Quantifying the slip rates, spatial distribution and evolution of active normal faults from geomorphic analysis: Field examples from an oblique-extensional graben, southern Turkey

Quantifying the extent to which geomorphic features can be used to extract tectonic signals is a key challenge in the Earth Sciences. Here we analyse the drainage patterns, geomorphic impact, and long profiles of bedrock rivers that drain across and around normal faults in a regionally significant oblique-extensional graben (Hatay Graben) in southern Turkey that has been mapped geologically, but for which there are poor constraints on the activity, slip rates and Plio-Pleistocene evolution of basin-bounding faults. We show that drainage in the Hatay Graben is strongly asymmetric, and by mapping the distribution of wind gaps, we are able to evaluate how the drainage network has evolved through time. By comparing the presence, size, and distribution of long profile convexities, we demonstrate that the northern margin of the graben is tectonically quiescent, whereas the southern margin is bounded by active faults. Our analysis suggests that rivers crossing these latter faults are undergoing a transient response to ongoing tectonic uplift, and this interpretation is supported by classic signals of transience such as gorge formation and hill slope rejuvenation within the convex reach. Additionally, we show that the height of long profile convexities varies systematically along the strike of the southern margin faults, and we argue that this effect is best explained if fault linkage has led to an increase in slip rate on the faults through time from ∼ 0.1 to 0.45 mm/yr. By measuring the average length of the original fault segments, we estimate the slip rate enhancement along the faults, and thus calculate the range of times for which fault acceleration could have occurred, given geological estimates of fault throw. These values are compared with the times and slip rates required to grow the documented long-profile convexities enabling us to quantify both the present-day slip rate on the fault (0.45 ± 0.05 mm/yr) and the timing of fault acceleration (1.4 ± 0.2 Ma). Our results have substantial implications for predicting earthquake hazard in this densely populated area (calculated potential Mw = 6.0-6.6), enable us to constrain the tectonic evolution of the graben through time, and more widely, demonstrate that geomorphic analysis can be used as an effective tool for estimating fault slip rates over time periods > 106 years, even in the absence of direct geodetic constraints. © 2008 Elsevier B.V. All rights reserved

Role of prostacyclin in pulmonary hypertension

Date of Acceptance: 11/12/2014 This is an open access article distributed under the terms of the Creative Commons Attribution license CC BY-4.0, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.Prostacyclin is a powerful cardioprotective hormone released by the endothelium of all blood vessels. Prostacyclin exists in equilibrium with other vasoactive hormones and a disturbance in the balance of these factors leads to cardiovascular disease including pulmonary arterial hypertension. Since it’s discovery in the 1980s concerted efforts have been made to make the best therapeutic utility of prostacyclin, particularly in the treatment of pulmonary arterial hypertension. This has centred on working out the detailed pharmacology of prostacyclin and then synthesising new molecules based on its structure that are more stable or more easily tolerated. In addition, newer molecules have been developed that are not analogues of prostacyclin but that target the receptors that prostacyclin activates. Prostacyclin and related drugs have without doubt revolutionised the treatment and management of pulmonary arterial hypertension but are seriously limited by side effects within the systemic circulation. With the dawn of nanomedicine and targeted drug or stem cell delivery systems it will, in the very near future, be possible to make new formulations of prostacyclin that can evade the systemic circulation allowing for safe delivery to the pulmonary vessels. In this way, the full therapeutic potential of prostacyclin can be realised opening the possibility that pulmonary arterial hypertension will become, if not curable, a chronic manageable disease that is no longer fatal. This review discusses these and other issues relating to prostacyclin and its use in pulmonary arterial hypertensionPeer reviewedFinal Published versio

Geomorphic and geological constraints on the active normal faulting of the Gediz (Alaşehir) Graben, Western Turkey.

The Gediz (Alaşehir) Graben is located in the highly tectonically active region of Western Turkey. Extension due to regional geodynamic controls has resulted in a broadly two-phase evolution of the graben; firstly, low-angle normal faulting relating to the exhumation of the Menderes Massif metamorphic core complex took place between 16 - 2.6 Ma. Secondly, high-angle normal faulting initiated ~ 2 Ma forming the Gediz and other E-W trending grabens in the region. Here we quantify the throw rate along the fault array over the last 2.6, 2 and 0.7 Ma using structural and geological constraints, along with analysis of topographic relief as a proxy for footwall uplift. We derive, for the first time, time averaged rates of fault motion from 0.4 mm/yr to 1.3 mm/yr along the strike of the Gediz Graben, with variation in throw-rate associated with the geometry of individual fault strands. Patterns in throw-rate along strike of the graben bounding fault array also suggest that the fault segments have become linked during the last 2.6 - 2 Ma, possibly at 0.8 – 0.7 Ma. Furthermore, these data suggest that an earthquake occurring along the graben bounding fault could have a maximum predicted Mw of 6.3 - 7.6

Normal fault growth and linkage in the Gediz (Alasehir) Graben, Western Turkey, revealed by transient river long-profiles and slope-break knickpoints

The Gediz (Alaşehir) Graben is located in the highly tectonically active and seismogenic region of Western Turkey. The rivers upstream of the normal fault-bounded graben each contain a non-lithologic knickpoint, including those that drain through inferred fault segment boundaries. Knickpoint heights measured vertically from the fault scale with footwall relief and documented fault throw (vertical displacement). Consequently, we deduce these knickpoints were initiated by an increase in slip rate on the basin-bounding fault, driven by linkage of the three main fault segments of the high-angle graben bounding fault array. Fault interaction theory and ratios of channel steepness suggest that the slip rate enhancement factor on linkage was a factor of 3. We combine this information with geomorphic and structural constraints to estimate that linkage took place between 0.6 Ma and 1 Ma. Calculated pre- and post-linkage throw rates are 0.6 and 2 mm/yr respectively. Maximum knickpoint retreat rates upstream of the faults range from 4.5 to 28 mm/yr, faster than for similar catchments upstream of normal faults in the Central Apennines and the Hatay Graben of Turkey, and implying a fluvial landscape response time of 1.6 to 2.7 Myr. We explore the relative controls of drainage area and precipitation on these retreat rates, and conclude that while climate variation and fault throw rate partially explain the variations seen, lithology remains a potentially important but poorly characterised variable

Spectrum of mutational signatures in T-cell lymphoma reveals a key role for UV radiation in cutaneous T-cell lymphoma

T-cell non-Hodgkin's lymphomas develop following transformation of tissue resident T-cells. We performed a meta-analysis of whole exome sequencing data from 403 patients with eight subtypes of T-cell non-Hodgkin's lymphoma to identify mutational signatures and associated recurrent gene mutations. Signature 1, indicative of age-related deamination, was prevalent across all T-cell lymphomas, reflecting the derivation of these malignancies from memory T-cells. Adult T-cell leukemia-lymphoma was specifically associated with signature 17, which was found to correlate with the IRF4 K59R mutation that is exclusive to Adult T-cell leukemia-lymphoma. Signature 7, implicating UV exposure was uniquely identified in cutaneous T-cell lymphoma (CTCL), contributing 52% of the mutational burden in mycosis fungoides and 23% in Sezary syndrome. Importantly this UV signature was observed in CD4 + T-cells isolated from the blood of Sezary syndrome patients suggesting extensive re-circulation of these T-cells through skin and blood. Analysis of non-Hodgkin's T-cell lymphoma cases submitted to the national 100,000 WGS project confirmed that signature 7 was only identified in CTCL strongly implicating UV radiation in the pathogenesis of cutaneous T-cell lymphoma

Tsunami Generation by Combined Fault Rupture and Landsliding

Tsunami generation and propagation mechanisms should be clearly understood in order to inform predictive models and improve coastal community preparedness. Experimental results, supported by mathematical models, could potentially provide valuable input data for standard predictive models of tsunami generation and propagation. A unique set-up has been developed to reproduce a dual-source tsunami generation mechanism. The test-rig replicates a two-dimensional underwater fault rupture followed by a submarine landslide. The set-up was placed in a 20m flume of the COAST laboratory at Plymouth University. The aim of the experiments is to provide quality data for developing a parametrization of the initial conditions for tsunami generation processes which are triggered by a dual-source. The free surface elevation changes are investigated in relation to the fault rupture and landslide motions. During the test programme, the water depth and the landslide density were varied. The position of the landslide model was tracked and the free surface elevation of the water body was measured. Hence tsunami characteristics of wave height, wavelength and propagation speed were determined. This paper provides a detailed description of the test rig and presents some preliminary results which highlight the performance of the test rig in terms of repeatability

Parametric study of tsunamis generated by earthquakes and landslides

Tsunami generation and propagation mechanisms need to be clearly understood in order to inform predictive models and improve coastal community preparedness. Physical experiments, supported by mathematical models, can potentially provide valuable input data for standard predictive models of tsunami generation and propagation. A unique experimental set-up has been developed to reproduce a coupled-source tsunami generation mechanism: a two-dimensional underwater fault rupture followed by a submarine landslide. The test rig was located in a 20 m flume in the COAST laboratory at the University of Plymouth. The aim of the experiments is to provide quality data for developing a parametrisation of the initial conditions for tsunami generation processes which are triggered by a dual-source. During the test programme, the water depth and the landslide density were varied. The position of the landslide model was tracked and the free surface elevation of the water body was measured. Hence the generated wave characteristics were determined. For a coupled-source scenario, the generated wave is crest led, followed by a trough of smaller amplitude decreasing steadily as it propagates along the flume. The crest amplitude was shown to be influenced by the fault rupture displacement scale, whereas the trough was influenced by the landslide’s relative density

Frequent and Persistent PLCG1 Mutations in Sezary Cells Directly Enhance PLC gamma 1 Activity and Stimulate NF kappa B, AP-1, and NFAT Signaling

Phospholipase C Gamma 1 (PLCG1) is frequently mutated in primary cutaneous T-cell lymphoma (CTCL). This study functionally interrogated nine PLCG1 mutations (p.R48W, p.S312L, p.D342N, p.S345F, p.S520F, p.R1158H, p.E1163K, p.D1165H, and the in-frame indel p.VYEEDM1161V) identified in Sézary Syndrome, the leukemic variant of CTCL. The mutations were demonstrated in diagnostic samples and persisted in multiple tumor compartments over time, except in patients who achieved a complete clinical remission. In basal conditions, the majority of the mutations confer PLCγ1 gain-of-function activity through increased inositol phosphate production and the downstream activation of NFκB, AP-1, and NFAT transcriptional activity. Phosphorylation of the p.Y783 residue is essential for the proximal activity of wild-type PLCγ1, but we provide evidence that activating mutations do not require p.Y783 phosphorylation to stimulate downstream NFκB, NFAT, and AP-1 transcriptional activity. Finally, the gain-of-function effects associated with the p.VYEEDM1161V indel suggest that the C2 domain may have a role in regulating PLCγ1 activity. These data provide compelling evidence to support the development of therapeutic strategies targeting mutant PLCγ1

Inhaled corticosteroids, blood eosinophils, and FEV1 decline in patients with COPD in a large UK primary health care setting.

Background: Inhaled corticosteroid (ICS)-containing medications slow rate of decline of FEV1. Blood eosinophil (EOS) levels are associated with the degree of exacerbation reduction with ICS. Purpose: We investigated whether FEV1 decline differs between patients with and without ICS, stratified by blood EOS level. Patients and methods: The UK Clinical Practice Research Datalink (primary care records) and Hospital Episode Statistics (hospital records) were used to identify COPD patients aged 35 years or older, who were current or ex-smokers with ≥2 FEV1 measurements ≥6 months apart. Prevalent ICS use and the nearest EOS count to start of follow-up were identified. Patients were classified at baseline as higher stratum EOS (≥150 cell/µL) on ICS; higher stratum EOS not on ICS; lower stratum EOS (<150 cells/µL) on ICS; and lower stratum EOS not on ICS. In addition, an incident ICS cohort was used to investigate the rate of FEV1 change by EOS and incident ICS use. Mixed-effects linear regression was used to compare rates of FEV1 change in mL/year. Results: A total of 26,675 COPD patients met our inclusion criteria (median age 69, 46% female). The median duration of follow up was 4.2 years. The rate of FEV1 change in prevalent ICS users was slower than non-ICS users (-12.6 mL/year vs -21.1 mL/year; P =0.001). The rate of FEV1 change was not significantly different when stratified by EOS level. The rate of FEV1 change in incident ICS users increased (+4.2 mL/year) vs -21.2 mL/year loss in non-ICS users; P<0.001. In patients with high EOS, incident ICS patients showed an increase in FEV1 (+12 mL/year) compared to non-ICS users whose FEV1 decreased (-20.8 mL/year); P<0.001. No statistical difference was seen in low EOS patients. Incident ICS use is associated with an improvement in FEV1 change, however, over time this association is lost. Conclusion: Regardless of blood EOS level, prevalent ICS use is associated with slower rates of FEV1 decline in COPD