Book reviews

Teaching/Communication/Extension/Profession,

Speleothem evidence for C3 dominated vegetation during the Late Miocene (Messinian) of South Africa

During the Late Miocene, Africa experienced a number of ecological transitions including the spread of C4 grasslands, the expansion of the Sahara Desert, the Messinian Salinity Crisis and a number of mammalian migrations and expansions, including the origin of the hominin clade. A detailed understanding of the relationship between environmental change and hominin evolution is hampered by the paucity of data available from terrestrial localities, especially in southern Africa. Here, we present a stable isotope and trace element record from a speleothem from the South African cave site of Hoogland. Uranium-lead dating and magnetostratigraphy places the speleothem within the Messinian Age (7.25–5.33 Ma) of the Late Miocene, making it the oldest known cave deposit from the region near the UNESCO Fossil Hominids of South Africa World Heritage Site (locally known as the “Cradle of Humankind”). Low carbon isotope values indicate a predominantly C3 vegetation in the vicinity of the cave throughout the period of speleothem growth. It is not possible to determine if this represents a C3 grassland or a C3 woodland, but it is clear that an equivalent C3-rich environment has yet to be found during the Messinian of east Africa. We conclude that the C4 grass expansion occurred millions of years later in South Africa than it did in eastern Africa, and that this vegetation shift should be considered when comparing African vegetation change with the late Miocene hominin fossil record

Submesoscale Rossby waves on the Antarctic circumpolar current.

The eastward-flowing Antarctic circumpolar current (ACC) plays a central role in the global ocean overturning circulation and facilitates the exchange of water between the ocean surface and interior. Submesoscale eddies and fronts with scales between 1 and 10 km are regularly observed in the upper ocean and are associated with strong vertical circulations and enhanced stratification. Despite their importance in other locations, comparatively little is known about submesoscales in the Southern Ocean. We present results from new observations, models, and theories showing that submesoscales are qualitatively changed by the strong jet associated with the ACC in the Scotia Sea, east of Drake Passage. Growing submesoscale disturbances develop along a dense filament and are transformed into submesoscale Rossby waves, which propagate upstream relative to the eastward jet. Unlike their counterparts in slower currents, the submesoscale Rossby waves do not destroy the underlying frontal structure. The development of submesoscale instabilities leads to strong net subduction of water associated with a dense outcropping filament, and later, the submesoscale Rossby waves are associated with intense vertical circulations

Minimum Information about a Neuroscience Investigation (MINI) Electrophysiology

This module represents the formalized opinion of the authors and the CARMEN consortium, which identifies the minimum information required to report the use of electrophysiology in a neuroscience study, for submission to the CARMEN system (www.carmen.org.uk).
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Pre-trial inter-laboratory analytical validation of the FOCUS4 personalised therapy trial.

INTRODUCTION: Molecular characterisation of tumours is increasing personalisation of cancer therapy, tailored to an individual and their cancer. FOCUS4 is a molecularly stratified clinical trial for patients with advanced colorectal cancer. During an initial 16-week period of standard first-line chemotherapy, tumour tissue will undergo several molecular assays, with the results used for cohort allocation, then randomisation. Laboratories in Leeds and Cardiff will perform the molecular testing. The results of a rigorous pre-trial inter-laboratory analytical validation are presented and discussed. METHODS: Wales Cancer Bank supplied FFPE tumour blocks from 97 mCRC patients with consent for use in further research. Both laboratories processed each sample according to an agreed definitive FOCUS4 laboratory protocol, reporting results directly to the MRC Trial Management Group for independent cross-referencing. RESULTS: Pyrosequencing analysis of mutation status at KRAS codons12/13/61/146, NRAS codons12/13/61, BRAF codon600 and PIK3CA codons542/545/546/1047, generated highly concordant results. Two samples gave discrepant results; in one a PIK3CA mutation was detected only in Leeds, and in the other, a PIK3CA mutation was only detected in Cardiff. pTEN and mismatch repair (MMR) protein expression was assessed by immunohistochemistry (IHC) resulting in 6/97 discordant results for pTEN and 5/388 for MMR, resolved upon joint review. Tumour heterogeneity was likely responsible for pyrosequencing discrepancies. The presence of signet-ring cells, necrosis, mucin, edge-effects and over-counterstaining influenced IHC discrepancies. CONCLUSIONS: Pre-trial assay analytical validation is essential to ensure appropriate selection of patients for targeted therapies. This is feasible for both mutation testing and immunohistochemical assays and must be built into the workup of such trials. TRIAL REGISTRATION NUMBER: ISRCTN90061564

Search for the Migdal effect in liquid xenon with keV-level nuclear recoils

The Migdal effect predicts that a nuclear recoil interaction can be accompanied by atomic ionization, allowing many dark matter direct detection experiments to gain sensitivity to sub-GeV masses. We report the first direct search for the Migdal effect for M- and L-shell electrons in liquid xenon using 7.0$\pm$1.6 keV nuclear recoils produced by tagged neutron scatters. Despite an observed background rate lower than that of expected signals in the region of interest, we do not observe a signal consistent with predictions. We discuss possible explanations, including inaccurate predictions for either the Migdal rate or the signal response in liquid xenon. We comment on the implications for direct dark-matter searches and future Migdal characterization efforts.Comment: 8 pages, 4 figure

A.S.P.E.N. Parenteral Nutrition Safety Consensus Recommendations

Parenteral nutrition (PN) serves as an important therapeutic modality that is used in adults, children, and infants for a variety of indications. The appropriate use of this complex therapy aims to maximize clinical benefit while minimizing the potential risks for adverse events. Complications can occur as a result of the therapy and as the result of the PN process. These consensus recommendations are based on practices that are generally accepted to minimize errors with PN therapy, categorized in the areas of PN prescribing, order review and verification, compounding, and administration. These recommendations should be used in conjunction with other A.S.P.E.N. publications, and researchers should consider studying the questions brought forth in this document

REFERQUAL: A pilot study of a new service quality assessment instrument in the GP Exercise Referral scheme setting

Background The development of an instrument accurately assessing service quality in the GP Exercise Referral Scheme (ERS) industry could potentially inform scheme organisers of the factors that affect adherence rates leading to the implementation of strategic interventions aimed at reducing client drop-out. Methods A modified version of the SERVQUAL instrument was designed for use in the ERS setting and subsequently piloted amongst 27 ERS clients. Results Test re-test correlations were calculated via Pearson's 'r' or Spearman's 'rho', depending on whether the variables were Normally Distributed, to show a significant (mean r = 0.957, SD = 0.02, p < 0.05; mean rho = 0.934, SD = 0.03, p < 0.05) relationship between all items within the questionnaire. In addition, satisfactory internal consistency was demonstrated via Cronbach's 'α'. Furthermore, clients responded favourably towards the usability, wording and applicability of the instrument's items. Conclusion REFERQUAL is considered to represent promise as a suitable tool for future evaluation of service quality within the ERS community. Future research should further assess the validity and reliability of this instrument through the use of a confirmatory factor analysis to scrutinise the proposed dimensional structure

Glycan shifting on hepatitis C virus (HCV) E2 glycoprotein is a mechanism for escape from broadly neutralizing antibodies

Hepatitis C virus (HCV) infection is a major cause of liver disease and hepatocellular carcinoma. Glycan shielding has been proposed to be a mechanism by which HCV masks broadly neutralizing epitopes on its viral glycoproteins. However, the role of altered glycosylation in HCV resistance to broadly neutralizing antibodies is not fully understood. Here, we have generated potent HCV neutralizing antibodies hu5B3.v3 and MRCT10.v362 that, similar to the previously described AP33 and HCV1, bind to a highly conserved linear epitope on E2. We utilize a combination of in vitro resistance selections using the cell culture infectious HCV and structural analyses to identify mechanisms of HCV resistance to hu5B3.v3 and MRCT10.v362. Ultra deep sequencing from in vitro HCV resistance selection studies identified resistance mutations at asparagine N417 (N417S, N417T and N417G) as early as 5 days post treatment. Comparison of the glycosylation status of soluble versions of the E2 glycoprotein containing the respective resistance mutations revealed a glycosylation shift from N417 to N415 in the N417S and N417T E2 proteins. The N417G E2 variant was glycosylated neither at residue 415 nor at residue 417 and remained sensitive to MRCT10.v362. Structural analyses of the E2 epitope bound to hu5B3.v3 Fab and MRCT10.v362 Fab using X-ray crystallography confirmed that residue N415 is buried within the antibody–peptide interface. Thus, in addition to previously described mutations at N415 that abrogate the β-hairpin structure of this E2 linear epitope, we identify a second escape mechanism, termed glycan shifting, that decreases the efficacy of broadly neutralizing HCV antibodies