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Snapshots of the reaction coordinate of a thermophilic 2'-deoxyribonucleoside/ribonucleoside transferase
Get PDFFunding: P.T. is funded by IBioIC (IBioIC 2020-2-1), and C.M.C. is funded by the Wellcome Trust (217078/Z/19/Z). C.M.C. and D.H. are funded by research grants from NuCana plc..Nucleosides are ubiquitous to life and are required for the synthesis of DNA, RNA, and other molecules crucial for cell survival. Despite the notoriously difficult organic synthesis of nucleosides, 2′-deoxynucleoside analogues can interfere with natural DNA replication and repair and are successfully employed as anticancer, antiviral, and antimicrobial compounds. Nucleoside 2′-deoxyribosyltransferase (dNDT) enzymes catalyze transglycosylation via a covalent 2′-deoxyribosylated enzyme intermediate with retention of configuration, having applications in the biocatalytic synthesis of 2′-deoxynucleoside analogues in a single step. Here, we characterize the structure and function of a thermophilic dNDT, the protein from Chroococcidiopsis thermalis (CtNDT). We combined enzyme kinetics with structural and biophysical studies to dissect mechanistic features in the reaction coordinate, leading to product formation. Bell-shaped pH-rate profiles demonstrate activity in a broad pH range of 5.5–9.5, with two very distinct pKa values. A pronounced viscosity effect on the turnover rate indicates a diffusional step, likely product (nucleobase1) release, to be rate-limiting. Temperature studies revealed an extremely curved profile, suggesting a large negative activation heat capacity. We trapped a 2′-fluoro-2′-deoxyarabinosyl-enzyme intermediate by mass spectrometry and determined high-resolution structures of the protein in its unliganded, substrate-bound, ribosylated, 2′-difluoro-2′-deoxyribosylated, and in complex with probable transition-state analogues. We reveal key features underlying (2′-deoxy)ribonucleoside selection, as CtNDT can also use ribonucleosides as substrates, albeit with a lower efficiency. Ribonucleosides are the building blocks of RNA and other key intracellular metabolites participating in energy and metabolism, expanding the scope of use of CtNDT in biocatalysis.Peer reviewe
The Gemini Planet Imager Exoplanet Survey : giant planet and brown dwarf demographics from 10 to 100 au
Get PDFWe present a statistical analysis of the first 300 stars observed by the Gemini Planet Imager Exoplanet Survey. This subsample includes six detected planets and three brown dwarfs; from these detections and our contrast curves we infer the underlying distributions of substellar companions with respect to their mass, semimajor axis, and host stellar mass. We uncover a strong correlation between planet occurrence rate and host star mass, with stars M* > 1.5 M⊙ more likely to host planets with masses between 2 and 13MJup and semimajor axes of 3–100 au at 99.92% confidence. We fit a double power-law model in planet mass (m) and semimajor axis (a) for planet populations around high-mass stars (M* > 1.5 M⊙) of the form d2N/(dm da) ∝ mα aβ, finding α = −2.4 ± 0.8 and β = −2.0 ± 0.5, and an integrated occurrence rate of 9+5-4% between 5–13MJup and 10–100 au. A significantly lower occurrence rate is obtained for brown dwarfs around all stars, with 0.8+0.8-0.5% of stars hosting a brown dwarf companion between 13–80MJup and 10–100 au. Brown dwarfs also appear to be distributed differently in mass and semimajor axis compared to giant planets; whereas giant planets follow a bottom-heavy mass distribution and favor smaller semimajor axes, brown dwarfs exhibit just the opposite behaviors. Comparing to studies of short-period giant planets from the radial velocity method, our results are consistent with a peak in occurrence of giant planets between ∼1 and 10 au. We discuss how these trends, including the preference of giant planets for high-mass host stars, point to formation of giant planets by core/pebble accretion, and formation of brown dwarfs by gravitational instability.Peer reviewe
Concluding remarks : methods and the future of Gypsy, Roma and Traveller-related research
No full textHow can the social sciences be an arena where positive social changes are achieved and not just discussed? How can social science help to shape social priorities in the post-pandemic world? These are immediate, practical questions for scholars planning and implementing research projects. Any answer must necessarily revolve around methods, since change starts close at hand, in the immediacy of one’s daily work, and it starts with practice and action, not with theory and argument. By paying close attention to research methods, it is possible to carry out engaged research – research that is relevant, reflexive, responsible and responsive – even in the midst of a global pandemic
A new approach to fuel cell electrodes : lanthanum aluminate yielding fine Pt nanoparticle exsolution for oxygen reduction reaction
Get PDFWe acknowledge support from the Engineering and Physical Sciences Research Council (EPSRC) Critical Mass Grant EP/R023522/1, EPSRC Light element Analysis Facility Grant EP/T019298/1 and the EPRC Strategic Equipment Resource grant EP/R023751/1.Designing an electrocatalyst with low Pt content is an immediate need for essential reactions in low temperature fuel cell systems. In the present work, La0.9925Ba0.0075Al0.995Pt0.005O3 is aimed at using with low (only 0.5%) Pt doping as an electrocatalyst for oxygen reduction reaction (ORR). The low doping level renders exsolution of 1–2 nm nanoparticles with uniform dispersion upon reduction in H2/N2 at low temperatures. Pt exsolved perovskite oxides deliver significantly enhanced catalytic activity for ORR and improved stability in alkaline media. This study demonstrates that LaAlO3 with low noble metal content holds immense potential as an electrocatalyst in real fuel cell systems.Peer reviewe
Virtuous leadership : ambiguities, challenges, and precedents
Get PDFVirtuous leadership is the focus of a growing body of academic literature but is little discussed by contemporary philosophers. Current treatments tend to over-generalisation: assimilating diverse features to a few broad categories and applying simplified ethical theories. This essay argues that virtue and character education need to be keyed to specific activities, that “virtuous leadership” is in danger of being confused with extrinsic activism, and that the history of ethics in health care provides an instructive example of thinking ethically about practice. Questions commonly posed in the literature—What specific virtues are required for leadership? How may these be formed?—are unduly simple and often rest on faulty assumptions about the nature of leadership and of the structure of virtuous action. Philosophers engaged in advising professionals about the virtues of leadership would do well to consider how the relevant points apply to their own practice.Peer reviewe
Theory-driven perspectives on generative artificial intelligence in business and management
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The state of FaaS : an analysis of public Functions-as-a-Service providers
Get PDFServerless computing is a growing and maturing field that is the focus of much research, industry interest and adoption. Previous works exploring Functions-as-a-Service providers have focused primarily on the most well known providers AWS Lambda, Google Cloud Functions and Microsoft Azure Functions without exploring other providers in similar detail. In this work, we conduct the first detailed review of ten currently publicly available FaaS platforms exploring everything from their history, to their features and pricing to where they sit within the overall public FaaS landscape, before making a number of observations as to the state of the FaaS
A perspective on non-local electronic transport in metals : viscous, ballistic, and beyond
No full textFunding: Open access funding enabled and organized by Projekt DEAL.Ohm's law for electrical conduction in metals is one of the first concepts taught in any physics curriculum. It is perfectly adequate in almost all practical circumstances, but breaks down in some special, interesting cases. To observe such breakdowns, one requires extremely pure materials, which are rare and often difficult to produce. Excitingly, forefront materials research is leading to the discovery of more and more examples in which one can break the ‘purity barrier’ and explore non-Ohmic transport. The rapid development of the field is seeing equally rapid developments in the understanding of exotic non-Ohmic regimes, but this is not always a smooth progression. New layers of insight often involve reversing what have previously been regarded as established facts. Indeed, the interpretations given of experimental data in many papers published less than a decade ago would (or should!) be different today. The goal of this article is to give an entry-level guide to some of the pertinent issues that have emerged from this intense decade of research, attempting to keep the style of the presentation as informal and non-mathematical as is practical. Although source literature will be cited, no attempt will be made at comprehensive citation, so the paper should not be regarded as a review. Rather, an effort will be made to identify and explain some issues that the authors believe are important but not sufficiently emphasized in the literature to date. In that sense the paper should be regarded as a kind of opinion piece, with, hopefully, some didactic value to a reader with a solid grounding in traditional condensed matter physics.Peer reviewe
Teaching eighteenth-century classical reception through university museum collections
No full textThis chapter focuses on the process, challenges and benefits of using phys- ical materials from museum collections of the University of St Andrews to teach eighteenth- century art and its engagement with archaeology and classical culture. The discussion will present the process of design- ing the module curriculum, the challenges it posed and the responses of the students; it will focus on the different ways museum objects were studied, displayed and utilised in order to enhance learning. This case study is a reflection on the practice of object-based learning (OBL) using museum and special collection objects to promote student engagement and understanding of concepts and ideas around classical reception. The discussion will also address the difficulties and possibilities of an object- based approach in the light of the recent COVID-19 pandemic, considering the use of digital objects through newly developed digital tools
The inspired intellect : Neoplatonism and its reception in Robert Graves, Jorge Luis Borges, Suzanne Lilar, and Kathleen Raine
No full textThis thesis argues that Neoplatonic philosophy made a significant contribution to the understanding and expression of inspiration in twentieth-century literary culture. In emphasising the importance of a text- based body of philosophical knowledge as well as its extra-textual, ritual aspects, Neoplatonism provided writers with a method of fostering inspiration that highlighted lived, bodily experience in addition to literary and cultural influences. Expounded by thinkers like Plotinus (ca.205-ca.270 CE), Porphyry (ca.234–ca.305 CE), Iamblichus (ca.240–ca.325 CE), and Proclus (ca.410/12-485 CE), Neoplatonism depended on discursive and non-discursive philosophical techniques that sought to develop a person’s capacity to contemplate intelligible reality and to achieve divine union with the transcendent first principle, the One. Within this metaphysical framework, the works of certain poets were viewed as resonating on a higher, noetic level. Although largely dismissed within mainstream academia, Neoplatonism nonetheless offered twentieth-century writers a way of cultivating an intuitive intellect that combined disciplined rationality with the rush of inspiration.
To demonstrate this, I focus on four twentieth-century writers: Robert Graves (1895-1985), Jorge Luis Borges (1899-1986), Suzanne Lilar (1901-1992), and Kathleen Raine (1908-2003). The analysis of Borges opens up South American receptions of Neoplatonism, while the examination of Lilar and Raine shifts attention to twentieth-century female writers, both of which are overlooked areas of research. These writers used Neoplatonic ideas to help construct their own literary identities and to add metaphysical and symbolic depth to their work. Neoplatonism offered a compelling way of articulating supra-rational experiences of inspiration amid the challenges and possibilities raised by both literary modernism and the social, political, cultural, scientific, and technological changes of the twentieth century. Their reading of Neoplatonism emphasised the “receptivity” of the reader and acknowledged how different responses (emotional, psychological, cognitive, physical) to an ancient text could alter one’s overall understanding of it. This thesis therefore shows how reception studies may be enriched through consideration of a fuller spectrum of readers’ responses. It also foregrounds the ability of writers outside the academy to make visible important and otherwise neglected aspects of literary and philosophical history."This work was generously supported by the Scottish Graduate School for Arts & Humanities Doctoral Training Partnership, funded by the Arts & Humanities Research Council. Special thanks go to the SGSAH team for creating such a supportive, inventive organisation. This work was also kindly supported by an annual research allowance from the University of St Andrews (School of Classics)."--Fundin
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