The effects of entry on incumbent innovation and productivity

How does firm entry affect innovation incentives in incumbent firms? Microdata suggest that there is heterogeneity across industries. Specifically, incumbent productivity growth and patenting is positively correlated with lagged greenfield foreign firm entry in technologically advanced industries, but not in laggard industries. In this paper we provide evidence that these correlations arise from a causal effect predicted by Schumpeterian growth theory—the threat of technologically advanced entry spurs innovation incentives in sectors close to the technology frontier, where successful innovation allows incumbents to survive the threat, but discourages innovation in laggard sectors, where the threat reduces incumbents' expected rents from innovating. We find that the empirical patterns hold using rich micro panel data for the United Kingdom. We control for the endogeneity of entry by exploiting major European and U.K. policy reforms, and allow for endogeneity of additional factors. We complement the analysis for foreign entry with evidence for domestic entry and entry through imports

Intensive management in grasslands causes diffuse water pollution at the farm scale

Arable land use is generally assumed to be the largest contributor to agricultural diffuse pollution. This study adds to the growing evidence that conventional temperate intensively managed lowland grasslands contribute significantly to soil erosion and diffuse pollution rates. This is the first grassland study to monitor hydrological characteristics and multiple pollutant fluxes (suspended sediment [SS] and the macronutrients: total oxidized nitrogen-N [TONN], total phosphorus [TP], and total carbon [TC]) at high temporal resolution (monitoring up to every 15 min) over 1 yr. Monitoring was conducted across three fields (6.5-7.5 ha) on the North Wyke Farm Platform, UK. The estimated annual erosion rates (up to 527.4 kg ha-1), TP losses (up to 0.9 kg ha-1), and TC losses (up to 179 kg ha-1) were similar to or exceeded the losses reported for other grassland, mixed land-use, and arable sites. Annual yields of TONN (up to 3 kg ha-1) were less than arable land-use fluxes and earlier grassland N studies, an important result as the study site is situated within a Nitrate Vulnerable Zone. The high-resolution monitoring allowed detailed "system's functioning" understanding of hydrological processes, mobilization- transport pathways of individual pollutants, and the changes of the relative importance of diffuse pollutants through flow conditions and time. Suspended sediment and TP concentrations frequently exceeded water quality guidelines recommended by the European Freshwater Fisheries Directive (25 mg L-1) and the European Water Framework Directive (0.04 mg soluble reactive P L-1), suggesting that intensively managed grasslands pose a significant threat to receiving surface waters. Such sediment and nutrient losses from intensively managed grasslands should be acknowledged in land management guidelines and advice for future compliance with surface water quality standards.NERC-Case PhD awardUK Biotechnology and Biological Sciences Research Counci

Going Small: Using Biophysical Screening to Implement Fragment Based Drug Discovery

Screening against biochemical targets with compact chemical fragments has developed a reputation as a successful early‐stage drug discovery approach, thanks to recent drug approvals. Having weak initial target affinities, fragments require the use of sensitive biophysical technologies (NMR, SPR, thermal shift, ITC, and X‐ray crystallography) to accommodate the practical limits of going smaller. Application of optimized fragment biophysical screening approaches now routinely allows for the rapid identification of fragments with high binding efficiencies. The aim of this chapter is to provide an introduction to fragment library selection and to discuss the suitability of screening approaches adapted for lower‐throughput biophysical techniques. A general description of metrics that are being used in the progression of fragment hits, the need for orthogonal assay testing, and guidance on potential pitfalls are included to assist scientists, considering initiating their own fragment discovery program

Refining the Candidate Environment: Interpersonal Stress, the Serotonin Transporter Polymorphism, and Gene-Environment Interactions in Major Depression.

Meta-analytic evidence supports a gene-environment (G×E) interaction between life stress and the serotonin transporter polymorphism (5-HTTLPR) on depression, but few studies have examined factors that influence detection of this effect, despite years of inconsistent results. We propose that the "candidate environment" (akin to a candidate gene) is key. Theory and evidence implicate major stressful life events (SLEs)-particularly major interpersonal SLEs-as well as chronic family stress. Participants (N = 400) from the Youth Emotion Project (which began with 627 high school juniors oversampled for high neuroticism) completed up to five annual diagnostic and life stress interviews and provided DNA samples. A significant G×E effect for major SLEs and S-carrier genotype was accounted for significantly by major interpersonal SLEs but not significantly by major non-interpersonal SLEs. S-carrier genotype and chronic family stress also significantly interacted. Identifying such candidate environments may facilitate future G×E research in depression and psychopathology more broadly

Evasion of cytotoxic T lymphocyte (CTL) responses by nef-dependent induction of Fas ligand (CD95L) expression on simian immunodeficiency virus-infected cells.

Published versio

Aromatase inhibition remodels the clonal architecture of estrogen-receptor-positive breast cancers

Resistance to oestrogen-deprivation therapy is common in oestrogen-receptor-positive (ER+) breast cancer. To better understand the contributions of tumour heterogeneity and evolution to resistance, here we perform comprehensive genomic characterization of 22 primary tumours sampled before and after 4 months of neoadjuvant aromatase inhibitor (NAI) treatment. Comparing whole-genome sequencing of tumour/normal pairs from the two time points, with coincident tumour RNA sequencing, reveals widespread spatial and temporal heterogeneity, with marked remodelling of the clonal landscape in response to NAI. Two cases have genomic evidence of two independent tumours, most obviously an ER− ‘collision tumour', which was only detected after NAI treatment of baseline ER+ disease. Many mutations are newly detected or enriched post treatment, including two ligand-binding domain mutations in ESR1. The observed clonal complexity of the ER+ breast cancer genome suggests that precision medicine approaches based on genomic analysis of a single specimen are likely insufficient to capture all clinically significant information

Comparisons of disease cluster patterns, prevalence and health factors in the USA, Canada, England and Ireland

Abstract Background Identification of those who are most at risk of developing specific patterns of disease across different populations is required for directing public health policy. Here, we contrast prevalence and patterns of cross-national disease incidence, co-occurrence and related risk factors across population samples from the U.S., Canada, England and Ireland. Methods Participants (n = 62,111) were drawn from the US Health and Retirement Study (n = 10,858); the Canadian Longitudinal Study on Ageing (n = 36,647); the English Longitudinal Study of Ageing (n = 7938) and The Irish Longitudinal Study on Ageing (n = 6668). Self-reported lifetime prevalence of 10 medical conditions, predominant clusters of multimorbidity and their specific risk factors were compared across countries using latent class analysis. Results The U.S. had significantly higher prevalence of multimorbid disease patterns and nearly all diseases when compared to the three other countries, even after adjusting for age, sex, BMI, income, employment status, education, alcohol consumption and smoking history. For the U.S. the most at-risk group were younger on average compared to Canada, England and Ireland. Socioeconomic gradients for specific disease combinations were more pronounced for the U.S., Canada and England than they were for Ireland. The rates of obesity trends over the last 50 years align with the prevalence of eight of the 10 diseases examined. While patterns of disease clusters and the risk factors related to each of the disease clusters were similar, the probabilities of the diseases within each cluster differed across countries. Conclusions This information can be used to better understand the complex nature of multimorbidity and identify appropriate prevention and management strategies for treating multimorbidity across countries