Towards quantitative prediction of proteasomal digestion patterns of proteins

We discuss the problem of proteasomal degradation of proteins. Though proteasomes are important for all aspects of the cellular metabolism, some details of the physical mechanism of the process remain unknown. We introduce a stochastic model of the proteasomal degradation of proteins, which accounts for the protein translocation and the topology of the positioning of cleavage centers of a proteasome from first principles. For this model we develop the mathematical description based on a master-equation and techniques for reconstruction of the cleavage specificity inherent to proteins and the proteasomal translocation rates, which are a property of the proteasome specie, from mass spectroscopy data on digestion patterns. With these properties determined, one can quantitatively predict digestion patterns for new experimental set-ups. Additionally we design an experimental set-up for a synthetic polypeptide with a periodic sequence of amino acids, which enables especially reliable determination of translocation rates.Comment: 14 pages, 4 figures, submitted to J. Stat. Mech. (Special issue for proceedings of 5th Intl. Conf. on Unsolved Problems on Noise and Fluctuations in Physics, Biology & High Technology, Lyon (France), June 2-6, 2008

Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease

Hepcidin is a critical inhibitor of iron export from macrophages, enterocytes, and hepatocytes. Given that it is filtered and degraded by the kidney, its elevated levels in renal failure have been suggested to play a role in the disordered iron metabolism of uremia, including erythropoietin resistance. Here, we used a novel radioimmunoassay for hepcidin-25, the active form of the hormone, to measure its levels in renal disease. There was a significant diurnal variation of hepcidin and a strong correlation to ferritin levels in normal volunteers. In 44 patients with mild to moderate kidney disease, hepcidin levels were significantly elevated, positively correlated with ferritin but inversely correlated with the estimated glomerular filtration rate. In 94 stable hemodialysis patients, hepcidin levels were also significantly elevated, but this did not correlate with interleukin-6 levels, suggesting that increased hepcidin was not due to a general inflammatory state. Elevated hepcidin was associated with anemia, but, intriguingly, the erythropoietin dose was negatively correlated with hepcidin, suggesting that erythropoietin suppresses hepcidin levels. This was confirmed in 7 patients when hepcidin levels significantly decreased after initiation of erythropoietin treatment. Our results show that hepcidin is elevated in renal disease and suggest that higher hepcidin levels do not predict increased erythropoietin requirements

Magnetic state of plutonium ion in metallic Pu and its compounds

By LDA+U method with spin-orbit coupling (LDA+U+SO) the magnetic state and electronic structure have been investigated for plutonium in \delta and \alpha phases and for Pu compounds: PuN, PuCoGa5, PuRh2, PuSi2, PuTe, and PuSb. For metallic plutonium in both phases in agreement with experiment a nonmagnetic ground state was found with Pu ions in f^6 configuration with zero values of spin, orbital, and total moments. This result is determined by a strong spin-orbit coupling in 5f shell that gives in LDA calculation a pronounced splitting of 5f states on f^{5/2} and f^{7/2} subbands. A Fermi level is in a pseudogap between them, so that f^{5/2} subshell is already nearly completely filled with six electrons before Coulomb correlation effects were taken into account. The competition between spin-orbit coupling and exchange (Hund) interaction (favoring magnetic ground state) in 5f shell is so delicately balanced, that a small increase (less than 15%) of exchange interaction parameter value from J_H=0.48eV obtained in constrain LDA calculation would result in a magnetic ground state with nonzero spin and orbital moment values. For Pu compounds investigated in the present work, predominantly f^6 configuration with nonzero magnetic moments was found in PuCoGa5, PuSi2, and PuTe, while PuN, PuRh2, and PuSb have f^5 configuration with sizeable magnetic moment values. Whereas pure jj coupling scheme was found to be valid for metallic plutonium, intermediate coupling scheme is needed to describe 5f shell in Pu compounds. The results of our calculations show that both spin-orbit coupling and exchange interaction terms in the Hamiltonian must be treated in a general matrix form for Pu and its compounds.Comment: 20 pages, LaTeX; changed discussion on reference pape

A new potassium-based intermediate and its role in the desorption properties of the K–Mg–N–H system

In situSR-PXD experiments revealed a new reaction mechanism of amide–hydride anionic exchange for the K–Mg–N–H system

Increased circulating ANG II and TNF-α represents important risk factors in obese Saudi adults with hypertension irrespective of diabetic status and BMI

Central adiposity is a significant determinant of obesity-related hypertension risk, which may arise due to the pathogenic inflammatory nature of the abdominal fat depot. However, the influence of pro-inflammatory adipokines on blood pressure in the obese hypertensive phenotype has not been well established in Saudi subjects. As such, our study investigated whether inflammatory factors may represent useful biomarkers to delineate hypertension risk in a Saudi cohort with and without hypertension and/or diabetes mellitus type 2 (DMT2). Subjects were subdivided into four groups: healthy lean controls (age: 47.9±5.1 yr; BMI: 22.9±2.1 Kg/m2), non-hypertensive obese (age: 46.1±5.0 yr; BMI: 33.7±4.2 Kg/m2), hypertensive obese (age: 48.6±6.1 yr; BMI: 36.5±7.7 Kg/m2) and hypertensive obese with DMT2 (age: 50.8±6.0 yr; BMI: 35.3±6.7 Kg/m2). Anthropometric data were collected from all subjects and fasting blood samples were utilized for biochemical analysis. Serum angiotensin II (ANG II) levels were elevated in hypertensive obese (p<0.05) and hypertensive obese with DMT2 (p<0.001) compared with normotensive controls. Systolic blood pressure was positively associated with BMI (p<0.001), glucose (p<0.001), insulin (p<0.05), HOMA-IR (p<0.001), leptin (p<0.01), TNF-α (p<0.001) and ANG II (p<0.05). Associations between ANG II and TNF-α with systolic blood pressure remained significant after controlling for BMI. Additionally CRP (p<0.05), leptin (p<0.001) and leptin/adiponectin ratio (p<0.001) were also significantly associated with the hypertension phenotype. In conclusion our data suggests that circulating pro-inflammatory adipokines, particularly ANG II and, TNF-α, represent important factors associated with a hypertension phenotype and may directly contribute to predicting and exacerbating hypertension risk

Does psychopathology at admission predict the length of inpatient stay in psychiatry? Implications for financing psychiatric services

Background: The debate on appropriate financing systems in inpatient psychiatry is ongoing. In this context, it is important to control resource use in terms of length of stay (LOS), which is the most costly factor in inpatient care and the one that can be influenced most easily. Previous studies have shown that psychiatric diagnoses provide only limited justification for explaining variation in LOS, and it has been suggested that measures such as psychopathology might be more appropriate to predict resource use. Therefore, we investigated the relationship between LOS and psychopathological syndromes or symptoms at admission as well as other characteristics such as sociodemographic and clinical variables. Methods: We considered routine medical data of patients admitted to the Psychiatric University Hospital Zurich in the years 2008 and 2009. Complete data on psychopathology at hospital admission were available in 3,220 inpatient episodes. A subsample of 2,939 inpatient episodes was considered in final statistical models, including psychopathology as well as complete datasets of further measures (e.g. sociodemographic, clinical, treatment-related and psychosocial variables). We used multivariate linear as well as logistic regression analysis with forward selection procedure to determine the predictors of LOS. Results: All but two syndrome scores (mania, hostility) were positively related to the length of stay. Final statistical models showed that syndromes or symptoms explained about 5% of the variation in length of stay. The inclusion of syndromes or symptoms as well as basic treatment variables and other factors led to an explained variation of up to 25%. Conclusions: Psychopathological syndromes and symptoms at admission and further characteristics only explained a small proportion of the length of inpatient stay. Thus, according to our sample, psychopathology might not be suitable as a primary indicator for estimating LOS and contingent costs. This might be considered in the development of future costing systems in psychiatry

Hydrogen storage systems from waste Mg alloys

The production cost of materials for hydrogen storage is one of the major issues to be addressed in order to consider them suitable for large scale applications. In the last decades several authors reported on the hydrogen sorption properties of Mg and Mg-based systems. In this work magnesium industrial wastes of AZ91 alloy and Mg-10 wt.% Gd alloy are used for the production of hydrogen storage materials. The hydrogen sorption properties of the alloys were investigated by means of volumetric technique, in situ synchrotron radiation powder X-ray diffraction (SR-PXD) and calorimetric methods. The measured reversible hydrogen storage capacity for the alloys AZ91 and Mg-10 wt.% Gd are 4.2 and 5.8 wt.%, respectively. For the Mg-10 wt.% Gd alloy, the hydrogenated product was also successfully used as starting reactant for the synthesis of Mg(NH2)2 and as MgH2 substitute in the Reactive Hydride Composite (RHC) 2LiBH4 + MgH 2. The results of this work demonstrate the concrete possibility to use Mg alloy wastes for hydrogen storage purposes

Self-organization with traveling waves: A case for a convective torus

A traveling wave of BaSO4 in the chlorite-thiourea reaction has shown concentric precipitation patterns upon being triggered by the autocatalyst HOCl. The precipitation patterns show circular rings of alternate null and full precipitation regions. This self-organization appears to be the result of the formation of a convective torus. The formation of the convective torus can be described as a Benard-Marangoni instability with lateral heating

Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition.

Mutations of the tricarboxylic acid cycle enzyme fumarate hydratase cause hereditary leiomyomatosis and renal cell cancer. Fumarate hydratase-deficient renal cancers are highly aggressive and metastasize even when small, leading to a very poor clinical outcome. Fumarate, a small molecule metabolite that accumulates in fumarate hydratase-deficient cells, plays a key role in cell transformation, making it a bona fide oncometabolite. Fumarate has been shown to inhibit α-ketoglutarate-dependent dioxygenases that are involved in DNA and histone demethylation. However, the link between fumarate accumulation, epigenetic changes, and tumorigenesis is unclear. Here we show that loss of fumarate hydratase and the subsequent accumulation of fumarate in mouse and human cells elicits an epithelial-to-mesenchymal-transition (EMT), a phenotypic switch associated with cancer initiation, invasion, and metastasis. We demonstrate that fumarate inhibits Tet-mediated demethylation of a regulatory region of the antimetastatic miRNA cluster mir-200ba429, leading to the expression of EMT-related transcription factors and enhanced migratory properties. These epigenetic and phenotypic changes are recapitulated by the incubation of fumarate hydratase-proficient cells with cell-permeable fumarate. Loss of fumarate hydratase is associated with suppression of miR-200 and the EMT signature in renal cancer and is associated with poor clinical outcome. These results imply that loss of fumarate hydratase and fumarate accumulation contribute to the aggressive features of fumarate hydratase-deficient tumours.This work was supported by the Medical Research Council (UK). S.F. was supported by a Herchel Smith Research Studentship and K.F. by an MRC Career Development Award. E.R.M is supported by the ERC Advanced Researcher award 323004–ONCOTREAT. P.H.M. is supported by Senior Investigator Awards from the Wellcome Trust and NIHR. The Cambridge Human Research Tissue Bank and A.W. are supported by the NIHR Cambridge Biomedical Research Centre.This is the author accepted manuscript. The final version is available from Nature Publishing at http://dx.doi.org/10.1038/nature19353

The Endogenous Th17 Response in NO<inf>2</inf>-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. © 2013 Martin et al