Interaction of Transforming growth factor-β receptor I with farnesyl-protein transferase-α in yeast and mammalian cells

Transforming growth factor beta (TGF-beta) signals through two transmembrane serine/threonine kinases, known as TbetaR-I and TbetaR-II. Several lines of evidence suggest that TbetaR-II acts as a primary receptor, binding TGF-beta and phosphorylating TbetaR-I whose kinase activity then propagates the signal to unknown substrates. We report an interaction between TbetaR-I and the farnesyl-protein transferase-alpha subunit (FT-alpha) both in a yeast two-hybrid system and in mammalian cells. These findings raise the possibility that TGF-beta might regulate cellular functions by altering the ability of FT-alpha to catalyze isoprenylation of targets such as G proteins, lamins, or cytoskeletal components. However, we provide evidence that TGF-beta action does not alter the overall protein isoprenyl transferase activity in Mv1Lu mink lung epithelial cells. In fact, the beta subunits of farnesyl transferase and geranylgeranyl transferase, which are necessary for the activity of FT-alpha, prevent the association of FT-alpha with TbetaR-I. Furthermore, farnesyl transferase activity is shown to be dispensable for TGF-beta signaling of growth inhibitory and transcriptional responses in these cells. These results suggest that the interaction between TbetaR-I and FT-alpha does not affect the known functions of these two proteins

Impact of slurry application method on phosphorus loss in runoff from grassland soils during periods of high soil moisture content

Abstract Previous studies have reported that the trailing shoe application technique reduces phosphorus (P) in the runoff postslurry application when compared to the traditional splash-plate application technique. However, the effectiveness of the trailing-shoe technique as a means of reducing P losses has not been evaluated when slurry is applied during periods of high soil moisture levels and lower herbage covers. To address this issue, three treatments were examined in a 3 × 4 factorial design split-plot experiment, with treatments comprising three slurry treatments: control (no slurry), splashplate and trailing-shoe, and four slurry application dates: 7 December, 18 January, 1 March and 10 April. Dairy cow slurry was applied at a rate of 20 m3/ha, while simulated runoff was generated 2, 9 and 16 days later and analysed for a range of P fractions. Dissolved reactive P concentrations in runoff at day two was 41% lower when slurry was applied using the trailing-shoe technique, compared to the splash-plate technique (P &lt; 0.05). In addition, P concentrations in runoff were higher (P &lt; 0.05) from slurry applied in December and March compared to slurry applied in January or April, coinciding with periods of higher soil moisture contents. While the latter highlights that ‘calendar’-based non-spreading periods might not always achieve the desired consequences, the study demonstrated that further field-scale investigations into the trailing shoe as a mitigation measure to reduced P loss from agricultural soils is warranted.</jats:p

Using mental-modelling to explore how irrigators in the Murray-Darling Basin make water-use decisions

Study region: Water stress and over-allocation are at the forefront of water management and policy challenges in Australia, especially in the Murray–Darling Basin (MDB). Because irrigated agriculture is a major social and economic component of the MDB, farmer decision-making plays a major role in water sustainability in the region. Study focus: This study used a fuzzy cognitive mapping methodology, ‘mental modeling’, to understand the perceived constraints of irrigator water-use decisions in the MDB, for two different types of irrigation: permanent and annual crops. The approach elicits and documents irrigator insights into the complex and networked nature of irrigation water use decisions in relation to farm-based dynamics. New hydrological insights for the region: Results suggest support for greater local and irrigator involvement in water management decisions. Many, if not most, of the irrigators understood the need for, or at least the inevitability of, governmental policies and regulations. However, a lack of accountability, predictability, and transparency has added to the uncertainty in farm-based water decision-making. Irrigators supported the concept of environmental sustainability, although they might not always agree with how the concept is implemented. The mental modelling approach facilitated knowledge sharing among stakeholders and can be used to identify common goals. Future research utilizing the mental modelling approach may encourage co-management and knowledge partnerships between irrigators, water managers and government officials.Ellen M. Douglas, Sarah Ann Wheeler, David J. Smith, Ian C. Overton, Steven A. Gray, Tanya M. Doody, Neville D. Crossma

Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden

Abstract Background It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection. Results Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember&#8482;, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced. Conclusions Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.http://deepblue.lib.umich.edu/bitstream/2027.42/78314/1/1750-1326-5-45.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/2/1750-1326-5-45.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/78314/3/1750-1326-5-45-S1.PDFPeer Reviewe

Elevated hemostasis markers after pneumonia increases one-year risk of all-cause and cardiovascular deaths

Background: Acceleration of chronic diseases, particularly cardiovascular disease, may increase long-term mortality after community-acquired pneumonia (CAP), but underlying mechanisms are unknown. Persistence of the prothrombotic state that occurs during an acute infection may increase risk of subsequent atherothrombosis in patients with pre-existing cardiovascular disease and increase subsequent risk of death. We hypothesized that circulating hemostasis markers activated during CAP persist at hospital discharge, when patients appear to have recovered clinically, and are associated with higher mortality, particularly due to cardiovascular causes. Methods: In a cohort of survivors of CAP hospitalization from 28 US sites, we measured D-Dimer, thrombin-antithrombin complexes [TAT], Factor IX, antithrombin, and plasminogen activator inhibitor-1 at hospital discharge, and determined 1-year all-cause and cardiovascular mortality. Results: Of 893 subjects, most did not have severe pneumonia (70.6% never developed severe sepsis) and only 13.4% required intensive care unit admission. At discharge, 88.4% of subjects had normal vital signs and appeared to have clinically recovered. D-dimer and TAT levels were elevated at discharge in 78.8% and 30.1% of all subjects, and in 51.3% and 25.3% of those without severe sepsis. Higher D-dimer and TAT levels were associated with higher risk of all-cause mortality (range of hazard ratios were 1.66-1.17, p = 0.0001 and 1.46-1.04, p = 0.001 after adjusting for demographics and comorbid illnesses) and cardiovascular mortality (p = 0.009 and 0.003 in competing risk analyses). Conclusions: Elevations of TAT and D-dimer levels are common at hospital discharge in patients who appeared to have recovered clinically from pneumonia and are associated with higher risk of subsequent deaths, particularly due to cardiovascular disease. © 2011 Yende et al

A Blood-Based Screening Tool for Alzheimer's Disease That Spans Serum and Plasma: Findings from TARC and ADNI

There is no rapid and cost effective tool that can be implemented as a front-line screening tool for Alzheimer's disease (AD) at the population level.To generate and cross-validate a blood-based screener for AD that yields acceptable accuracy across both serum and plasma. status) data.Alzheimer's disease.11 proteins met our criteria and were utilized for the biomarker risk score. The random forest (RF) biomarker risk score from the TARC serum samples (training set) yielded adequate accuracy in the ADNI plasma sample (training set) (AUC = 0.70, sensitivity (SN) = 0.54 and specificity (SP) = 0.78), which was below that obtained from ADNI cerebral spinal fluid (CSF) analyses (t-tau/Aβ ratio AUC = 0.92). However, the full algorithm yielded excellent accuracy (AUC = 0.88, SN = 0.75, and SP = 0.91). The likelihood ratio of having AD based on a positive test finding (LR+) = 7.03 (SE = 1.17; 95% CI = 4.49–14.47), the likelihood ratio of not having AD based on the algorithm (LR−) = 3.55 (SE = 1.15; 2.22–5.71), and the odds ratio of AD were calculated in the ADNI cohort (OR) = 28.70 (1.55; 95% CI = 11.86–69.47).It is possible to create a blood-based screening algorithm that works across both serum and plasma that provides a comparable screening accuracy to that obtained from CSF analyses

Integrated copy number and gene expression analysis detects a CREB1 association with Alzheimer’s disease

Genetic variation, both single-nucleotide variations and copy number variations (CNV), contribute to changes in gene expression. In some cases these variations are meaningfully correlated with disease states. We hypothesized that in a genetically heterogeneous disorder such as sporadic Alzheimer's disease (AD), utilizing gene expression as a quantitative trait and CNVs as a genetic marker map within the same individuals in the context of case–control status may increase the power to detect relevant loci. Using this approach an 8-kb deletion was identified that contains a PAX6-binding site on chr2q33.3 upstream of CREB1 encoding the cAMP responsive element-binding protein1 transcription factor. The association of the CNV to AD was confirmed by a case–control association study consisting of the Texas Alzheimer Research and Care Consortium and NIA-LOAD Family Study data sets

Antibiotic use and risk of non-Hodgkin's lymphoma: a population-based case–control study

Antibiotic use in 759 non-Hodgkin's lymphoma (NHL) patients and 589 controls was compared. Neither total antibiotic use (odds ratio=0.7, 95% confidence interval=0.5–1.2), nor antibiotic use by site, was associated with total NHL, or NHL subtypes. There were no trends with frequency or age at first use (P trend=0.23 and 0.26, respectively)

Interaction Testing and Polygenic Risk Scoring to Estimate the Association of Common Genetic Variants With Treatment Resistance in Schizophrenia

Importance: About 20% to 30% of people with schizophrenia have psychotic symptoms that do not respond adequately to first-line antipsychotic treatment. This clinical presentation, chronic and highly disabling, is known as treatment-resistant schizophrenia (TRS). The causes of treatment resistance and their relationships with causes underlying schizophrenia are largely unknown. Adequately powered genetic studies of TRS are scarce because of the difficulty in collecting data from well-characterized TRS cohorts. Objective: To examine the genetic architecture of TRS through the reassessment of genetic data from schizophrenia studies and its validation in carefully ascertained clinical samples. Design, Setting, and Participants: Two case-control genome-wide association studies (GWASs) of schizophrenia were performed in which the case samples were defined as individuals with TRS (n = 10 501) and individuals with non-TRS (n = 20 325). The differences in effect sizes for allelic associations were then determined between both studies, the reasoning being such differences reflect treatment resistance instead of schizophrenia. Genotype data were retrieved from the CLOZUK and Psychiatric Genomics Consortium (PGC) schizophrenia studies. The output was validated using polygenic risk score (PRS) profiling of 2 independent schizophrenia cohorts with TRS and non-TRS: a prevalence sample with 817 individuals (Cardiff Cognition in Schizophrenia [CardiffCOGS]) and an incidence sample with 563 individuals (Genetics Workstream of the Schizophrenia Treatment Resistance and Therapeutic Advances [STRATA-G]). Main Outcomes and Measures: GWAS of treatment resistance in schizophrenia. The results of the GWAS were compared with complex polygenic traits through a genetic correlation approach and were used for PRS analysis on the independent validation cohorts using the same TRS definition. Results: The study included a total of 85 490 participants (48 635 [56.9%] male) in its GWAS stage and 1380 participants (859 [62.2%] male) in its PRS validation stage. Treatment resistance in schizophrenia emerged as a polygenic trait with detectable heritability (1% to 4%), and several traits related to intelligence and cognition were found to be genetically correlated with it (genetic correlation, 0.41-0.69). PRS analysis in the CardiffCOGS prevalence sample showed a positive association between TRS and a history of taking clozapine (r2 = 2.03%; P = .001), which was replicated in the STRATA-G incidence sample (r2 = 1.09%; P = .04). Conclusions and Relevance: In this GWAS, common genetic variants were differentially associated with TRS, and these associations may have been obscured through the amalgamation of large GWAS samples in previous studies of broadly defined schizophrenia. Findings of this study suggest the validity of meta-analytic approaches for studies on patient outcomes, including treatment resistance