Was there a '4.2ka event' in Great Britain and Ireland? Evidence from the peatland record

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this record.Palaeoenvironmental and archaeological data from several regions around the world show evidence of a multi-centennial climatic event occurring approximately 4200cal yr BP (4.2ka). Whilst the climatic change and/or impact of the 4.2ka event is clear in certain regions, such as western Asia, evidence for the event has yet to be fully evaluated in northwest Europe. This study presents high-resolution, multi-proxy palaeoclimate records from sites in Northern Ireland, ideally located for an objective examination of the nature of the event in Great Britain and Ireland within the broader context of mid-Holocene climate change c. 6.5-2.5ka. The peatlands of northwest Europe possess considerable potential for the examination of climatic change in the North Atlantic region, demonstrated by the range of palaeohydrological proxy data generated during this study (peat humification, plant macrofossil and testate amoebae analyses) supported by a high-resolution chronology (including comprehensive AMS 14 C and tephrochronology). The inter-site testate amoebae reconstructions appear coherent and were combined to produce a regional climatic record, in marked contrast to the plant macrofossil and peat humification records that appear climatically complacent. The testate amoebae reconstruction, however, provides no compelling evidence for a 4.2ka event signal and is consistent with previously reported studies from across northwest Europe, suggesting the origin and impact of this event is spatially complex. © 2013 Elsevier Ltd.This research was carried out while T.P.R. held a UK Natural Environment Research Council studentship (NE/G524328/1) at the University of Exeter.

Role of the vector genome and underlying factor IX mutation in immune responses to AAV gene therapy for hemophilia B

BACKGROUND: Self-complementary adeno-associated virus (scAAV) vectors have become a desirable vector for therapeutic gene transfer due to their ability to produce greater levels of transgene than single-stranded AAV (ssAAV). However, recent reports have suggested that scAAV vectors are more immunogenic than ssAAV. In this study, we investigated the effects of a self-complementary genome during gene therapy with a therapeutic protein, human factor IX (hF.IX). METHODS: Hemophilia B mice were injected intramuscularly with ss or scAAV1 vectors expressing hF.IX. The outcome of gene transfer was assessed, including transgene expression as well as antibody and CD8(+) T cell responses to hF.IX. RESULTS: Self-complementary AAV1 vectors induced similar antibody responses (which eliminated systemic hF.IX expression) but stronger CD8(+) T cell responses to hF.IX relative to ssAAV1 in mice with F9 gene deletion. As a result, hF.IX-expressing muscle fibers were effectively eliminated in scAAV-treated mice. In contrast, mice with F9 nonsense mutation (late stop codon) lacked antibody or T cell responses, thus showing long-term expression regardless of the vector genome. CONCLUSIONS: The nature of the AAV genome can impact the CD8(+) T cell response to the therapeutic transgene product. In mice with endogenous hF.IX expression, however, this enhanced immunogenicity did not break tolerance to hF.IX, suggesting that the underlying mutation is a more important risk factor for transgene-specific immunity than the molecular form of the AAV genome

The 5.2 ka climate event: Evidence from stable isotope and multi-proxy palaeoecological peatland records in Ireland

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.Evidence for a major climate event at 5.2 ka has been reported globally and is associated with considerable societal disruption, but is poorly characterised in northwest Europe. This event forms part of a broader period of re-organisation in the Earth's ocean-atmosphere circulation system between 6 and 5 ka. This study tests the nature and timing of the event in northwest Europe, a region highly sensitive to change in meridional overturning circulation and mid-latitude westerly airflow. Here we report three high-resolution Irish multi-proxy records obtained from ombrotrophic peatlands that have robust chronological frameworks. We identify the 5.2 ka event by a sustained decrease in δ 18 O cellulose at all three sites, with additional and parallel changes in δ 13 C cellulose and palaeoecological (testate amoebae, plant macrofossil and humification) data from two sites in northern Ireland. Data from Sluggan Moss demonstrate a particularly coherent shift towards wetter conditions. These data support the hypothesis that the event was caused by a prolonged period of positive North Atlantic Oscillation conditions, resulting in pervasive cyclonic weather patterns across northwest Europe, increasing precipitation over Ireland.This research was carried out while T.P.R. held UK Natural Environment Research Council studentship at the University of Exeter (NE/G524328/1) and T.J.D held a studentship at the University of Southampton tied to the NERC RAPID Programme (NER/T/S/2002/00460). Radiocarbon support was provided by the NERC 14C Steering Committee (Allocation No.: 1523.0910), the NERC RAPID Programme and the Irish Quaternary Association via the IQUA Bill Watts 14Chrono award

Zygapophysial joint blocks in chronic low back pain: a test of Revel's model as a screening test

BACKGROUND: Only controlled blocks are capable of confirming the zygapophysial joints (ZJ) as the pain generator in LBP patients. However, previous workers have found that a cluster of clinical signs ("Revel's criteria"), may be valuable in predicting the results of an initial screening ZJ block. It was suggested that these clinical findings are unsuitable for diagnosis, but may be of value in selecting patients for diagnostic blocks of the lumbar ZJ's. To constitute evidence in favour of a clinical management strategy, these results need confirmation. This study evaluates the utility of 'Revel's criteria' as a screening tool for selection of chronic low back pain patients for controlled ZJ diagnostic blocks. METHODS: This study utilized a prospective blinded concurrent reference standard related validity design. Consecutive chronic LBP patients completed pain drawings, psychosocial distress and disability questionnaires, received a clinical examination and lumbar zygapophysial blocks. Two reference standards were evaluated simultaneously: 1. 75% reduction of pain on a visual analogue scale (replication of previous work), and 2. abolition of the dominant or primary pain. Using "Revel's criteria" as predictors, logistic regression analyses were used to test the model. Estimates of sensitivity, specificity, predictive values and likelihood ratios for selected variables were calculated for the two proposed clinical strategies. RESULTS: Earlier results were not replicated. Sensitivity of "Revel's criteria" was low sensitivity (<17%), and specificity high (approximately 90%). Absence of pain with cough or sneeze just reached significance (p = 0.05) within one model. CONCLUSIONS: "Revel's criteria" are unsuitable as a clinical screening test to select chronic LBP patients for initial ZJ blocks. However, the criteria may have use in identifying a small subset (11%) of patients likely to respond to the initial block (specificity 93%)

Catastrophizing mediates the relationship between the personal belief in a just world and pain outcomes among chronic pain support group attendees

Health-related research suggests the belief in a just world can act as a personal resource that protects against the adverse effects of pain and illness. However, currently, little is known about how this belief, particularly in relation to one’s own life, might influence pain. Consistent with the suggestions of previous research, the present study undertook a secondary data analysis to investigate pain catastrophizing as a mediator of the relationship between the personal just world belief and chronic pain outcomes in a sample of chronic pain support group attendees. Partially supporting the hypotheses, catastrophizing was negatively correlated with the personal just world belief and mediated the relationship between this belief and pain and disability, but not distress. Suggestions for future research and intervention development are made

Bell Correlations and the Common Future

Reichenbach's principle states that in a causal structure, correlations of classical information can stem from a common cause in the common past or a direct influence from one of the events in correlation to the other. The difficulty of explaining Bell correlations through a mechanism in that spirit can be read as questioning either the principle or even its basis: causality. In the former case, the principle can be replaced by its quantum version, accepting as a common cause an entangled state, leaving the phenomenon as mysterious as ever on the classical level (on which, after all, it occurs). If, more radically, the causal structure is questioned in principle, closed space-time curves may become possible that, as is argued in the present note, can give rise to non-local correlations if to-be-correlated pieces of classical information meet in the common future --- which they need to if the correlation is to be detected in the first place. The result is a view resembling Brassard and Raymond-Robichaud's parallel-lives variant of Hermann's and Everett's relative-state formalism, avoiding "multiple realities."Comment: 8 pages, 5 figure

Nox4 regulates InsP3 receptor‐dependent Ca2+ release into mitochondria to promote cell survival

Cells subjected to environmental stresses undergo regulated cell death (RCD) when homeostatic programs fail to maintain viability. A major mechanism of RCD is the excessive calcium loading of mitochondria and consequent triggering of the mitochondrial permeability transition (mPT), which is especially important in post-mitotic cells such as cardiomyocytes and neurons. Here, we show that stress-induced upregulation of the ROS-generating protein Nox4 at the ER-mitochondria contact sites (MAMs) is a pro-survival mechanism that inhibits calcium transfer through InsP 3 receptors (InsP 3R). Nox4 mediates redox signaling at the MAM of stressed cells to augment Akt-dependent phosphorylation of InsP 3R, thereby inhibiting calcium flux and mPT-dependent necrosis. In hearts subjected to ischemia–reperfusion, Nox4 limits infarct size through this mechanism. These results uncover a hitherto unrecognized stress pathway, whereby a ROS-generating protein mediates pro-survival effects through spatially confined signaling at the MAM to regulate ER to mitochondria calcium flux and triggering of the mPT. </p

Proteomic analysis of the Plasmodium male gamete reveals the key role for glycolysis in flagellar motility.

BACKGROUND: Gametogenesis and fertilization play crucial roles in malaria transmission. While male gametes are thought to be amongst the simplest eukaryotic cells and are proven targets of transmission blocking immunity, little is known about their molecular organization. For example, the pathway of energy metabolism that power motility, a feature that facilitates gamete encounter and fertilization, is unknown. METHODS: Plasmodium berghei microgametes were purified and analysed by whole-cell proteomic analysis for the first time. Data are available via ProteomeXchange with identifier PXD001163. RESULTS: 615 proteins were recovered, they included all male gamete proteins described thus far. Amongst them were the 11 enzymes of the glycolytic pathway. The hexose transporter was localized to the gamete plasma membrane and it was shown that microgamete motility can be suppressed effectively by inhibitors of this transporter and of the glycolytic pathway. CONCLUSIONS: This study describes the first whole-cell proteomic analysis of the malaria male gamete. It identifies glycolysis as the likely exclusive source of energy for flagellar beat, and provides new insights in original features of Plasmodium flagellar organization

Enhanced Membrane Pore Formation through High-Affinity Targeted Antimicrobial Peptides

Many cationic antimicrobial peptides (AMPs) target the unique lipid composition of the prokaryotic cell membrane. However, the micromolar activities common for these peptides are considered weak in comparison to nisin, which follows a targeted, pore-forming mode of action. Here we show that AMPs can be modified with a high-affinity targeting module, which enables membrane permeabilization at low concentration. Magainin 2 and a truncated peptide analog were conjugated to vancomycin using click chemistry, and could be directed towards specific membrane embedded receptors both in model membrane systems and whole cells. Compared with untargeted vesicles, a gain in permeabilization efficacy of two orders of magnitude was reached with large unilamellar vesicles that included lipid II, the target of vancomycin. The truncated vancomycin-peptide conjugate showed an increased activity against vancomycin resistant Enterococci, whereas the full-length conjugate was more active against a targeted eukaryotic cell model: lipid II containing erythrocytes. This study highlights that AMPs can be made more selective and more potent against biological membranes that contain structures that can be targeted