data. Using both synthetic and real data, we show that the simulation-based methods provide an accurate, robust and flexible tool for inferring burst kinetics from scRNA-seq data. In particular, in a supervised manner, a simulation-based inference method based on neural networks proves to be accurate and useful when applied to both allele and non-allele-specific scRNA-seq data. AVAILABILITY: The code for Neural Network and Approximate Bayesian Computation inference is available at https://github.com/WT215/nnRNA and https://github.com/WT215/Julia_ABC respectively. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online

The regional economic impact of more graduates in the labour market: a “micro-to-macro” analysis for Scotland

This paper explores the system-wide impact of graduates on the regional economy. Graduates enjoy a significant wage premium, often interpreted as reflecting their greater productivity relative to non-graduates. If this is so there is a clear and direct supply-side impact of HEI activities on regional economies. We use an HEI-disaggregated computable general equilibrium model of Scotland to estimate the impact of the growing proportion of graduates in the Scottish labour force that is implied by the current participation rate and demographic change, taking the graduate wage premium in Scotland as an indicator of productivity enhancement. While the detailed results vary with alternative assumptions about the extent to which wage premia reflect productivity, they do suggest that the long-term supply-side impacts of HEIs provide a significant boost to regional GDP. Furthermore, the results suggest that the supply-side impacts of HEIs are likely to be more important than the expenditure impacts that are the focus of most HEI impact studies

A Relativistic Type Ibc Supernova Without a Detected Gamma-ray Burst

Long duration gamma-ray bursts (GRBs) mark the explosive death of some massive stars and are a rare sub-class of Type Ibc supernovae (SNe Ibc). They are distinguished by the production of an energetic and collimated relativistic outflow powered by a central engine (an accreting black hole or neutron star). Observationally, this outflow is manifested in the pulse of gamma-rays and a long-lived radio afterglow. To date, central engine-driven SNe have been discovered exclusively through their gamma-ray emission, yet it is expected that a larger population goes undetected due to limited satellite sensitivity or beaming of the collimated emission away from our line-of-sight. In this framework, the recovery of undetected GRBs may be possible through radio searches for SNe Ibc with relativistic outflows. Here we report the discovery of luminous radio emission from the seemingly ordinary Type Ibc SN 2009bb, which requires a substantial relativistic outflow powered by a central engine. The lack of a coincident GRB makes SN 2009bb the first engine-driven SN discovered without a detected gamma-ray signal. A comparison with our extensive radio survey of SNe Ibc reveals that the fraction harboring central engines is low, ~1 percent, measured independently from, but consistent with, the inferred rate of nearby GRBs. Our study demonstrates that upcoming optical and radio surveys will soon rival gamma-ray satellites in pinpointing the nearest engine-driven SNe. A similar result for a different supernova is reported independently.Comment: To appear in Nature on Jan 28 2010. Embargoed for discussion in the press until 13:00 US Eastern Time on Jan 27 (Accepted version, 27 pages, Manuscript and Suppl. Info.

Examining the Connections within the Startup Ecosystem: A Case Study of St. Louis

This paper documents the resurgence of entrepreneurial activity in St. Louis by reporting on the collaboration and local learning within the startup community. This activity is happening both between entrepreneurs and between organizations that provide support, such as mentoring and funding, to entrepreneurs. As these connections deepen, the strength of the entrepreneurial ecosystem grows. Another finding from the research is that activity-based events, where entrepreneurs have the chance to use and practice the skills needed to grow their businesses, are most useful. St. Louis provides a multitude of these activities, such as Startup Weekend, 1 Million Cups, Code Until Dawn, StartLouis, and GlobalHack. Some of these are St. Louis specific, but others have nationwide or global operations, providing important implications for other cities

Evaluating the difference in neuropsychological profiles of individuals with FASD based on the number of sentinel facial features: a service evaluation of the FASD UK National Clinic Database

It might be implied that those with Fetal Alcohol Spectrum Disorder (FASD) with fewer sentinel facial features have a “milder” neuropsychological presentation, or present with fewer impairments than those with more sentinel facial features. The aim of this service evaluation was to compare the neuropsychological profile of people with FASD with varying numbers of sentinel facial features. (2) A clinical sample of 150 individuals with FASD, aged between 6 and 37 years, completed various standardised assessments as part of their diagnostic profiling. These included the documented level of risk of prenatal alcohol exposure (4-Digit Diagnostic Code), sensory needs (Short Sensory Profile), cognition (Wechsler Intelligence Scale for Children—4th Edition; WISC-IV), and communication and socialisation adaptive behaviours (Vineland Adaptive Behavior Scale—2nd Edition; VABS-II). As FASD has high comorbidity rates of Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD), these were also reviewed. The profiles of the ‘FASD with 2 or 3 sentinel facial features’ group (n = 41; 28 male, 13 female) were compared with the ‘FASD with 0 or 1 sentinel facial features’ group (n = 109; 50 male, 59 female) using Chi2 tests, independent sample t-tests, and Mann-Whitney U analyses (where appropriate). (3) There were no significant differences between the two comparison groups across any measure included in this service evaluation. (4) Whilst sentinel facial features remain an important aspect in recognising FASD, our service evaluation indicates that there is no significant relationship between the number of sentinel facial features and the neuropsychological profile of people with FASD in terms of severity of presentation