Stratigraphy and Chronology of Karst Features on Rodriguez Island, Southwestern Indian Ocean

This publication has been made available with the permission of the National Speleological Society (www.caves.org). The attached file is the published version of the article

The 18 kDa translocator protein, microglia and neuroinflammation

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is expressed in the injured brain. It has become known as an imaging marker of “neuroinflammation” indicating active disease, and is best interpreted as a nondiagnostic biomarker and disease staging tool that refers to histopathology rather than disease etiology. The therapeutic potential of TSPO as a drug target is mostly based on the understanding that it is an outer mitochondrial membrane protein required for the translocation of cholesterol, which thus regulates the rate of steroid synthesis. This pivotal role together with the evolutionary conservation of TSPO has underpinned the belief that any loss or mutation of TSPO should be associated with significant physiological deficits or be outright incompatible with life. However, against prediction, full Tspo knockout mice are viable and across their lifespan do not show the phenotype expected if cholesterol transport and steroid synthesis were significantly impaired. Thus, the “translocation” function of TSPO remains to be better substantiated. Here, we discuss the literature before and after the introduction of the new nomenclature for TSPO and review some of the newer findings. In light of the controversy surrounding the function of TSPO, we emphasize the continued importance of identifying compounds with confirmed selectivity and suggest that TSPO expression is analyzed within specific disease contexts rather than merely equated with the reified concept of “neuroinflammation.” © 2014 The Authors© 2014 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

A randomized control trial of intensive aphasia therapy after acute stroke: The Very Early Rehabilitation for SpEech (VERSE) study.

BACKGROUND:Effectiveness of early intensive aphasia rehabilitation after stroke is unknown. The Very Early Rehabilitation for SpEech trial (VERSE) aimed to determine whether intensive aphasia therapy, beginning within 14 days after stroke, improved communication recovery compared to usual care. METHODS:Prospective, randomized, single-blinded trial conducted at 17 acute-care hospitals across Australia/New Zealand from 2014 to 2018. Participants with aphasia following acute stroke were randomized to receive usual care (direct usual care aphasia therapy), or one of two higher intensity regimens (20 sessions of either non-prescribed (usual care-plus or prescribed (VERSE) direct aphasia therapy). The primary outcome was improvement of communication on the Western Aphasia Battery-Revised Aphasia Quotient (AQ) at 12 weeks after stroke. Our pre-planned intention to treat analysis combined high intensity groups for the primary outcome. FINDINGS:Among 13,654 acute stroke patients screened, 25% (3477) had aphasia, of whom 25% (866) were eligible and 246 randomized to usual care (n = 81; 33%), usual care-plus (n = 82; 33%) or VERSE (n = 83; 34%). At 12 weeks after stroke, the primary outcome was assessed in 217 participants (88%); 14 had died, 9 had withdrawn, and 6 were too unwell for assessment. Communication recovery was 50.3% (95% CI 45.7-54.8) in the high intensity group (n = 147) and 52.1% (95% CI 46.1-58.1) in the usual care group (n = 70; difference -1.8, 95% CI -8.7-5.0). There was no difference between groups in non-fatal or fatal adverse events (p = 0.72). INTERPRETATION:Early, intensive aphasia therapy did not improve communication recovery within 12 weeks post stroke compared to usual care

Current measurement by real-time counting of single electrons

The fact that electrical current is carried by individual charges has been known for over 100 years, yet this discreteness has not been directly observed so far. Almost all current measurements involve measuring the voltage drop across a resistor, using Ohm's law, in which the discrete nature of charge does not come into play. However, by sending a direct current through a microelectronic circuit with a chain of islands connected by small tunnel junctions, the individual electrons can be observed one by one. The quantum mechanical tunnelling of single charges in this one-dimensional array is time correlated, and consequently the detected signal has the average frequency f=I/e, where I is the current and e is the electron charge. Here we report a direct observation of these time-correlated single-electron tunnelling oscillations, and show electron counting in the range 5 fA-1 pA. This represents a fundamentally new way to measure extremely small currents, without offset or drift. Moreover, our current measurement, which is based on electron counting, is self-calibrated, as the measured frequency is related to the current only by a natural constant.Comment: 9 pages, 4 figures; v2: minor revisions, 2 refs added, words added to title, typos correcte

Changing Landscapes for the Third Sector: Enhancing Knowledge and Informing Practice. Report on the Timescapes Archive.

The broad aim of the Changing Landscapes project, as set out in the proposal to ESRC, was “to bring together a body of qualitative longitudinal and life course research on the third sector in order to exchange knowledge and data of relevance to the future development of the sector”. Underpinning this aim is the Timescapes Archive – a specialist archive of Qualitative Longitudinal (QL) data for sharing and re-use. The long term strategy for the archive is to build collections of thematically related QL datasets, including non ESRC funded datasets, in order to facilitate data discovery and secondary analysis across a range of substantive topics. This is in a context where QL methodology is fast advancing and a growing number of projects are being funded. The archive originally contained a collection of 9 datasets (Changing Relationships and Identities through the Life Course - short hand title, Changing Relationships and Identities). Under the new funding, the aim was to develop a new collection of datasets (Changing Landscapes for the Third Sector). The specific objective was to “prepare data from two complementary datasets (NCVO and Birmingham) and ingest the data into the Timescapes Archive” (ESRC proposal). This report describes the work undertaken in order to achieve the objective of adding two datasets to the Timescapes Archive, but also details the important development work undertaken to establish the Timescapes Archive on a new technical platform which will support the long term strategy for the Archive and ensure that the Archive is aligned with the University of Leeds institutional data management provision

The management of non-valvular atrial fibrillation (NVAF) in Australian general practice: bridging the evidence-practice gap. A national, representative postal survey

<p>Abstract</p> <p>Background</p> <p>General practitioners (GPs) are ideally placed to bridge the widely noted evidence-practice gap between current management of NVAF and the need to increase anticoagulant use to reduce the risk of fatal and disabling stroke in NVAF. We aimed to identify gaps in current care, and asked GPs to identify potentially useful strategies to overcome barriers to best practice.</p> <p>Methods</p> <p>We obtained contact details for a random sample of 1000 GPs from a national commercial data-base. Randomly selected GPs were mailed a questionnaire after an advance letter. Standardised reminders were administered to enhance response rates. As part of a larger survey assessing GP management of NVAF, we included questions to explore GPs' risk assessment, estimates of stroke risk and GPs' perceptions of the risks and benefits of anticoagulation with warfarin. In addition, we explored GPs' perceived barriers to the wider uptake of anticoagulation, quality control of anticoagulation and their assessment of strategies to assist in managing NVAF.</p> <p>Results</p> <p>596 out of 924 eligible GPs responded (64.4% response rate). The majority of GPs recognised that the benefits of warfarin outweighed the risks for three case scenarios in which warfarin is recommended according to Australian guidelines. In response to a hypothetical case scenario describing a patient with a supratherapeutic INR level of 5, 41.4% of the 596 GPs (n = 247) and 22.0% (n = 131) would be "highly likely" or "likely", respectively, to cease warfarin therapy and resume at a lower dose when INR levels are within therapeutic range. Only 27.9% (n = 166/596) would reassess the patient's INR levels within one day of recording the supratherapeutic INR. Patient contraindications to warfarin was reported to "usually" or "always" apply to the patients of 40.6% (n = 242/596) of GPs when considering whether or not to prescribe warfarin. Patient refusal to take warfarin "usually" or "always" applied to the patients of 22.3% (n = 133/596) of GPs. When asked to indicate the usefulness of strategies to assist in managing NVAF, the majority of GPs (89.1%, n = 531/596) reported that they would find patient educational resources outlining the benefits and risks of available treatments "quite useful" or "very useful". Just under two-thirds (65.2%; n = 389/596) reported that they would find point of care INR testing "quite" or "very" useful. An outreach specialist service and training to enable GPs to practice stroke medicine as a special interest were also considered to be "quite" or "very useful" by 61.9% (n = 369/596) GPs.</p> <p>Conclusion</p> <p>This survey identified gaps, based on GP self-report, in the current care of NVAF. GPs themselves have provided guidance on the selection of implementation strategies to bridge these gaps. These results may inform future initiatives designed to reduce the risk of fatal and disabling stroke in NVAF.</p

MiR-34a/c-Dependent PDGFR-α/β Downregulation Inhibits Tumorigenesis and Enhances TRAIL-Induced Apoptosis in Lung Cancer.

Lung cancer is the leading cause of cancer mortality in the world today. Although some advances in lung cancer therapy have been made, patient survival is still poor. MicroRNAs (miRNAs) can act as oncogenes or tumor-suppressor genes in human malignancy. The miR-34 family consists of tumor-suppressive miRNAs, and its reduced expression has been reported in various cancers, including non-small cell lung cancer (NSCLC). In this study, we found that miR-34a and miR-34c target platelet-derived growth factor receptor alpha and beta (PDGFR-α and PDGFR-β), cell surface tyrosine kinase receptors that induce proliferation, migration and invasion in cancer. MiR-34a and miR-34c were downregulated in lung tumors compared to normal tissues. Moreover, we identified an inverse correlation between PDGFR-α/β and miR-34a/c expression in lung tumor samples. Finally, miR-34a/c overexpression or downregulation of PDGFR-α/β by siRNAs, strongly augmented the response to TNF-related apoptosis inducing ligand (TRAIL) while reducing migratory and invasive capacity of NSCLC cells

X-ray Absorption and Reflection in Active Galactic Nuclei

X-ray spectroscopy offers an opportunity to study the complex mixture of emitting and absorbing components in the circumnuclear regions of active galactic nuclei, and to learn about the accretion process that fuels AGN and the feedback of material to their host galaxies. We describe the spectral signatures that may be studied and review the X-ray spectra and spectral variability of active galaxies, concentrating on progress from recent Chandra, XMM-Newton and Suzaku data for local type 1 AGN. We describe the evidence for absorption covering a wide range of column densities, ionization and dynamics, and discuss the growing evidence for partial-covering absorption from data at energies > 10 keV. Such absorption can also explain the observed X-ray spectral curvature and variability in AGN at lower energies and is likely an important factor in shaping the observed properties of this class of source. Consideration of self-consistent models for local AGN indicates that X-ray spectra likely comprise a combination of absorption and reflection effects from material originating within a few light days of the black hole as well as on larger scales. It is likely that AGN X-ray spectra may be strongly affected by the presence of disk-wind outflows that are expected in systems with high accretion rates, and we describe models that attempt to predict the effects of radiative transfer through such winds, and discuss the prospects for new data to test and address these ideas.Comment: Accepted for publication in the Astronomy and Astrophysics Review. 58 pages, 9 figures. V2 has fixed an error in footnote

Correction: MiR-34a/c-Dependent PDGFR-α/β Downregulation Inhibits Tumorigenesis and Enhances TRAIL-Induced Apoptosis in Lung Cancer.

[This corrects the article DOI: 10.1371/journal.pone.0067581.]

Killer immunoglobulin-like Receptors (KIR) haplogroups A and B track with Natural Killer Cells and Cytokine Profile in Aged Subjects: Observations from Octo/Nonagenarians in the Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST)

BACKGROUND: Natural Killer Cells (NK) play an important role in detection and elimination of virus-infected, damaged or cancer cells. NK cell function is guided by expression of Killer Immunoglobulin-like Receptors (KIRs) and contributed to by the cytokine milieu. KIR molecules are grouped on NK cells into stimulatory and inhibitory KIR haplotypes A and B, through which NKs sense and tolerate HLA self-antigens or up-regulate the NK-cytotoxic response to cells with altered HLA self-antigens, damaged by viruses or tumours. We have previously described increased numbers of NK and NK-related subsets in association with sIL-2R cytokine serum levels in BELFAST octo/nonagenarians. We hypothesised that changes in KIR A and B haplotype gene frequencies could explain the increased cytokine profiles and NK compartments previously described in Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST) octo/nonagenarians, who show evidence of ageing well. RESULTS: In the BELFAST study, 24% of octo/nonagenarians carried the KIR A haplotype and 76% KIR B haplotype with no differences for KIR A haplogroup frequency between male or female subjects (23% v 24%; p=0.88) or for KIR B haplogroup (77% v 76%; p=0.99). Octo/nonagenarian KIR A haplotype carriers showed increased NK numbers and percentage compared to Group B KIR subjects (p=0.003; p=0.016 respectively). There were no KIR A/ B haplogroup-associated changes for related CD57+CD8 ((high or low)) subsets. Using logistic regression, KIR B carriers were predicted to have higher IL-12 cytokine levels compared to KIR A carriers by about 3% (OR 1.03, confidence limits CI 0.99–1.09; p=0.027) and 14% higher levels for TGF-β (active), a cytokine with an anti-inflammatory role, (OR 1.14, confidence limits CI 0.99–1.09; p=0.002). CONCLUSION: In this observational study, BELFAST octo/nonagenarians carrying KIR A haplotype showed higher NK cell numbers and percentage compared to KIR B carriers. Conversely, KIR B haplotype carriers, with genes encoding for activating KIRs, showed a tendency for higher serum pro-inflammatory cytokines compared to KIR A carriers. While the findings in this study should be considered exploratory they may serve to stimulate debate about the immune signatures of those who appear to age slowly and who represent a model for good quality survivor-hood