Mitochondrial F0F1-ATP synthase is a molecular target of 3-iodothyronamine, an endogenous metabolite of thyroid hormone

Background & Purpose:\u2002 T1AM is a thyronamine derivative of thyroid hormone acting as a signalling molecule via non-genomic effectors and can reach intracellular targets. In light of the importance of F(0) F(1) -ATPsynthase as a target in drug development, T1AM interaction with the enzyme is demonstrated by its effects on the activity and a model of binding locations is depicted. Experimental Approach:\u2002 Kinetic analyses were performed on F(0) F(1) -ATPsynthase in sub-mitochondrial particles and soluble F(1) -ATPase. Activity assays and immunodetection of the inhibitor protein IF(1) were used and combined with molecular docking analyses. In situ respirometric analysis of T1AM effect was investigated on H9c2 cardiomyocytes. Key Results:\u2002 T1AM is a non-competitive inhibitor of F(0) F(1) -ATPsynthase whose binding is mutually exclusive with that of the inhibitors IF(1) and aurovertin B. Distinct T1AM binding sites are consistent with results from both kinetic and docking analyses: at low nanomolar concentrations, T1AM binds to a high affinity-region likely located within the IF(1) binding site, causing IF(1) release; at higher concentrations, T1AM binds to a low affinity-region likely located within the aurovertin binding cavity and inhibits enzyme activity. Low nanomolar concentrations of T1AM elicit in cardiomyocytes an increase in ADP-stimulated mitochondrial respiration indicative for an activation of F(0) F(1) -ATPsynthase consistent with displacement of endogenous IF(1, ) thereby reinforcing the in vitro results. Conclusions & Implications:\u2002 The T1AM effects upon F(0) F(1) -ATPsynthase are twofold: IF(1) displacement and enzyme inhibition. By targeting F(0) F(1) -ATPsynthase within mitochondria T1AM might affect cell bioenergetics with a positive effect on mitochondrial energy production at low endogenous concentration. T1AM putative binding locations overlapping with IF(1) and aurovertin binding sites are depicted

Adaptability and stability of wheat cultivars in the Northern region of Rio Grande do Sul

Abstract: The experiment evaluated the performance of 12 wheat cultivars indicated to be grown in the northern of Rio Grande do Sul. According to Scott-Knott?s mean comparison test, they obtained higher grain yields of Ametista, Marfím, ORS Vintecinco, TBIO Mestre, TBIO Sintonia and TBIO Sinuelo, and regarding grain quality, Ametista, Jadeíte 11, ORS Vintecinco and Topázio. According to the method by Eberhart and Russell, Ametista, BRS Marcante, TBIO Iguaçu and TBIO Sinuelo were stable in relation to productivity and hectolitre weight. Using the Lin and Binns analysis, the Ametista showed higher average yield and greater stability in the evaluated cultivation conditions, and the TBIO Sintonia is indicated for favorable environments. In reference to the AMMI method, Ametista and TBIO Sinuelo were the most stable regarding productivity, and the 2014 and 2016 harvests were stable. In relation to hectolitre weight, Jadeíte 11 and TBIO Mestre and the year 2016 showed more stability. Resumo: O experimento avaliou o desempenho de 12 cultivares de trigo indicadas para cultivo no norte do estado do Rio Grande do Sul. De acordo com o teste de comparação da média de Scott-Knott, obtiveram maiores rendimentos de grãos as cultivares Ametista, Marfím, ORS Vintecinco, TBIO Mestre, TBIO Sintonia e TBIO Sinuelo, e em relação à qualidade dos grãos, Ametista, Jadeíte 11, ORS Vintecinco e Topázio. De acordo com o método de Eberhart e Russell, Ametista, BRS Marcante, TBIO Iguaçu e TBIO Sinuelo foram cultivares mais estáveis em relação à produtividade e peso do hectolitro. Utilizando a análise de Lin e Binns, a cultivar Ametista mostrou maior rendimento médio e maior estabilidade nas condições de cultivo avaliadas, e o TBIO Sintonia é o mais indicado para ambientes favoráveis. Em referência ao método AMMI, Ametista e TBIO Sinuelo foram as cultivares mais estáveis em relação à produtividade, e os cultivos de 2014 e 2016 foram estáveis. Em relação ao peso hectolitro, Jadeíte 11 e TBIO Mestre e o ano de 2016 demostraram mais estabilidade

WITHDRAWN: Procalcitonin and mid regional-pro-adrenomedullin promising markers for sepsis diagnosis and prognosis

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The osmotic pressure of charged colloidal suspensions: A unified approach to linearized Poisson-Boltzmann theory

We study theoretically the osmotic pressure of a suspension of charged objects (e.g., colloids, polyelectrolytes, clay platelets, etc.) dialyzed against an electrolyte solution using the cell model and linear Poisson-Boltzmann (PB) theory. From the volume derivative of the grand potential functional of linear theory we obtain two novel expressions for the osmotic pressure in terms of the potential- or ion-profiles, neither of which coincides with the expression known from nonlinear PB theory, namely, the density of microions at the cell boundary. We show that the range of validity of linearization depends strongly on the linearization point and proof that expansion about the selfconsistently determined average potential is optimal in several respects. For instance, screening inside the suspension is automatically described by the actual ionic strength, resulting in the correct asymptotics at high colloid concentration. Together with the analytical solution of the linear PB equation for cell models of arbitrary dimension and electrolyte composition explicit and very general formulas for the osmotic pressure ensue. A comparison with nonlinear PB theory is provided. Our analysis also shows that whether or not linear theory predicts a phase separation depends crucially on the precise definition of the pressure, showing that an improper choice could predict an artificial phase separation in systems as important as DNA in physiological salt solution.Comment: 16 pages, 5 figures, REVTeX4 styl

Topologically non-trivial metal-organic assemblies inhibit \u3b22-microglobulin amyloidogenesis

Inhibiting amyloid aggregation through high-turnover dynamic interactions could be an efficient strategy that is already used by small heat-shock proteins in different biological contexts. We report the interactions of three topologically non-trivial, zinc-templated metal-organic assemblies, a [2]catenane, a trefoil knot (TK), and Borromean rings, with two \u3b22-microglobulin (\u3b22m) variants responsible for amyloidotic pathologies. Fast exchange and similar patterns of preferred contact surface are observed by NMR, consistent with molecular dynamics simulations. In vitro fibrillation is inhibited by each complex, whereas the zinc-free TK induces protein aggregation and does not inhibit fibrillogenesis. The metal coordination imposes structural rigidity that determines the contact area on the \u3b22m surface depending on the complex dimensions, ensuring in vitro prevention of fibrillogenesis. Administration of TK, the best protein-contacting species, to a disease-model organism, namely a Caenorhabditis elegans mutant expressing the D76N \u3b22m variant, confirms the bioactivity potential of the knot topology and suggests new developments

A specific nanobody prevents amyloidogenesis of D76N β2-microglobulin in vitro and modifies its tissue distribution in vivo

Systemic amyloidosis is caused by misfolding and aggregation of globular proteins in vivo for which effective treatments are urgently needed. Inhibition of protein self-aggregation represents an attractive therapeutic strategy. Studies on the amyloidogenic variant of β2-microglobulin, D76N, causing hereditary systemic amyloidosis, have become particularly relevant since fibrils are formed in vitro in physiologically relevant conditions. Here we compare the potency of two previously described inhibitors of wild type β2-microglobulin fibrillogenesis, doxycycline and single domain antibodies (nanobodies). The β2-microglobulin -binding nanobody, Nb24, more potently inhibits D76N β2-microglobulin fibrillogenesis than doxycycline with complete abrogation of fibril formation. In β2-microglobulin knock out mice, the D76N β2-microglobulin/ Nb24 pre-formed complex, is cleared from the circulation at the same rate as the uncomplexed protein; however, the analysis of tissue distribution reveals that the interaction with the antibody reduces the concentration of the variant protein in the heart but does not modify the tissue distribution of wild type β2-microglobulin. These findings strongly support the potential therapeutic use of this antibody in the treatment of systemic amyloidosis

Amino acid "little Big Bang": Representing amino acid substitution matrices as dot products of Euclidian vectors

<p>Abstract</p> <p>Background</p> <p>Sequence comparisons make use of a one-letter representation for amino acids, the necessary quantitative information being supplied by the substitution matrices. This paper deals with the problem of finding a representation that provides a comprehensive description of amino acid intrinsic properties consistent with the substitution matrices.</p> <p>Results</p> <p>We present a Euclidian vector representation of the amino acids, obtained by the singular value decomposition of the substitution matrices. The substitution matrix entries correspond to the dot product of amino acid vectors. We apply this vector encoding to the study of the relative importance of various amino acid physicochemical properties upon the substitution matrices. We also characterize and compare the PAM and BLOSUM series substitution matrices.</p> <p>Conclusions</p> <p>This vector encoding introduces a Euclidian metric in the amino acid space, consistent with substitution matrices. Such a numerical description of the amino acid is useful when intrinsic properties of amino acids are necessary, for instance, building sequence profiles or finding consensus sequences, using machine learning algorithms such as Support Vector Machine and Neural Networks algorithms.</p

Adsorption of mono- and multivalent cat- and anions on DNA molecules

Adsorption of monovalent and multivalent cat- and anions on a deoxyribose nucleic acid (DNA) molecule from a salt solution is investigated by computer simulation. The ions are modelled as charged hard spheres, the DNA molecule as a point charge pattern following the double-helical phosphate strands. The geometrical shape of the DNA molecules is modelled on different levels ranging from a simple cylindrical shape to structured models which include the major and minor grooves between the phosphate strands. The densities of the ions adsorbed on the phosphate strands, in the major and in the minor grooves are calculated. First, we find that the adsorption pattern on the DNA surface depends strongly on its geometrical shape: counterions adsorb preferentially along the phosphate strands for a cylindrical model shape, but in the minor groove for a geometrically structured model. Second, we find that an addition of monovalent salt ions results in an increase of the charge density in the minor groove while the total charge density of ions adsorbed in the major groove stays unchanged. The adsorbed ion densities are highly structured along the minor groove while they are almost smeared along the major groove. Furthermore, for a fixed amount of added salt, the major groove cationic charge is independent on the counterion valency. For increasing salt concentration the major groove is neutralized while the total charge adsorbed in the minor groove is constant. DNA overcharging is detected for multivalent salt. Simulations for a larger ion radii, which mimic the effect of the ion hydration, indicate an increased adsorbtion of cations in the major groove.Comment: 34 pages with 14 figure

Effective interaction between helical bio-molecules

The effective interaction between two parallel strands of helical bio-molecules, such as deoxyribose nucleic acids (DNA), is calculated using computer simulations of the "primitive" model of electrolytes. In particular we study a simple model for B-DNA incorporating explicitly its charge pattern as a double-helix structure. The effective force and the effective torque exerted onto the molecules depend on the central distance and on the relative orientation. The contributions of nonlinear screening by monovalent counterions to these forces and torques are analyzed and calculated for different salt concentrations. As a result, we find that the sign of the force depends sensitively on the relative orientation. For intermolecular distances smaller than $6\AA$ it can be both attractive and repulsive. Furthermore we report a nonmonotonic behaviour of the effective force for increasing salt concentration. Both features cannot be described within linear screening theories. For large distances, on the other hand, the results agree with linear screening theories provided the charge of the bio-molecules is suitably renormalized.Comment: 18 pages, 18 figures included in text, 100 bibliog