Chemical generation and modification of peptides containing multiple dehydroalanines

Chemical formation of dehydroalanine has been widely used for the post-translational modification of protein and peptides, however methods to incorporate multiple dehydroalanine residues into a single peptide have not been defined. We report the use of methyl 2,5-dibromovalerate which can be used to cleanly carry out this transformation

The "healthy dose" of nature: A cautionary tale

This is the author accepted manuscript. The final version is available on open access from Wiley via the DOI in this recordGrowing cross‐disciplinary interest in understanding if, how, and why time spent with nature can contribute to human health and well‐being has recently prompted efforts to identify an ideal healthy dose of nature; exposure to a specific type of nature at a specified frequency and duration. These efforts build on longstanding attempts to prescribe nature in some way, most recently in the form of so‐called “green prescriptions.” In this critical discussion paper, we draw on key examples from within the fields of health and cultural geography to encourage deeper and more critical reflection on the value of such reductionist dose‐response frameworks. By foregrounding the relationally emergent qualities of people's dynamic nature encounters, we suggest such efforts may be both illusory and potentially exclusionary for the many individuals and groups whose healthy nature interactions diverge from the statistical average or “normal” way of being. We suggest value in working towards alternative more‐than‐human approaches to health and well‐being, drawing on posthumanist theories of social practice. We present two practice examples—beach‐going and citizen science—to demonstrate how a focus on social practices can better cater for the diverse and dynamic ways in which people come to conceptualise, embody, and interpret nature in their everyday lives. We close by reflecting on the wider societal transformations required to foster greater respect for embodied difference and diversity.Economic and Social Research Council. Grant Number: ES/N015851/

Stakeholder discourse coalitions and polarisation in the hen harrier conservation debate in news media

This is the final version. Available on open access from Wiley via the DOI in this recordData availability statement: All the relevant data are available in the Nexis UK news online database.Conservation conflicts are complex and can be deep-rooted, with stakeholders holding entrenched policy positions. The actors involved producing verbal interconnected interactions that form policy debates. Thus, conservation debates can be viewed as network phenomena with stakeholders forming coalitions in support of, or opposition to, certain policies and practices. We used Discourse Network Analysis of print media to investigate the structure and dynamics of the stakeholder debate around the management of hen harriers Circus cyaneus, a bird of prey at the centre of a long-standing conservation conflict in the United Kingdom. We aimed to determine whether the structure of discourse coalitions changed among the diverse aspects of the debate and whether the polarisation of the debate has changed through time. Our search and selection criteria led to the analysis of 737 statements within 131 newspaper articles published from August 1993 to December 2019. We show that, while the discourse network of the overall debate is quite unstructured, actors formed divergent coalitions when defining the conservation problem and its solutions. In contrast, discourses converged around reactions with positive or negative emotions in relation to events and issues of hen harrier conservation. Polarisation among actors has increased over time and peaked in the second half of the 2010s, concurrent with the release of the species recovery plan. Our study highlights the value of analysing discourse networks in conservation policy debates. Discourse networks reveal which aspects of any conservation problem cause stakeholders to converge or diverge and can identify periods of intensified debate that, ultimately, contribute to informing conflict mitigation and resolution processes. Read the free Plain Language Summary for this article on the Journal blog.University of ExeterNatural Englan

Day occupation is associated with psychopathology for adolescents and young adults with Down syndrome

Background: Young adults with Down syndrome experience increased rates of emotional and behavioural problems compared with the general population. Most adolescents with Down syndrome living in Western Australia participate in sheltered employment as their main day occupation. Relationship between day occupation and changes in behaviour has not been examined. Therefore, the aim of this research was to explore any relationship between post school day occupations and changes in the young person’s behaviour. Methods: The Down syndrome Needs Opinion Wishes database was used for case ascertainment of young adults aged 15 to 32 years with Down syndrome. Families of 118 young people in this population-based database completed questionnaires in 2004, 2009 and 2011. The questionnaires addressed both young person characteristics such as age, gender, presence of impairments, behaviour, functioning in activities of daily living, and family characteristics such as income and family functioning. Post-school day occupations in which the young people were participating included open and sheltered employment, training and day recreation programs. Change in behaviour of young adults who remained in the same post-school day occupation from 2009 to 2011 (n = 103) were examined in a linear regression model adjusting for confounding variables including age, gender, prior functioning and behaviour in 2004 and family income.Results: In comparison to those young adults attending open employment from 2009 to 2011, those attending day recreation programs were reported to experience worsening in behaviour both in the unadjusted (effect size -0.14, 95% CI -0.24, -0.05) and adjusted models (effect size -0.15, 95% CI -0.29, -0.01). Conclusions: We found that the behaviour of those participating in open employment improved compared to those attending other day occupations. Further examination of the direction of this association is required

High-throughput identification of genotype-specific cancer vulnerabilities in mixtures of barcoded tumor cell lines.

Hundreds of genetically characterized cell lines are available for the discovery of genotype-specific cancer vulnerabilities. However, screening large numbers of compounds against large numbers of cell lines is currently impractical, and such experiments are often difficult to control. Here we report a method called PRISM that allows pooled screening of mixtures of cancer cell lines by labeling each cell line with 24-nucleotide barcodes. PRISM revealed the expected patterns of cell killing seen in conventional (unpooled) assays. In a screen of 102 cell lines across 8,400 compounds, PRISM led to the identification of BRD-7880 as a potent and highly specific inhibitor of aurora kinases B and C. Cell line pools also efficiently formed tumors as xenografts, and PRISM recapitulated the expected pattern of erlotinib sensitivity in vivo

eXtraembryonic ENdoderm (XEN) Stem Cells Produce Factors that Activate Heart Formation

Initial specification of cardiomyocytes in the mouse results from interactions between the extraembryonic anterior visceral endoderm (AVE) and the nascent mesoderm. However the mechanism by which AVE activates cardiogenesis is not well understood, and the identity of specific cardiogenic factors in the endoderm remains elusive. Most mammalian studies of the cardiogenic potential of the endoderm have relied on the use of cell lines that are similar to the heart-inducing AVE. These include the embryonal-carcinoma-derived cell lines, END2 and PYS2. The recent development of protocols to isolate eXtraembryonic ENdoderm (XEN) stem cells, representing the extraembryonic endoderm lineage, from blastocyst stage mouse embryos offers new tools for the genetic dissection of cardiogenesis.Here, we demonstrate that XEN cell-conditioned media (CM) enhances cardiogenesis during Embryoid Body (EB) differentiation of mouse embryonic stem (ES) cells in a manner comparable to PYS2-CM and END2-CM. Addition of CM from each of these three cell lines enhanced the percentage of EBs that formed beating areas, but ultimately, only XEN-CM and PYS2-CM increased the total number of cardiomyocytes that formed. Furthermore, our observations revealed that both contact-independent and contact-dependent factors are required to mediate the full cardiogenic potential of the endoderm. Finally, we used gene array comparison to identify factors in these cell lines that could mediate their cardiogenic potential.These studies represent the first step in the use of XEN cells as a molecular genetic tool to study cardiomyocyte differentiation. Not only are XEN cells functionally similar to the heart-inducing AVE, but also can be used for the genetic dissection of the cardiogenic potential of AVE, since they can be isolated from both wild type and mutant blastocysts. These studies further demonstrate the importance of both contact-dependent and contact-independent factors in cardiogenesis and identify potential heart-inducing proteins in the endoderm

Usability of myfood24 Healthcare and Mathematical Diet Optimisation in Clinical Populations: A Pilot Feasibility Randomised Controlled Trial

Monitoring nutritional intake is of clinical value, but few existing tools offer electronic dietary recording, instant nutritional analysis, and a platform connecting healthcare teams with patients that provides timely, personalised support. This feasibility randomised controlled trial tests the usability of ‘myfood24 Healthcare’, a dietary assessment app and healthcare professional website, in two clinical populations. Patients were recruited from a weight management programme (n21) and from a group of gastroenterology surgery outpatients (n = 27). They were randomised into three groups: standard care, myfood24, or myfood24 + diet optimisation (automated suggestions for dietary improvement). The participants were asked to record their diet at least four times over eight weeks. During the study, healthcare professionals viewed recorded dietary information to facilitate discussions about diet and nutritional targets. The participants provided feedback on usability and acceptability. A total of 48 patients were recruited, and 16 were randomised to each of the three groups. Compliance among app users (n = 32) was reasonable, with 25 (78%) using it at least once and 16 (50%) recording intake for four days or more. Among users, the mean (standard deviation) number of days used was 14.0 (17.5), and the median (interquartile range) was six (2.5–17.0) over 2 months. Feedback questionnaires were completed by only 23 of 46 participants (50%). The mean System Usability Score (n = 16) was 59 (95% confidence interval, 48–70). Patient and healthcare professional feedback indicates a need for more user training and the improvement of some key app features such as the food search function. This feasibility study shows that myfood24 Healthcare is acceptable for patients and healthcare professionals. These data will inform app refinements and its application in a larger clinical effectiveness trial

Environmental Factors in the Relapse and Recurrence of Inflammatory Bowel Disease:A Review of the Literature

The causes of relapse in patients with Crohn's disease (CD) and ulcerative colitis (UC) are largely unknown. This paper reviews the epidemiological and clinical data on how medications (non-steroidal anti-inflammatory drugs, estrogens and antibiotics), lifestyle factors (smoking, psychological stress, diet and air pollution) may precipitate clinical relapses and recurrence. Potential biological mechanisms include: increasing thrombotic tendency, imbalances in prostaglandin synthesis, alterations in the composition of gut microbiota, and mucosal damage causing increased permeability

An FDA bioinformatics tool for microbial genomics research on molecular characterization of bacterial foodborne pathogens using microarrays

<p>Abstract</p> <p>Background</p> <p>Advances in microbial genomics and bioinformatics are offering greater insights into the emergence and spread of foodborne pathogens in outbreak scenarios. The Food and Drug Administration (FDA) has developed a genomics tool, ArrayTrack^TM, which provides extensive functionalities to manage, analyze, and interpret genomic data for mammalian species. ArrayTrack^TM has been widely adopted by the research community and used for pharmacogenomics data review in the FDA’s Voluntary Genomics Data Submission program. </p> <p>Results</p> <p>ArrayTrack^TM has been extended to manage and analyze genomics data from bacterial pathogens of human, animal, and food origin. It was populated with bioinformatics data from public databases such as NCBI, Swiss-Prot, KEGG Pathway, and Gene Ontology to facilitate pathogen detection and characterization. ArrayTrack^TM’s data processing and visualization tools were enhanced with analysis capabilities designed specifically for microbial genomics including flag-based hierarchical clustering analysis (HCA), flag concordance heat maps, and mixed scatter plots. These specific functionalities were evaluated on data generated from a custom Affymetrix array (FDA-ECSG) previously developed within the FDA. The FDA-ECSG array represents 32 complete genomes of <it>Escherichia coli</it> and<it> Shigella.</it> The new functions were also used to analyze microarray data focusing on antimicrobial resistance genes from <it>Salmonella</it> isolates in a poultry production environment using a universal antimicrobial resistance microarray developed by the United States Department of Agriculture (USDA).</p> <p>Conclusion</p> <p>The application of ArrayTrack^TM to different microarray platforms demonstrates its utility in microbial genomics research, and thus will improve the capabilities of the FDA to rapidly identify foodborne bacteria and their genetic traits (e.g., antimicrobial resistance, virulence, etc.) during outbreak investigations. ArrayTrack^TM is free to use and available to public, private, and academic researchers at <url>http://www.fda.gov/ArrayTrack</url>. </p