The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain

The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially “druggable” point of intervention. To deliver the safety profile required for chronic, nonlife threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein we describe how the use of SBDD, 2D QSAR models, and matched molecular pair data in compound design enabled the delivery of the highly potent, kinase-selective, and peripherally restricted clinical candidate PF-06273340

Impact of target site distribution for Type I restriction enzymes on the evolution of methicillin-resistant Staphylococcus aureus (MRSA) populations.

A limited number of Methicillin-resistant Staphylococcus aureus (MRSA) clones are responsible for MRSA infections worldwide, and those of different lineages carry unique Type I restriction-modification (RM) variants. We have identified the specific DNA sequence targets for the dominant MRSA lineages CC1, CC5, CC8 and ST239. We experimentally demonstrate that this RM system is sufficient to block horizontal gene transfer between clinically important MRSA, confirming the bioinformatic evidence that each lineage is evolving independently. Target sites are distributed randomly in S. aureus genomes, except in a set of large conjugative plasmids encoding resistance genes that show evidence of spreading between two successful MRSA lineages. This analysis of the identification and distribution of target sites explains evolutionary patterns in a pathogenic bacterium. We show that a lack of specific target sites enables plasmids to evade the Type I RM system thereby contributing to the evolution of increasingly resistant community and hospital MRSA

A large‐scale assessment of plant dispersal mode and seed traits across human‐modified Amazonian forests

1. Quantifying the impact of habitat disturbance on ecosystem function is critical to understanding and predicting the future of tropical forests. Many studies have examined post-disturbance changes in animal traits related to mutualistic interactions with plants, but the effect of disturbance on plant traits in diverse forests has received much less attention. 2. Focusing on two study regions in the eastern Brazilian Amazon, we used a trait-based approach to examine how seed dispersal functionality within tropical plant communities changes across a landscape-scale gradient of human modification, including both regenerating secondary forests and primary forests disturbed by burning and selective logging. 3. Surveys of 230 forest plots recorded 26,533 live stems from 846 tree species. Using herbarium material and literature, we compiled trait information for each tree species, focusing on dispersal mode and seed size. 4. Disturbance reduced tree diversity and increased the proportion of lower wood density and small-seeded tree species in study plots. Disturbance also increased the proportion of stems with seeds that are ingested by animals and reduced those dispersed by other mechanisms (e.g. wind). Older secondary forests had function-ally similar plant communities to the most heavily disturbed primary forests. Mean seed size and wood density per plot were positively correlated for plant species with seeds ingested by animals. 5. Synthesis. Anthropogenic disturbance has major effects on the seed traits of tree communities, with implications for mutualistic interactions with animals. The important role of animal-mediated seed dispersal in disturbed and recovering forests highlights the need to avoid defaunation or promote faunal recovery. The changes in mean seed width suggest larger vertebrates hold especially important functional roles in these human-modified forests. Monitoring fruit and seed traits can provide a valuable indicator of ecosystem condition, emphasizing the importance of developing a comprehensive plant traits database for the Amazon and other biomes

Public Acceptability in the UK and USA of Nudging to Reduce Obesity: The Example of Reducing Sugar-Sweetened Beverages Consumption.

BACKGROUND: "Nudging"-modifying environments to change people's behavior, often without their conscious awareness-can improve health, but public acceptability of nudging is largely unknown. METHODS: We compared acceptability, in the United Kingdom (UK) and the United States of America (USA), of government interventions to reduce consumption of sugar-sweetened beverages. Three nudge interventions were assessed: i. reducing portion Size, ii. changing the Shape of the drink containers, iii. changing their shelf Location; alongside two traditional interventions: iv. Taxation and v. Education. We also tested the hypothesis that describing interventions as working through non-conscious processes decreases their acceptability. Predictors of acceptability, including perceived intervention effectiveness, were also assessed. Participants (n = 1093 UK and n = 1082 USA) received a description of each of the five interventions which varied, by randomisation, in how the interventions were said to affect behaviour: (a) via conscious processes; (b) via non-conscious processes; or (c) no process stated. Acceptability was derived from responses to three items. RESULTS: Levels of acceptability for four of the five interventions did not differ significantly between the UK and US samples; reducing portion size was less accepted by the US sample. Within each country, Education was rated as most acceptable and Taxation the least, with the three nudge-type interventions rated between these. There was no evidence to support the study hypothesis: i.e. stating that interventions worked via non-conscious processes did not decrease their acceptability in either the UK or US samples. Perceived effectiveness was the strongest predictor of acceptability for all interventions across the two samples. CONCLUSION: In conclusion, nudge interventions to reduce consumption of sugar-sweetened beverages seem similarly acceptable in the UK and USA, being more acceptable than taxation, but less acceptable than education. Contrary to prediction, we found no evidence that highlighting the non-conscious processes by which nudge interventions may work decreases their acceptability. However, highlighting the effectiveness of all interventions has the potential to increase their acceptability.The study was funded by the UK Department of Health Policy Research Programme (Policy Research Unit in Behaviour and Health) (Grant ID: PRUN-0409-10109)This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pone.015599

A dimensional summation account of polymorphous category learning

This is the author accepted manuscript. The final version is available from Springer via the DOI in this record.Data and code availaibility: The data and code for all analyses for all experiments are available at the OSF addresses given in each Results section. The stimuli are available at the same locations.Polymorphous concepts are hard to learn, and this is perhaps surprising because they, like many natural concepts, have an overall similarity structure. However, the dimensional summation hypothesis (Milton & Wills, 2004) predicts this difficulty. It also makes a number of other predictions about polymorphous concept formation, which are tested here. In Experiment 1 we confirm the theory’s prediction that polymorphous concept formation should be facilitated by deterministic pretraining on the constituent features of the stimulus. This facilitation is relative to an equivalent amount of training on the polymorphous concept itself. In Experiments 2–4, the dimensional summation account of this single feature pretraining effect is contrasted with some other accounts, including a more general strategic account (Experiment 2), seriality of training and stimulus decomposition accounts (Experiment 3), and the role of errors (Experiment 4). The dimensional summation hypothesis provides the best account of these data. In Experiment 5, a further prediction is confirmed — the single feature pretraining effect is eliminated by a concurrent counting task. The current experiments suggest the hypothesis that natural concepts might be acquired by the deliberate serial summation of evidence. This idea has testable implications for classroom learning.Biotechnology and Biological Sciences Research Council (BBSRC

Oral abstracts 1: SpondyloarthropathiesO1. Detecting axial spondyloarthritis amongst primary care back pain referrals

Background: Inflammatory back pain (IBP) is an early feature of ankylosing spondylitis (AS) and its detection offers the prospect of early diagnosis of AS. However, since back pain is very common but only a very small minority of back pain sufferers have ASpA or AS, screening of back pain sufferers for AS is problematic. In early disease radiographs are often normal so that fulfilment of diagnostic criteria for AS is impossible though a diagnosis of axial SpA can be made if MRI evidence of sacroiliitis is present. This pilot study was designed to indicate whether a cost-effective pick up rate for ASpA/early AS could be achieved by identifying adults with IBP stratified on the basis of age. Methods: Patients aged between 18 and 45 years who were referred to a hospital physiotherapy service with back pain of more than 3 months duration were assessed for IBP. All were asked to complete a questionnaire based on the Berlin IBP criteria. Those who fulfilled IBP criteria were also asked to complete a second short questionnaire enquiring about SpA comorbidities, to have a blood test for HLA-B27 and CRP level and to undergo an MRI scan of the sacroiliac joints. This was a limited scan, using STIR, diffusion-weighted, T1 and T2 sequences of the sacroiliac joints to minimize time in the scanner and cost. The study was funded by a research grant from Abbott Laboratories Ltd. Results: 50 sequential patients agreed to participate in the study and completed the IBP questionnaire. Of these 27 (54%) fulfilled criteria for IBP. Of these, 2 patients reported a history of an SpA comorbidity - 1 psoriasis; 1 ulcerative colitis - and 3 reported a family history of an SpA comorbidity - 2 psoriasis; 1 Crohn's disease. 4 were HLA-B27 positive, though results were not available for 7. Two patients had marginally raised CRP levels (6, 10 -NR ≤ 5). 19 agreed to undergo MRI scanning of the sacroiliac joints and lumbar spine; 4 scans were abnormal, showing evidence of bilateral sacroiliitis on STIR sequences. In all cases the changes met ASAS criteria but were limited. Of these 4 patients 3 were HLA-B27 positive but none gave a personal or family history of an SpA-associated comorbidity and all had normal CRP levels. Conclusions: This was a pilot study yielding only limited conclusions. However, it is clear that: Screening of patients referred for physiotherapy for IBP is straightforward, inexpensive and quick. It appears that IBP is more prevalent in young adults than overall population data suggest so that targeting this population may be efficient. IBP questionnaires could be administered routinely during a physiotherapy assessment. HLA-B27 testing in this group of patients with IBP is a suitable screening tool. The sacroiliac joint changes identified were mild and their prognostic significance is not yet clear so that the value of early screening needs further evaluation. Disclosure statement: C.H. received research funding for this study from Abbott. A.K. received research funding for this study, and speaker and consultancy fees, from Abbott. All other authors have declared no conflicts of interes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Reducing safety-related drug attrition: The use of in vitro pharmacological profiling

In vitro pharmacological profiling is increasingly being used earlier in the drug discovery process to identify undesirable off-target activity profiles that could hinder or halt the development of candidate drugs or even lead to market withdrawal if discovered after a drug is approved. Here, for the first time, the rationale, strategies and methodologies for in vitro pharmacological profiling at four major pharmaceutical companies (AstraZeneca, GlaxoSmithKline, Novartis and Pfizer) are presented and illustrated with examples of their impact on the drug discovery process. We hope that this will enable other companies and academic institutions to benefit from this knowledge and consider joining us in our collaborative knowledge sharing