Overriding water table control on managed peatland greenhouse gas emissions.

Global peatlands store more carbon than is naturally present in the atmosphere1,2. However, many peatlands are under pressure from drainage-based agriculture, plantation development and fire, with the equivalent of around 3 per cent of all anthropogenic greenhouse gases emitted from drained peatland3-5. Efforts to curb such emissions are intensifying through the conservation of undrained peatlands and re-wetting of drained systems6. Here we report eddy covariance data for carbon dioxide from 16 locations and static chamber measurements for methane from 41 locations in the UK and Ireland. We combine these with published data from sites across all major peatland biomes. We find that the mean annual effective water table depth (WTDe; that is, the average depth of the aerated peat layer) overrides all other ecosystem- and management-related controls on greenhouse gas fluxes. We estimate that every 10 centimetres of reduction in WTDe could reduce the net warming impact of CO2 and CH4 emissions (100-year global warming potentials) by the equivalent of at least 3 tonnes of CO2 per hectare per year, until WTDe is less than 30 centimetres. Raising water levels further would continue to have a net cooling effect until WTDe is within 10 centimetres of the surface. Our results suggest that greenhouse gas emissions from peatlands drained for agriculture could be greatly reduced without necessarily halting their productive use. Halving WTDe in all drained agricultural peatlands, for example, could reduce emissions by the equivalent of over 1 per cent of global anthropogenic emissions.

First Demonstration of Electrostatic Damping of Parametric Instability at Advanced LIGO.

Interferometric gravitational wave detectors operate with high optical power in their arms in order to achieve high shot-noise limited strain sensitivity. A significant limitation to increasing the optical power is the phenomenon of three-mode parametric instabilities, in which the laser field in the arm cavities is scattered into higher-order optical modes by acoustic modes of the cavity mirrors. The optical modes can further drive the acoustic modes via radiation pressure, potentially producing an exponential buildup. One proposed technique to stabilize parametric instability is active damping of acoustic modes. We report here the first demonstration of damping a parametrically unstable mode using active feedback forces on the cavity mirror. A 15 538 Hz mode that grew exponentially with a time constant of 182 sec was damped using electrostatic actuation, with a resulting decay time constant of 23 sec. An average control force of 0.03 nN was required to maintain the acoustic mode at its minimum amplitude.

Evaluation of the use of rotational thromboelastometry in the assessment of FXI deficency.

INTRODUCTION: The absence of a reliable clinical test to predict bleeding tendency leaves factor XI (FXI)-deficient individuals at risk of overtreatment or under treatment. AIM: To assess whether rotational thromboelastometry has value in detection of FXI deficiency and identification of bleeding tendency. METHODS: Thromboelastometry was measured in whole blood and platelet-rich plasma (PRP) samples containing corn trypsin inhibitor (CTI) from controls (n = 50) and FXI-deficient individuals (n = 93) at tissue factor (TF) 0.12 pm. The effect of tissue plasminogen activator was also assessed. For analysis, FXI-deficient individuals were divided into bleeders (n = 24) and non-bleeders (n = 44) based on experience of tonsillectomy and/or dental extraction prior to diagnosis. RESULTS: In whole blood, thromboelastometry distinguished those with major FXI deficiency (FXI:C ≤ 15 IU dL-1 ) but not partial deficiency from control populations, but did not identify bleeding phenotype. In PRP, bleeders had significantly longer clot formation time [CFT; 434 ± 179 s vs. 277 ± 70 s (mean ± SD); P < 0.05] and smaller α angle [43.8 ± 9.5° vs. 52.4 ± 5.8° (mean ± SD); P < 0.05] compared to non-bleeders. However, these parameters were found to depend on multiple additional variables and on an individual basis, ROC analysis showed test specificity for bleeding phenotype identification to be only 38.5% at 100% sensitivity: CFT (area under first derivative curve: AUC = 0.8091, P = 0.0014), α angle (AUC = 0.7804, P = 0.006). CONCLUSION: Thromboelastometry in PRP with CTI samples triggered with TF 0.12 pm was able to distinguish between bleeders and non-bleeders in FXI deficiency, but poor specificity restricts its clinical application as a test to identify bleeding phenotype. Further technical advances to the assay may allow better discrimination.

Evaluation of the use of global haemostasis assays to monitor treatment in factor XI deficiency.

INTRODUCTION: Previous guidelines recommend that FXI:C levels should be used to monitor FXI replacement in factor XI (FXI) deficiency. However, FXI:C levels do not correlate with bleeding tendency in this disorder and may not be the optimal test by which to monitor and determine further treatment in the postoperative period. AIM: To assess whether the thrombin generation assay (TGA) and rotational thromboelastometry can be used to monitor FXI replacement peri-operatively in FXI deficiency and to determine if changes in FXI:C levels correlate with changes in thrombin generation and clot formation parameters following treatment with solvent-detergent fresh frozen plasma (SD-FFP). METHODS: The TGA and rotational thromboelastometry were used to measure thrombin generation and clot formation in 11 adults with FXI deficiency who were treated with either SD-FFP (n = 8) or FXI concentrate (n = 3) as prophylaxis peri-operatively. Blood samples were taken pre- and 30 min post-treatment. RESULTS: Global haemostasis assays can be used to measure the effect of FXI replacement with SD-FFP or FXI concentrate in FXI deficiency. Both treatment types improved thrombin generation and clot formation. However, the remaining response to treatment at 24 h post SD-FFP was variable and changes in FXI:C levels were not predictive of changes in thrombin generation/thromboelastometry parameters after treatment with SD-FFP. CONCLUSION: Global haemostasis assays may provide a more reliable means of monitoring SD-FFP treatment with the potential to prevent individuals receiving unnecessary treatment, however, their clinical use in decision making needs to be tested in a larger prospective study.

In vitro comparison of the effect of two factor XI (FXI) concentrates on thrombin generation in major FXI deficiency.

INTRODUCTION: Bleeding risk in factor XI (FXI) deficiency following surgery may be reduced by treatment with either of two FXI concentrates, but indications for their use are unclear and treatment has been associated with thrombosis. AIM: To quantify and compare the effects of two different FXI concentrates on thrombin generation (TG) in major FXI deficiency (FXI:C < 15 IU dL(-1) ). METHODS: Thrombin generation was measured in controls (n = 50), FXI-deficient individuals pre and post in vitro spiking with FXI concentrates (n = 10), and in ex vivo samples following treatment with FXI concentrate (n = 3). RESULTS: Thrombin generation was significantly impaired in FXI deficiency but improved following FXI replacement in vitro and in vivo. LFB Hemoleven(®) had greater effect on TG than BPL FXI concentrate in vitro (equivalent in vivo doses 10, 20 and 30 U kg(-1) ): higher endogenous thrombin potential (ETP) (P < 0.0001), peak height (P < 0.01) velocity (P < 0.0002) and shorter lag time and time to peak (both P < 0.003). Some measurements with LFB Hemoleven(®) exceeded the reference range. At lower dose (5 U kg(-1) ), BPL FXI concentrate normalized all TG parameters and LFB Hemoleven(®) normalized the ETP but exceeded the reference range with other parameters. CONCLUSION: Both FXI concentrates improve TG in vitro in major FXI deficiency but differ in dose response, and for both products, doses lower than previously recommended normalized TG in vitro. Comparison of in vitro spiked and ex vivo samples suggest that in vitro results could be used to estimate an expected in vivo response to FXI replacement.

Synthesis of a simplified triazole analogue of pateamine A.

Pateamine A is a naturally occurring metabolite extracted from the marine sponge Mycale hentscheli. It exhibits potent cytotoxicity towards cancer cell lines and has been shown to target protein translation initiation via inhibition of the function of eukaryotic initiation factor 4A proteins. We have synthesised a simplified analogue of pateamine A, consisting of the skeletal core of the natural product but with the thiazole heterocycle replaced by a triazole. The convergent design of the synthesis features a base-induced opening of a δ-valerolactone to access the Z,E-dienoate moiety, Julia-Kocienski olefination and copper-catalysed azide-alkyne cycloaddition. Bioactivity testing of the simplified pateamine A analogue (3) indicated a significant reduction in cytotoxicity, compared to natural pateamine A. We propose that this reduced activity is due mainly to the substitution of the thiazole for the triazole heterocycle. This supports the hypothesis that the thiazole of pateamine A is important for binding to its biological target.

Disordered nuclear pasta, magnetic field decay, and crust cooling in neutron stars.

Nuclear pasta, with nonspherical shapes, is expected near the base of the crust in neutron stars. Large-scale molecular dynamics simulations of pasta show long lived topological defects that could increase electron scattering and reduce both the thermal and electrical conductivities. We model a possible low-conductivity pasta layer by increasing an impurity parameter Q_{imp}. Predictions of light curves for the low-mass x-ray binary MXB 1659-29, assuming a large Q_{imp}, find continued late time cooling that is consistent with Chandra observations. The electrical and thermal conductivities are likely related. Therefore, observations of late time crust cooling can provide insight on the electrical conductivity and the possible decay of neutron star magnetic fields (assuming these are supported by currents in the crust).

Osteosarcoma is characterised by reduced expression of markers of osteoclastogenesis and antigen presentation compared with normal bone.

BACKGROUND: Osteosarcoma (OS) is the most common primary bone tumour in children and adolescents. Patients who respond poorly to chemotherapy have a higher risk of metastatic disease and 5-year survival rates of only 10-20%. Therefore, identifying molecular targets that are specific for OS, or more specifically, metastatic OS, will be critical to the development of new treatment strategies to improve patient outcomes. METHODS: We performed a transcriptomic analysis of chemo-naive OS biopsies and non-malignant bone biopsies to identify differentially expressed genes specific to OS, which could provide insight into OS biology and chemoresistance. RESULTS: Statistical analysis of the OS transcriptomes found differential expression of several metallothionein family members, as well as deregulation of genes involved in antigen presentation. Tumours also exhibited significantly increased expression of ID1 and profound down-regulation of S100A8, highlighting their potential as therapeutic targets for OS. Finally, we found a significant correlation between OS and impaired osteoclastogenesis and antigen-presenting activity. The reduced osteoclastogenesis and antigen-presenting activity were more profound in the chemoresistant OS samples. CONCLUSION: Our results indicate that OS displays gene signatures consistent with decreased antigen-presenting activity, enhanced chemoresistance, and impaired osteoclastogenesis. Moreover, these alterations are more pronounced in chemoresistant OS tumour samples.

The mutation spectrum associated with type 3 von Willebrand disease in a cohort of patients from the north west of England.

Type 3 von Willebrand disease (VWD) is a severe autosomal recessive inherited bleeding disorder. In affected individuals the underlying von Willebrand factor gene (VWF) mutations frequently remain uncharacterized. The aim of this study was to investigate the molecular basis of type 3 VWD in patients (11 Caucasians and 9 of Asian origin) attending the haemophilia centres at Central Manchester NHS Trust. A combination of DNA sequencing of VWF genomic and complementary DNA was performed to identify mutations in the patient cohort. Fifteen different VWF mutations were identified at the genomic DNA level: two gene conversion events, three nonsense, three frameshift, one missense, two splice site, one insertion-deletion and three deletion mutations. Homozygosity or compound heterozygosity for mutations was present in 15 of the 20 patients. In the remaining five individuals, heterozygosity for a single VWF mutation was identified in four cases and one patient had no detectable VWF mutation. Analysis of platelet-derived VWF RNA from these five individuals revealed heterozygosity for a deletion of exons 4 and 5 in four cases. The remaining patient was heterozygous for a three base deletion which had already been identified at the DNA level. Overall the observed VWF genotype explained the phenotype in 18 of the 20 patients investigated. In genetic studies in type 3 VWD, if VWF mutations are not detected at the DNA level, RNA analysis should be performed to search for intronic mutations, heterozygous deletions or aberrant splicing/post-transcriptional events. However, this may still not explain all cases of previously phenotypically diagnosed type 3 VWD.

The molecular analysis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors' Organisation Haemophilia Genetics Laboratory Network.

von Willebrand disease (VWD) is a common autosomally inherited bleeding disorder associated with mucosal or trauma-related bleeding in affected individuals. VWD results from a quantitative or qualitative deficiency of von Willebrand factor (VWF), a glycoprotein that is essential for primary haemostasis and that carries and protects coagulation factor VIII (FVIII) in the circulation. Through characterization of the phenotype and identification of mutations in the VWF gene in patients with VWD, understanding of the genetics and biochemistry of VWF and VWD has advanced considerably. The importance of specific regions of VWF for its interaction with other components of the vasculature has been revealed, and this has facilitated the formal classification of VWD into three subtypes based upon quantitative (types 1 and 3) and qualitative (type 2) deficiency of VWF. The underlying genetic lesions and associated molecular pathology have been identified in many cases of the qualitative type 2 VWD variants (2A, 2B, 2M, 2N) and in the severe quantitative deficiency, type 3 VWD. However in the partial quantitative deficiency, type 1 VWD, the picture is less clear: there is a variable relationship between plasma levels of VWF and bleeding, there is incomplete penetrance and variable expressivity within affected families, the causative molecular defect is unknown in a substantial number of cases, and even in those cases where the causative mutation is known, the associated molecular pathology is not necessarily understood. This guideline aims to provide a framework for best laboratory practice for the genetic diagnosis of VWD, based upon current knowledge and understanding.

Type 1 von Willebrand disease: application of emerging data to clinical practice.

There has been much recent data published on type 1 von Willebrand disease (VWD) predominantly from three multi-centre cohort studies. These data have influenced a revision of the classification of type 1 VWD and have important implications for the management of this disorder. Patients with low von Willebrand factor (VWF) levels tend to have VWF mutations and VWD is transmitted predictably within families. In patients with VWF levels close to the lower end of the normal range, candidate mutations are found less often, ABO blood group is a more important factor and the disease has variable heritability within families. The importance of bleeding symptoms, in addition to VWF levels, in the diagnosis of type 1 VWD has been highlighted.

Effect of water table management and elevated CO2 on radish productivity and on CH4 and CO2 fluxes from peatlands converted to agriculture.

Anthropogenic activity is affecting the global climate through the release of greenhouse gases (GHGs) e.g. CO2 and CH4. About a third of anthropogenic GHGs are produced from agriculture, including livestock farming and horticulture. A large proportion of the UK's horticultural farming takes place on drained lowland peatlands, which are a source of significant amounts of CO2 into the atmosphere. This study set out to establish whether raising the water table from the currently used -50cm to -30cm could reduce GHGs emissions from agricultural peatlands, while simultaneously maintaining the current levels of horticultural productivity. A factorial design experiment used agricultural peat soil collected from the Norfolk Fens (among the largest of the UK's lowland peatlands under intensive cultivation) to assess the effects of water table levels, elevated CO2, and agricultural production on GHG fluxes and crop productivity of radish, one of the most economically important fenland crops. The results of this study show that a water table of -30cm can increase the productivity of the radish crop while also reducing soil CO2 emissions but without a resultant loss of CH4 to the atmosphere, under both ambient and elevated CO2 concentrations. Elevated CO2 increased dry shoot biomass, but not bulb biomass nor root biomass, suggesting no immediate advantage of future CO2 levels to horticultural farming on peat soils. Overall, increasing the water table could make an important contribution to global warming mitigation while not having a detrimental impact on crop yield.

Effects of transients in LIGO suspensions on searches for gravitational waves.

This paper presents an analysis of the transient behavior of the Advanced LIGO (Laser Interferometer Gravitational-wave Observatory) suspensions used to seismically isolate the optics. We have characterized the transients in the longitudinal motion of the quadruple suspensions during Advanced LIGO's first observing run. Propagation of transients between stages is consistent with modeled transfer functions, such that transient motion originating at the top of the suspension chain is significantly reduced in amplitude at the test mass. We find that there are transients seen by the longitudinal motion monitors of quadruple suspensions, but they are not significantly correlated with transient motion above the noise floor in the gravitational wave strain data, and therefore do not present a dominant source of background noise in the searches for transient gravitational wave signals. Using the suspension transfer functions, we compared the transients in a week of gravitational wave strain data with transients from a quadruple suspension. Of the strain transients between 10 and 60 Hz, 84% are loud enough that they would have appeared above the sensor noise in the top stage quadruple suspension monitors if they had originated at that stage at the same frequencies. We find no significant temporal correlation with the suspension transients in that stage, so we can rule out suspension motion originating at the top stage as the cause of those transients. However, only 3.2% of the gravitational wave strain transients are loud enough that they would have been seen by the second stage suspension sensors, and none of them are above the sensor noise levels of the penultimate stage. Therefore, we cannot eliminate the possibility of transient noise in the detectors originating in the intermediate stages of the suspension below the sensing noise.

The -48 C/T polymorphism in the presenilin 1 promoter is associated with an increased risk of developing Alzheimer's disease and an increased Abeta load in brain.

Mutations in the presenilin 1 gene (PS1) account for the majority of early onset, familial, autosomal dominant forms of Alzheimer's disease (AD), whereas its role in other late onset forms of AD remains unclear. A -48 C/T polymorphism in the PS1 promoter has been associated with an increased genetic risk in early onset complex AD and moreover has been shown to influence the expression of the PS1 gene. This raises the possibility that previous conflicting findings from association studies with homozygosity for the PS1 intron 8 polymorphism might be the result of linkage disequilibrium with the -48 CC genotype. Here we provide further evidence of increased risk of AD associated with homozygosity for the -48 CC genotype (odds ratio=1.6). We also report a phenotypic correlation with Abeta(40), Abeta(42(43)), and total Abeta load in AD brains. The -48 CC genotype was associated with 47% greater total Abeta load (p<0.003) compared to CT + TT genotype bearers. These results suggest that the -48 C/T polymorphism in the PS1 promoter may increase the risk of AD, perhaps by altering PS1 gene expression and thereby influencing Abeta load.

Endothelin in the kidney in malignant phase hypertension.

A role for endothelin in malignant phase hypertension has been suggested on the basis of reported increases of circulating plasma immunoreactive endothelins in animal models. Recently, a hypertensive rat model that exhibits a genetically determined tendency for developing spontaneous onset malignant hypertension has been described. Expression of the three genes endothelin-1, endothelin-2, and endothelin-3 was quantified in the kidney by specific RNase protection assays in rats with established malignant hypertension, in rats with benign hypertension with and without a genetic susceptibility to malignant hypertension, and in normotensive Sprague-Dawley rats. Endothelin-1 mRNA levels were significantly elevated in the group with malignant hypertension compared with the other three groups. For determination of whether endothelin-1-mediated effects were crucial in the transition from benign to malignant phase hypertension, an oral nonspecific combined endothelin-A and endothelin-B receptor antagonist (bosentan) was given to hypertensive rats susceptible to malignant hypertension. No hypotensive effects were observed, and no significant difference in the incidence of malignant hypertension was observed between treated and control groups. In conclusion, although increased endothelin-1 mRNA expression was found in kidney tissue from rats developing malignant hypertension, blockade of endothelin-1-mediated effects did not prevent the transition from benign phase hypertension. Hence, increased renal endothelin-1 expression in this model of malignant hypertension does not appear to have a causative role and may simply reflect cellular damage and ischemia.

Response of aldosterone and 18-hydroxycorticosterone to angiotensin II in normal subjects and patients with essential hypertension, Conn's syndrome, and nontumorous hyperaldosteronism.

Dose-response curves relating plasma angiotensin II (AII) concentration during AII infusion to blood pressure (BP), to plasma aldosterone, and to plasma 18-hydroxycorticosterone were compared in normal subjects and in patients with essential hypertension, Conn's syndrome, and nontumorous hyperaldosteronism. The BP response was steeper than normal in patients with Conn's syndrome and essential hypertension. Before infusion, mean plasma aldosterone concentration was approximately four-fold higher in Conn's syndrome than in the normal group, while that of 18-hydroxycorticosterone was ninefold higher. Neither increased significantly during AII infusion. In essential hypertension, both corticosteroids were within the normal range, but their responses to AII infusion were greater than normal. In the three subjects with non-tumorous hyperaldosteronism, plasma aldosterone and 18-hydroxycorticosterone concentrations were raised, and their responses to AII infusion resembled those found in essential hypertension and were different from those found in Conn's syndrome. This suggests that nontumorous hyperaldosteronism is not a variant of Conn's syndrome. In the response to AII and in other ways, it is indistinguishable from essential hypertension.

Glomerular hyperfiltration, high renin, and low- extracellular volume in high blood pressure.

Abnormal renovascular resistance and glomerular filtration rate are characteristic of established hypertension and may also be involved in its pathogenesis. To determine renal and body fluid correlates of the predisposition to high blood pressure, we examined 100 healthy young adults with high or low blood pressure. Within each group, half had parents with high blood pressures, and half had parents with low blood pressures. Renal function and hemodynamics, body fluid volumes, and relevant hormones and genotypes were measured. Subjects with high personal and parental blood pressures had the highest levels of glomerular filtration rate (P<0.02) and plasma active renin concentration and low levels of exchangeable sodium and plasma volume (P<0.02). High glomerular filtration rate was not associated with differences in urinary kallikrein or prostaglandins. Polymorphisms of the renin, angiotensin-converting enzyme, and angiotensinogen genes were not associated with differences in glomerular filtration rate or renin. Subjects with high personal, but low parental, blood pressures had low exchangeable sodium and plasma volumes (P<0.02) but normal glomerular filtration rates. In this population, extracellular volume depletion and high renin are correlates of high blood pressure in early adulthood, and glomerular hyperfiltration is a feature of those who also have familial predisposition to high blood pressure.

No association between Glu/Asp polymorphism of NOS3 gene and ischemic stroke.

Endothelial nitric oxide synthase (NOS3) gene has been shown to modulate the degree of cerebral ischemia following stroke in animal models and is thus a candidate genetic risk factor for stroke. We compared 265 ischemic stroke cases with 293 controls and found no difference in distribution of the common structural variant Glu/Asp in codon 298 of exon 7 in the NOS3 gene. Our data do not support the hypothesis that NOS3 is a genetic risk factor for stroke.