Increased DNA dicarbonyl glycation and oxidation markers in patients with type 2 diabetes and link to diabetic nephropathy

Aim. The aim of this study was to assess the changes of markers of DNA damage by glycation and oxidation in patients with type 2 diabetes and the association with diabetic nephropathy. Methodology. DNA oxidation and glycation adducts were analysed in plasma and urine by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. DNA markers analysed were as follows: the oxidation adduct 7,8-dihydro-8-oxo-2′-deoxyguanosine (8-OxodG) and glycation adducts of glyoxal and methylglyoxal—imidazopurinones GdG, MGdG, and N2-(1,R/S-carboxyethyl)deoxyguanosine (CEdG). Results. Plasma 8-OxodG and GdG were increased 2-fold and 6-fold, respectively, in patients with type 2 diabetes, with respect to healthy volunteers. Median urinary excretion rates of 8-OxodG, GdG, MGdG, and CEdG were increased 28-fold, 10-fold, 2-fold, and 2-fold, respectively, in patients with type 2 diabetes with respect to healthy controls. In patients with type 2 diabetes, nephropathy was associated with increased plasma 8-OxodG and increased urinary GdG and CEdG. In a multiple logistic regression model for diabetic nephropathy, diabetic nephropathy was linked to systolic blood pressure and urinary CEdG. Conclusion. DNA oxidative and glycation damage-derived nucleoside adducts are increased in plasma and urine of patients with type 2 diabetes and further increased in patients with diabetic nephropathy

Bispecific antibody detection using antigen-conjugated synthetic nucleic acid strands

We report here the development of two different sensing strategies based on the use of antigen-conjugated nucleic acid strands for the detection of a bispecific antibody against the tumor-related proteins Mucin1 and epidermal growth factor receptor. Both approaches work well in serum samples (nanomolar sensitivity), show high specificity against the two monospecific antibodies, and are rapid. The results presented here demonstrate the versatility of DNA-based platforms for the detection of bispecific antibodies and could represent a versatile alternative to other more reagent-intensive and time-consuming analytical approaches

String Field Theory Projectors for Fermions of Integral Weight

The interaction vertex for a fermionic first order system of weights (1,0) such as the twisted bc-system, the fermionic part of N=2 string field theory and the auxiliary \eta\xi system of N=1 strings is formulated in the Moyal basis. In this basis, the Neumann matrices are diagonal; as usual, the eigenvectors are labeled by \kappa\in\R. Oscillators constructed from these eigenvectors make up two Clifford algebras for each nonzero value of \kappa. Using a generalization of the Moyal-Weyl map to the fermionic case, we classify all projectors of the star-algebra which factorize into projectors for each \kappa-subspace. At least for the case of squeezed states we recover the full set of bosonic projectors with this property. Among the subclass of ghost number-homogeneous squeezed state projectors, we find a single class of BPZ-real states parametrized by one (nearly) arbitrary function of \kappa. This class is shown to contain the generalized butterfly states. Furthermore, we elaborate on sufficient and necessary conditions which have to be fulfilled by our projectors in order to constitute surface states. As a byproduct we find that the full star product of N=2 string field theory translates into a canonically normalized continuous tensor product of Moyal-Weyl products up to an overall normalization. The divergent factors arising from the translation to the continuous basis cancel between bosons and fermions in any even dimension.Comment: LaTeX, 1+23 pages, minor improvements, references adde

Magnetic order in orbital models of the iron pnictides

We examine the appearance of the experimentally-observed stripe spin-density-wave magnetic order in five different orbital models of the iron pnictide parent compounds. A restricted mean-field ansatz is used to determine the magnetic phase diagram of each model. Using the random phase approximation, we then check this phase diagram by evaluating the static spin susceptibility in the paramagnetic state close to the mean-field phase boundaries. The momenta for which the susceptibility is peaked indicate in an unbiased way the actual ordering vector of the nearby mean-field state. The dominant orbitally resolved contributions to the spin susceptibility are also examined to determine the origin of the magnetic instability. We find that the observed stripe magnetic order is possible in four of the models, but it is extremely sensitive to the degree of the nesting between the electron and hole Fermi pockets. In the more realistic five-orbital models, this order competes with a strong-coupling incommensurate state which appears to be controlled by details of the electronic structure below the Fermi energy. We conclude by discussing the implications of our work for the origin of the magnetic order in the pnictides.Comment: 19 pages, 19 figures; published version, typos corrected, references adde

String Field Theory Vertices for Fermions of Integral Weight

We construct Witten-type string field theory vertices for a fermionic first order system with conformal weights (0,1) in the operator formulation using delta-function overlap conditions as well as the Neumann function method. The identity, the reflector and the interaction vertex are treated in detail paying attention to the zero mode conditions and the U(1) charge anomaly. The Neumann coefficients for the interaction vertex are shown to be intimately connected with the coefficients for bosons allowing a simple proof that the reparametrization anomaly of the fermionic first order system cancels the contribution of two real bosons. This agrees with their contribution c=-2 to the central charge. The overlap equations for the interaction vertex are shown to hold. Our results have applications in N=2 string field theory, Berkovits' hybrid formalism for superstring field theory, the \eta\xi-system and the twisted bc-system used in bosonic vacuum string field theory.Comment: 1+28 pages, minor improvements, references adde

Streptozotocin-induced beta-cell damage, high fat diet, and metformin administration regulate Hes3 expression in the adult mouse brain

Diabetes mellitus is a group of disorders characterized by prolonged high levels of circulating blood glucose. Type 1 diabetes is caused by decreased insulin production in the pancreas whereas type 2 diabetes may develop due to obesity and lack of exercise;it begins with insulin resistance whereby cells fail to respond properly to insulin and it may also progress to decreased insulin levels. The brain is an important target for insulin, and there is great interest in understanding how diabetes affects the brain. In addition to the direct effects of insulin on the brain, diabetes may also impact the brain through modulation of the inflammatory system. Here we investigate how perturbation of circulating insulin levels affects the expression of Hes3, a transcription factor expressed in neural stem and progenitor cells that is involved in tissue regeneration. Our data show that streptozotocin-induced beta-cell damage, high fat diet, as well as metformin, a common type 2 diabetes medication, regulate Hes3 levels in the brain. This work suggests that Hes3 is a valuable biomarker helping to monitor the state of endogenous neural stem and progenitor cells in the context of diabetes mellitus

t4 Workshop Report: Integrated Testing Strategies (ITS) for Safety Assessment

Integrated testing strategies (ITS), as opposed to single definitive tests or fixed batteries of tests, are expected to efficiently combine different information sources in a quantifiable fashion to satisfy an information need, in this case for regulatory safety assessments. With increasing awareness of the limitations of each individual tool and the development of highly targeted tests and predictions, the need for combining pieces of evidence increases. The discussions that took place during this workshop, which brought together a group of experts coming from different related areas, illustrate the current state of the art of ITS, as well as promising developments and identifiable challenges. The case of skin sensitization was taken as an example to understand how possible ITS can be constructed, optimized and validated. This will require embracing and developing new concepts such as adverse outcome pathways (AOP), advanced statistical learning algorithms and machine learning, mechanistic validation and “Good ITS Practices”.JRC.I.5-Systems Toxicolog