High Angular Resolution Stellar Imaging with Occultations from the Cassini Spacecraft II: Kronocyclic Tomography

We present an advance in the use of Cassini observations of stellar occultations by the rings of Saturn for stellar studies. Stewart et al. (2013) demonstrated the potential use of such observations for measuring stellar angular diameters. Here, we use these same observations, and tomographic imaging reconstruction techniques, to produce two dimensional images of complex stellar systems. We detail the determination of the basic observational reference frame. A technique for recovering model-independent brightness profiles for data from each occulting edge is discussed, along with the tomographic combination of these profiles to build an image of the source star. Finally we demonstrate the technique with recovered images of the {\alpha} Centauri binary system and the circumstellar environment of the evolved late-type giant star, Mira.Comment: 8 pages, 8 figures, Accepted by MNRA

Gut microbiota modulation of chemotherapy efficacy and toxicity

Evidence is growing that the gut microbiota modulates the host response to chemotherapeutic drugs, with three main clinical outcomes: facilitation of drug efficacy; abrogation and compromise of anticancer effects; and mediation of toxicity. The implication is that gut microbiota are critical to the development of personalized cancer treatment strategies and, therefore, a greater insight into prokaryotic co-metabolism of chemotherapeutic drugs is now required. This thinking is based on evidence from human, animal and in vitro studies that gut bacteria are intimately linked to the pharmacological effects of chemotherapies (5-fluorouracil, cyclophosphamide, irinotecan, oxaliplatin, gemcitabine, methotrexate) and novel targeted immunotherapies such as anti-PD-L1 and anti-CLTA-4 therapies. The gut microbiota modulate these agents through key mechanisms, structured as the 'TIMER' mechanistic framework: Translocation, Immunomodulation, Metabolism, Enzymatic degradation, and Reduced diversity and ecological variation. The gut microbiota can now, therefore, be targeted to improve efficacy and reduce the toxicity of current chemotherapy agents. In this Review, we outline the implications of pharmacomicrobiomics in cancer therapeutics and define how the microbiota might be modified in clinical practice to improve efficacy and reduce the toxic burden of these compounds

Synaptotagmin 1 oligomers clamp and regulate different modes of neurotransmitter release

Release of neurotransmitters relies on submillisecond coupling of synaptic vesicle fusion to the triggering signal: AP-evoked presynaptic Ca2+ influx. The key player that controls exocytosis of the synaptic vesicle is the Ca2+ sensor synaptotagmin 1 (Syt1). While the Ca2+ activation of Syt1 has been extensively characterized, how Syt1 reversibly clamps vesicular fusion remains enigmatic. Here, using a targeted mutation combined with fluorescence imaging and electrophysiology, we show that the structural feature of Syt1 to self-oligomerize provides the molecular basis for clamping of spontaneous and asynchronous release but is not required for triggering of synchronous release. Our findings propose a mechanistic model that explains how Syt1 oligomers regulate different modes of transmitter release in neuronal synapses

The diagnostic accuracy of a single CEA blood test in detecting colorectal cancer recurrence: Results from the FACS trial

Objective: To evaluate the diagnostic accuracy of a single CEA (carcinoembryonic antigen) blood test in detecting colorectal cancer recurrence. Background: Patients who have undergone curative resection for primary colorectal cancer are typically followed up with scheduled CEA testing for 5 years. Decisions to investigate further (usually by CT imaging) are based on single test results, reflecting international guidelines. Methods: A secondary analysis was undertaken of data from the FACS trial (two arms included CEA testing). The composite reference standard applied included CT-CAP imaging, clinical assessment and colonoscopy. Accuracy in detecting recurrence was evaluated in terms of sensitivity, specificity, likelihood ratios, predictive values, time-dependent area under the ROC curves, and operational performance when used prospectively in clinical practice are reported. Results: Of 582 patients, 104 (17.9%) developed recurrence during the 5 year follow-up period. Applying the recommended threshold of 5µg/L achieves at best 50.0% sensitivity (95% CI: 40.1-59.9%); in prospective use in clinical practice it would lead to 56 missed recurrences (53.8%; 95% CI: 44.2-64.4%) and 89 false alarms (56.7% of 157 patients referred for investigation). Applying a lower threshold of 2.5µg/L would reduce the number of missed recurrences to 36.5% (95% CI: 26.5-46.5%) but would increase the false alarms to 84.2% (924/1097 referred). Some patients are more prone to false alarms than others – at the 5µg/L threshold, the 89 episodes of unnecessary investigation were clustered in 29 individuals. Conclusion: Our results demonstrated very low sensitivity for CEA, bringing to question whether it could ever be used as an independent triage test. It is not feasible to improve the diagnostic performance of a single test result by reducing the recommended action threshold because of the workload and false alarms generated. Current national and international guidelines merit re-evaluation and options to improve performance, such as making clinical decisions on the basis of CEA trend, should be further assessed

Conceptual frameworks linking agriculture and food security

Many conceptual frameworks have been developed to facilitate understanding and analysis of the linkages between agriculture and food security. Despite having usefully guided analysis and investment, these frameworks exhibit wide diversity in perspectives, assumptions and application. This Review Article examines this diversity, providing an approach to assess frameworks and suggesting improvements in the way they are specified and applied. Using criteria-based systems modelling conventions, we evaluate 36 frameworks. We find that many frameworks are developed for the purpose of illustration rather than analysis and do not clearly indicate causal relationships, tending to ignore the dynamic (stability) dimensions of agriculture and food security and lacking clear intervention points for improving food security through agriculture. By applying system modelling conventions to a widely used framework, we illustrate how such conventions can enhance the usefulness of a framework for overall illustration purposes, delineate hypotheses on agriculture–food security links and examine potential impacts of interventions.acceptedVersio

Outcome of Diagnostic Tests Using Samples from Patients with Culture-Proven Human Monocytic Ehrlichiosis: Implications for Surveillance

We describe the concordance among results from various laboratory tests using samples derived from nine culture-proven cases of human monocytic ehrlichiosis (HME) caused by Ehrlichia chaffeensis. A class-specific indirect immunofluorescence assay for immunoglobulin M (IgM) and IgG, using E. chaffeensis antigen, identified 44 and 33% of the isolation-confirmed HME patients on the basis of samples obtained at initial clinical presentation, respectively; detection of morulae in blood smears was similarly insensitive (22% positive). PCR amplifications of ehrlichial DNA targeting the 16S rRNA gene, the variable-length PCR target gene, and the groESL operon were positive for whole blood specimens obtained from all patients at initial presentation. As most case definitions of HME require a serologic response with compatible illness for a categorization of even probable disease, PCR would have been required to confirm the diagnosis of HME in all nine of these patients without the submission of a convalescent-phase serum sample. These data suggest that many, if not most, cases of HME in patients who present early in the course of the disease may be missed and underscore the limitations of serologically based surveillance systems

A comparison of collision cross section values obtained via travelling wave ion mobility-mass spectrometry and ultra high performance liquid chromatography-ion mobility-mass spectrometry : application to the characterisation of metabolites in rat urine

A comprehensive Collision Cross Section (CCS) library was obtained via Travelling Wave Ion Guide mobility measurements through direct infusion (DI). The library consists of CCS and Mass Spectral (MS) data in negative and positive ElectroSpray Ionisation (ESI) mode for 463 and 479 endogenous metabolites, respectively. For both ionisation modes combined, TWCCSN2 data were obtained for 542 non-redundant metabolites. These data were acquired on two different ion mobility enabled orthogonal acceleration QToF MS systems in two different laboratories, with the majority of the resulting TWCCSN2 values (from detected compounds) found to be within 1% of one another. Validation of these results against two independent, external TWCCSN2 data sources and predicted TWCCSN2 values indicated to be within 1-2% of these other values. The same metabolites were then analysed using a rapid reversed-phase ultra (high) performance liquid chromatographic (U(H)PLC) separation combined with IM and MS (IM-MS) thus providing retention time (tr), m/z and TWCCSN2 values (with the latter compared with the DI-IM-MS data). Analytes for which TWCCSN2 values were obtained by U(H)PLC-IM-MS showed good agreement with the results obtained from DI-IM-MS. The repeatability of the TWCCSN2 values obtained for these metabolites on the different ion mobility QToF systems, using either DI or LC, encouraged the further evaluation of the U(H)PLC-IM-MS approach via the analysis of samples of rat urine, from control and methotrexate-treated animals, in order to assess the potential of the approach for metabolite identification and profiling in metabolic phenotyping studies. Based on the database derived from the standards 63 metabolites were identified in rat urine, using positive ESI, based on the combination of tr, TWCCSN2 and MS data.</p