Interrogating fragments using a protein thermal shift assay

Protein thermal shift is a relatively rapid and inexpensive technique for the identification of low molecular weight compound interactions with protein targets. An increase in the melting temperature of the target protein in the presence of a test ligand is indicative of a promising ligand-protein interaction. Due to its simplicity, protein thermal shift is an attractive method for screening libraries and validating hits in drug discovery programs. The methodology has been used successfully in high throughput screens of small molecule libraries, and its application has been extended to report on protein-drug-like-fragment interactions. Here, we review how protein thermal shift has been employed recently in fragment-based drug discovery (FBDD) efforts, and highlight its application to protein-protein interaction targets. Multiple validation of fragment hits by independent means is paramount to ensure efficient and economical progress in a FBDD campaign. We discuss the applicability of thermal shift assays in this light, and discuss more generally what one does when orthogonal approaches disagree

Backbone and side chain H-1, N-15 and C-13 assignments for the oxidised and reduced forms of the oxidoreductase protein DsbA from Staphylococcus aureus

The function and dynamics of the thiol-disulfide oxidoreductase DsbA in the low-GC gram positive bacterium, Staphylococcus aureus, are yet to be elucidated. Here we report 13C, 15N and 1H assignments for the oxidised and reduced forms of SaDsbA as a prelude to further studies on the enzyme

The Robertson v. Princeton Case: Too Important to Be Left to the Lawyers

Offers comments from eleven contributors on the Robertson family's donor rights suit against the Woodrow Wilson School of Public and International Affairs for violation of donor intent. Explores its effects on and implications for the nonprofit sector

Influence of positional correlations on the propagation of waves in a complex medium with polydisperse resonant scatterers

We present experimental results on a model system for studying wave propagation in a complex medium exhibiting low frequency resonances. These experiments enable us to investigate a fundamental question that is relevant for many materials, such as metamaterials, where low-frequency scattering resonances strongly influence the effective medium properties. This question concerns the effect of correlations in the positions of the scatterers on the coupling between their resonances, and hence on wave transport through the medium. To examine this question experimentally, we measure the effective medium wave number of acoustic waves in a sample made of bubbles embedded in an elastic matrix over a frequency range that includes the resonance frequency of the bubbles. The effective medium is highly dispersive, showing peaks in the attenuation and the phase velocity as functions of the frequency, which cannot be accurately described using the Independent Scattering Approximation (ISA). This discrepancy may be explained by the effects of the positional correlations of the scatterers, which we show to be dependent on the size of the scatterers. We propose a self-consistent approach for taking this "polydisperse correlation" into account and show that our model better describes the experimental results than the ISA

Counting lattice points and o-minimal structures

Let $\Lambda$ be a lattice in $\R^n$, and let $Z\subseteq \R^{m+n}$ be a definable family in an o-minimal structure over $\R$. We give sharp estimates for the number of lattice points in the fibers $Z_T={x\in \R^n: (T,x)\in Z}$. Along the way we show that for any subspace $\Sigma\subseteq\R^n$ of dimension $j>0$ the $j$-volume of the orthogonal projection of $Z_T$ to $\Sigma$ is, up to a constant depending only on the family $Z$, bounded by the maximal $j$-dimensional volume of the orthogonal projections to the $j$-dimensional coordinate subspaces.Comment: Revised versio

Some Definability Results in Abstract Kummer Theory

Let $S$ be a semiabelian variety over an algebraically closed field, and let $X$ be an irreducible subvariety not contained in a coset of a proper algebraic subgroup of $S$. We show that the number of irreducible components of $[n]^{-1}(X)$ is bounded uniformly in $n$, and moreover that the bound is uniform in families $X_t$. We prove this by purely Galois-theoretic methods. This proof applies in the more general context of divisible abelian groups of finite Morley rank. In this latter context, we deduce a definability result under the assumption of the Definable Multiplicity Property (DMP). We give sufficient conditions for finite Morley rank groups to have the DMP, and hence give examples where our definability result holds.Comment: 21 pages; minor notational fixe

Innovating Pedagogy 2017: Exploring new forms of teaching, learning and assessment, to guide educators and policy makers. Open University Innovation Report 6

This series of reports explores new forms of teaching, learning and assessment for an interactive world, to guide teachers and policy makers in productive innovation. This sixth report proposes ten innovations that are already in currency but have not yet had a profound influence on education. To produce it, a group of academics at the Institute of Educational Technology in The Open University collaborated with researchers from the Learning In a NetworKed Society (LINKS) Israeli Center of Research Excellence (I-CORE). Themes: • Big-data inquiry: thinking with data • Learners making science • Navigating post-truth societies • Immersive learning • Learning with internal values • Student-led analytics • Intergroup empathy • Humanistic knowledge-building communities • Open Textbooks • Spaced Learnin

Births and their outcomes by time, day and year: a retrospective birth cohort data linkage study

Background Studies of daily variations in the numbers of births in England and Wales since the 1970s have found a pronounced weekly cycle, with numbers of daily births being highest from Tuesdays to Fridays and lowest at weekends and on public holidays. Mortality appeared to be higher at weekends. As time of birth was not included in national data systems until 2005, there have been no previous analyses by time of day. Objectives To link data from birth registration and birth notification to data about care during birth and any subsequent hospital admissions and to quality assure the linkage. To use the linked data to analyse births and their outcomes by time of day, day of the week and year of birth. Design A retrospective birth cohort analysis of linked routine data. Setting England and Wales. Outcome measures Mortality of babies and mothers, and morbidity recorded at birth and any subsequent hospital admission. Population and data sources Birth registration and notification records of 7,013,804 births in 2005–14, already linked to subsequent death registration records for babies, children and women who died within 1 year of giving birth, were provided by the Office for National Statistics. Stillbirths and neonatal deaths data from confidential enquiries for 2005–9 were linked to the registration records. Data for England were linked to Hospital Episode Statistics (HES) and data for Wales were linked to the Patient Episode Database for Wales and the National Community Child Health Database. Results Cross-sectional analysis of all births in England and Wales showed a regular weekly cycle. Numbers of births each day increased from Mondays to Fridays. Numbers were lowest at weekends and on public holidays. Overall, numbers of births peaked between 09.00 and 12.00, followed by a much smaller peak in the early afternoon and a decrease after 17.00. Numbers then increased from 20.00, peaking at around 03.00–05.00, before falling again after 06.00. Singleton births after spontaneous onset and birth, including births in freestanding midwifery units and at home, were most likely to occur between midnight and 06.00, peaking at 04.00–06.00. Elective caesarean births were concentrated in weekday mornings. Births after induced labours were more likely to occur at hours around midnight on Tuesdays to Saturdays, irrespective of the mode of birth. Limitations The project was delayed by data access and information technology infrastructure problems. Data from confidential enquiries were available only for 2005–9 and some HES variables were incomplete. There was insufficient time to analyse the mortality and morbidity outcomes. Conclusions The timing of birth varies by place of birth, onset of labour and mode of birth. These patterns have implications for midwifery and medical staffing. Future work An application has now been submitted for funding to analyse the mortality outcomes and further funding will be sought to undertake the other outstanding analyses. Funding This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 7, No. 18. See the NIHR Journals Library website for further project information

Why Should Ecosystem Services Be Governed to Support Poverty Alleviation? Philosophical Perspectives on Positions in the Empirical Literature

In light of trade-offs related to the allocation of ecosystem services we investigate the prevalent norms that are drawn upon to justify why ecosystem governance should prioritise poverty alleviation. We are specifically concerned with poverty alleviation because we consider this an urgent problem of justice. We review empirical literature on social trade-offs in ecosystem services governance in order to identify the prevalent conceptions of justice that inform scholarly assessments of current practice. We find that empirical studies do present specific notions of justice as desirable benchmarks for ecosystem services governance but that they rarely attempt to spell out the precise meaning of these notions or what makes them desirable. For those notions of justice that we identify in this literature - sufficientarianism, egalitarianism and participatory approaches - we draw on philosophical justice literature in order to better articulate the normative arguments that could support them and to be more precise about the kind of actions and expectations that they invoke. Moreover, we point to some striking normative silences in the ecosystem services literature. We conclude that the ecosystem services justice discourse would benefit from more conceptual clarity and a broader examination of different aspects of justice