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

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

Lithic technological responses to Late Pleistocene glacial cycling at Pinnacle Point Site 5-6, South Africa

There are multiple hypotheses for human responses to glacial cycling in the Late Pleistocene, including changes in population size, interconnectedness, and mobility. Lithic technological analysis informs us of human responses to environmental change because lithic assemblage characteristics are a reflection of raw material transport, reduction, and discard behaviors that depend on hunter-gatherer social and economic decisions. Pinnacle Point Site 5-6 (PP5-6), Western Cape, South Africa is an ideal locality for examining the influence of glacial cycling on early modern human behaviors because it preserves a long sequence spanning marine isotope stages (MIS) 5, 4, and 3 and is associated with robust records of paleoenvironmental change. The analysis presented here addresses the question, what, if any, lithic assemblage traits at PP5-6 represent changing behavioral responses to the MIS 5-4-3 interglacial-glacial cycle? It statistically evaluates changes in 93 traits with no a priori assumptions about which traits may significantly associate with MIS. In contrast to other studies that claim that there is little relationship between broad-scale patterns of climate change and lithic technology, we identified the following characteristics that are associated with MIS 4: increased use of quartz, increased evidence for outcrop sources of quartzite and silcrete, increased evidence for earlier stages of reduction in silcrete, evidence for increased flaking efficiency in all raw material types, and changes in tool types and function for silcrete. Based on these results, we suggest that foragers responded to MIS 4 glacial environmental conditions at PP5-6 with increased population or group sizes, 'place provisioning', longer and/or more intense site occupations, and decreased residential mobility. Several other traits, including silcrete frequency, do not exhibit an association with MIS. Backed pieces, once they appear in the PP5-6 record during MIS 4, persist through MIS 3. Changing paleoenvironments explain some, but not all temporal technological variability at PP5-6.Social Science and Humanities Research Council of Canada; NORAM; American-Scandinavian Foundation; Fundacao para a Ciencia e Tecnologia [SFRH/BPD/73598/2010]; IGERT [DGE 0801634]; Hyde Family Foundations; Institute of Human Origins; National Science Foundation [BCS-9912465, BCS-0130713, BCS-0524087, BCS-1138073]; John Templeton Foundation to the Institute of Human Origins at Arizona State Universit

Sea Surface Temperature of the mid-Piacenzian Ocean:A Data-Model Comparison

The mid-Piacenzian climate represents the most geologically recent interval of long-term average warmth relative to the last million years, and shares similarities with the climate projected for the end of the 21st century. As such, it represents a natural experiment from which we can gain insight into potential climate change impacts, enabling more informed policy decisions for mitigation and adaptation. Here, we present the first systematic comparison of Pliocene sea surface temperature (SST) between an ensemble of eight climate model simulations produced as part of PlioMIP (Pliocene Model Intercomparison Project) with the PRISM (Pliocene Research, Interpretation and Synoptic Mapping) Project mean annual SST field. Our results highlight key regional and dynamic situations where there is discord between the palaeoenvironmental reconstruction and the climate model simulations. These differences have led to improved strategies for both experimental design and temporal refinement of the palaeoenvironmental reconstruction