Open access: effective measures to put UK research online under threat?

The universities of the UK should not squander the opportunity to put in place an effective mechanism for making their published research freely available</p

Harnessing the Metric Tide: indicators, infrastructures & priorities for UK responsible research assessment

This review was commissioned by the joint UK higher education (HE) funding bodies as part of the Future Research Assessment Programme (FRAP). It revisits the findings of the 2015 review The Metric Tide to take a fresh look at the use of indicators in research management and assessment.  While this review feeds into the larger FRAP process, the authors have taken full advantage of their independence and sought to stimulate informed and robust discussion about the options and opportunities of future REF exercises. The report should be read in that spirit: as an input to ongoing FRAP deliberations, rather than a reflection of their likely or eventual conclusions.  The report is written in three sections. Section 1 plots the development of the responsible research assessment agenda since 2015 with a focus on the impact of The Metric Tide review and progress against its recommendations. Section 2 revisits the potential use of metrics and indicators in any future REF exercise, and proposes an increased uptake of ‘data for good’. Section 3 considers opportunities to further support the roll-out of responsible research assessment policies and practices across the UK HE sector. Appendices include an overview of progress against the recommendations of The Metric Tide and a literature review.  We make ten recommendations targeted at different actors in the UK research system, summarised as:  1: Put principles into practice.  2: Evaluate with the evaluated.  3: Redefine responsible metrics.  4: Revitalise the UK Forum.  5: Avoid all-metric approaches to REF.  6: Reform the REF over two cycles.  7: Simplify the purposes of REF.  8: Enhance environment statements.  9: Use data for good.  10: Rethink university rankings.</p

Harnessing the Metric Tide: indicators, infrastructures & priorities for UK responsible research assessment

This review was commissioned by the joint UK higher education (HE) funding bodies as part of the Future Research Assessment Programme (FRAP). It revisits the findings of the 2015 review The Metric Tide to take a fresh look at the use of indicators in research management and assessment.  While this review feeds into the larger FRAP process, the authors have taken full advantage of their independence and sought to stimulate informed and robust discussion about the options and opportunities of future REF exercises. The report should be read in that spirit: as an input to ongoing FRAP deliberations, rather than a reflection of their likely or eventual conclusions.  The report is written in three sections. Section 1 plots the development of the responsible research assessment agenda since 2015 with a focus on the impact of The Metric Tide review and progress against its recommendations. Section 2 revisits the potential use of metrics and indicators in any future REF exercise, and proposes an increased uptake of ‘data for good’. Section 3 considers opportunities to further support the roll-out of responsible research assessment policies and practices across the UK HE sector. Appendices include an overview of progress against the recommendations of The Metric Tide and a literature review.  We make ten recommendations targeted at different actors in the UK research system, summarised as:  1: Put principles into practice.  2: Evaluate with the evaluated.  3: Redefine responsible metrics.  4: Revitalise the UK Forum.  5: Avoid all-metric approaches to REF.  6: Reform the REF over two cycles.  7: Simplify the purposes of REF.  8: Enhance environment statements.  9: Use data for good.  10: Rethink university rankings.</p

Variations in the crystal packing of the MNV NS6^pro A and B chains in the asymmetric unit.

<p>(A) Crystal packing of A and B chains of MNV NS6^pro. The A and B chains of one asymmetric unit are shown along with the neighbouring molecules (labelled A' and B') into which they insert their C-termini. (B) This panel shows the same molecules that are depicted in panel A (with the same colouring) but in this case the A and B chains within the asymmetric unit are superposed; this reveals the very different contacts that they make with their closest neighbour in the crystal. (C) Here the A' and B' chains from panel A are now superposed in order to show the similarity of the conformations of the bound C-termini (shown as sticks) from the A and B chains respectively. Colour-coding is the same as panel A.</p

Structural comparison of the MNV NS6 protease with human norovirus NS6^pro and foot-and-mouth disease virus 3C^pro.

<p>(A) Cartoon representation of the MNV NS6^pro structure. The N and C-terminal domains are coloured green and orange respectively. The side-chains of the amino acids that make up the catalytic triad, A139 (mutated from Cys), H30 and D54, are shown as sticks. A disordered loop formed by residues 124–130 (residues 124–131 in chain B) is indicated as a dashed line. The peptide bound to NS6^pro is not shown in this representation. (B) Overlay of HuNV NS6 protease structures from Chiba (PDB-ID: 1WQS), Norwalk (PDB-ID: 2FYQ) and Southampton (PDB-ID: 2IPH) viruses <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038723#pone.0038723-Nakamura1" target="_blank">[19]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038723#pone.0038723-Zeitler1" target="_blank">[22]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038723#pone.0038723-Hussey1" target="_blank">[23]</a>. Excluding the variable C-termini, the root mean square deviations of the backbone atoms of Chiba, Norwalk and Southampton virus NS6^pro from MNV NS6^pro are 0.62, 0.43 and 0.41 respectively. The disordered C-terminus of the Chibavirus protease is shown as a dashed line. (C) Structure of FMDV 3C^pro (PDB-ID: 2J92) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038723#pone.0038723-Sweeney1" target="_blank">[26]</a>, coloured as in panel (A).</p

Cloning and C139A mutagenic primers used in the course of the study.

<p>Restriction sites used in cloning are underlined. Mutations introduced using QuikChange mutagenesis are in boldface.</p

Sequence conservation of polyprotein junction in MNV that are cleaved by NS6^pro.

<p>(A) The five cleavage junctions of MNV CW1 polyprotein (NCBI accession number YP_720001) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038723#pone.0038723-Sosnovtsev1" target="_blank">[14]</a>. (B) Weblogo of polyprotein cleavage junctions cleaved by MNV NS6^pro. This Weblogo was generated using 39 MNV polyprotein sequences and the Weblogo sequence logo generator <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038723#pone.0038723-Crooks1" target="_blank">[44]</a>. The height of the letter in each case is indicative of the degree of conservation. The Genbank accession numbers of the other sequences used to prepare the alignment are ABU55618, ABU55627, ABU55615, ABU55621, ABU55612, ABU55624, AEE10026, ABU55600, AEY83582, AEE10023, ABU55606, AEE10020, ABU55609, AEE10017, ABB02416, AEE10002, ACJ72215, AEE09999, ABU55591, AEE10005, ABU55570, AEE10008, ABU55585, AEE10014, ABU55579, AEE10011, ABU55576, ABU55597, ABU55573, ABU55603, ABU55582, ABU55594, ABU55588, ABU55567, ACS70958, ACJ72218, ABS29272, ABS29274.</p

Comparative analysis of protease-peptide interactions for the P6–P1 residues in MNV and SV NS6^pro and CAV 3C^pro.

<p>The N-terminal and C-terminal β-barrel domains of each protease are coloured green and orange respectively. (A) Binding of residues P5–P1 (C-terminus of NS6^pro), shown as sticks colour-coded by atom type (Carbon – light-blue; Oxygen – red; Nitrogen – blue), within the peptide binding grove of MNV NS6^pro. Selected side-chains from the protease are also shown as sticks. Hydrogen bonds and salt-bridges mentioned in the text are indicated by black dashed lines; all such bonds shown are ≤3.1 Å. (B) Same view as in A but showing the surface of MNV NS6^pro. (C) Binding of residues P5–P1 from a peptide-like inhibitor to SV (a human norovirus) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038723#pone.0038723-Hussey1" target="_blank">[23]</a>. Water molecules involved in the protease-peptide interaction are shown as red spheres. (D) Same view as in B but showing the surface of SV NS6^pro. (E) The refined σ-weighted 2F_o-F_c map electron density (where F_o and F_c are the observed and calculated structure factors respectively) for an A-chain C-terminal peptide, shown at 1.5 σ. (F) The interaction between residues P6–P1 of a peptide ‘product’ and CAV 3C^pro<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038723#pone.0038723-Lu1" target="_blank">[30]</a>.</p

Crystallographic data collection and model refinement statistics for MNV NS6^pro.

1<p>Values for highest resolution shell given in parentheses.</p>2<p>R_merge  = 100 ×Σ_hkl|I_j(hkl) − j(hkl)>|/Σ_hklΣ_jI(hkl), where I_j(hkl) and j(hkl)> are the intensity of measurement j and the mean intensity for the reflection with indices hkl, respectively.</p>3<p>R_work  = 100 ×Σ_hkl||F_obs| − |F_calc||/Σ_hkl|F_obs|.</p>4<p>R_free is the R_model calculated using a randomly selected 5% sample of reflection data that were omitted from the refinement.</p>5<p>RMS, root-mean-square; deviations are from the ideal geometry defined by the Engh and Huber parameters <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038723#pone.0038723-Engh1" target="_blank">[45]</a>.</p

Genetic Engineering of the Heme Pocket in Human Serum Albumin: Modulation of O₂ Binding of Iron Protoporphyrin IX by Variation of Distal Amino Acids

Complexing an iron protoporphyrin IX into a genetically engineered heme pocket of recombinant human serum albumin (rHSA) generates an artificial hemoprotein, which can bind O2 in much the same way as hemoglobin (Hb). We previously demonstrated a pair of mutations that are required to enable the prosthetic heme group to bind O2 reversibly:  (i) Ile-142 → His, which is axially coordinated to the central Fe2+ ion of the heme, and (ii) Tyr-161 → Phe or Leu, which makes the sixth coordinate position available for ligand interactions [I142H/Y161F (HF) or I142H/Y161L (HL)]. Here we describe additional new mutations designed to manipulate the architecture of the heme pocket in rHSA−heme complexes by specifically altering distal amino acids. We show that introduction of a third mutation on the distal side of the heme (at position Leu-185, Leu-182, or Arg-186) can modulate the O2 binding equilibrium. The coordination structures and ligand (O2 and CO) binding properties of nine rHSA(triple mutant)−heme complexes have been physicochemically and kinetically characterized. Several substitutions were severely detrimental to O2 binding:  for example, Gln-185, His-185, and His-182 all generated a weak six-coordinate heme, while the rHSA(HF/R186H)−heme complex possessed a typical bis-histidyl hemochrome that was immediately autoxidized by O2. In marked contrast, HSA(HL/L185N)−heme showed very high O2 binding affinity (P1/2O2 1 Torr, 22 °C), which is 18-fold greater than that of the original double mutant rHSA(HL)−heme and very close to the affinities exhibited by myoglobin and the high-affinity form of Hb. Introduction of Asn at position 185 enhances O2 binding primarily by reducing the O2 dissociation rate constant. Replacement of polar Arg-186 with Leu or Phe increased the hydrophobicity of the distal environment, yielded a complex with reduced O2 binding affinity (P1/2O2 9−10 Torr, 22 °C), which nevertheless is almost the same as that of human red blood cells and therefore better tuned to a role in O2 transport