Atypical perceptual narrowing in prematurely born infants is associated with compromised language acquisition at 2 years of age

Background

Protein aggregation plays important roles in several neurodegenerative disorders. For instance, insoluble aggregates of phosphorylated tau and of Aβ peptides are cornerstones in the pathology of Alzheimer's disease. Soluble protein aggregates are therefore potential diagnostic and prognostic biomarkers for their cognate disorders. Detection of the aggregated species requires sensitive tools that efficiently discriminate them from monomers of the same proteins. Here we have established a proximity ligation assay (PLA) for specific and sensitive detection of Aβ protofibrils via simultaneous recognition of three identical determinants present in the aggregates. PLA is a versatile technology in which the requirement for multiple target recognitions is combined with the ability to translate signals from detected target molecules to amplifiable DNA strands, providing very high specificity and sensitivity.

Results

For specific detection of Aβ protofibrils we have used a monoclonal antibody, mAb158, selective for Aβ protofibrils in a modified PLA, where the same monoclonal antibody was used for the three classes of affinity reagents required in the assay. These reagents were used for detection of soluble Aβ aggregates in solid-phase reactions, allowing detection of just 0.1 pg/ml Aβ protofibrils, and with a dynamic range greater than six orders of magnitude. Compared to a sandwich ELISA setup of the same antibody the PLA increases the sensitivity of the Aβ protofibril detection by up to 25-fold. The assay was used to measure soluble Aβ aggregates in brain homogenates from mice transgenic for a human allele predisposing to Aβ aggregation.

Conclusions

The proximity ligation assay is a versatile analytical technology for proteins, which can provide highly sensitive and specific detection of Aβ aggregates - and by implication other protein aggregates of relevance in Alzheimer's disease and other neurodegenerative disorders.     

Light scattering modeling of small feldspar aerosol particles using polyhedral prisms and spheroids

The use of simplified particle shapes for modeling scattering by irregularly shaped mineral-dust particles is studied using polyhedral prisms and spheroids as model particles. Simulated phase matrices averaged over shape and size distributions at wavelength 633 nm are compared with a laboratory-measured phase matrix of feldspar particles with known size distribution with effective radius of . When an equi-probable shape distribution is assumed, prisms and oblate spheroids agree with measurements to a similar degree, whereas prolate spheroids perform markedly better. Both spheroids and prisms perform much better than spheres. When an automatic fitting method is applied for finding optimal shape distributions, it is found that the most elongated spheroids are most important for good fits, whereas nearly-spherical spheroids are generally of very little importance. The phase matrices for the different polyhedral prisms, on the other hand, are found to be similar, thus their shape-averaged phase matrices are insensitive to the shape distribution assumed. For spheroids, a simple parameterization for the shape distribution, where weights increase with increasing departure from spherical shape, is proposed and tested. This parameterization improves the fit of most phase matrix elements attained with an equi-probable shape distribution, and it performs particularly well for reproducing the measured phase function.     

Vibrational spectroscopy and normal-mode analysis of Fe(II) octaethylporphyrin

The normal-mode spectrum for the four-coordinated heme compound Fe(II) octaethylporphyrin, Fe(OEP), has been determined by refining force constants to the experimental Fe vibrational density of states measured with nuclear resonance vibrational spectroscopy (NRVS). Convergence of the calculated spectrum to the data was achieved by first imposing D4 symmetry on the model structure as well as the force constants, progressively including different internal coordinates of motion, then allowing the true Ci (or S2) point group symmetry of the C(i)1 Fe(OEP) crystal structure. The NRVS-refined normal modes are in good agreement with Raman and IR spectra at high frequencies. Prior density functional theory predictions for a model porphyrin are similar to the core modes computed with the best-fit force field, but significant differences between D4 and Ci modes underline the sensitivity of porphyrin Fe normal modes to structural details. Some differences between the Ci best fit and the NRVS data can be attributed to intermolecular contacts not included in the normal-mode analysis.     

Diffraction of compatible random substitutions in one dimension

As a guiding example, the diffraction measure of a random local mixture of the two classic Fibonacci substitutions is determined and reanalysed via self-similar measures of Hutchinson type, defined by a finite family of contractions. Our revised approach yields explicit formulas for the pure point and the absolutely continuous parts, as well as a proof for the absence of singular continuous components. This approach is then extended to the family of random noble means substitutions and, as an example with an underlying 2-adic structure, to a locally randomised version of the period doubling chain. As a first step towards a more general approach, we interpret our findings in terms of a disintegration over the Kronecker factor, which is the maximal equicontinuous factor of a covering model set.     

A duality theorem for Tate–Shafarevich groups of curves over algebraically closed fields

In this note, we prove a duality theorem for the Tate–Shafarevich group of a finite discrete Galois module over the function field K of a curve over an algebraically closed field: there is a perfect duality of finite groups Open image in new window for F a finite étale Galois module on K of order invertible in K and with \(F' = {{\mathrm{Hom}}}(F,\mathbf{Q}/\mathbf {Z}(1))\). Furthermore, we prove that \(\mathrm {H}^1(K,G) = 0\) for G a simply connected, quasisplit semisimple group over K not of type \(E_8\).     

Hierarchies from D-brane instantons in globally defined Calabi-Yau orientifolds

We construct the first globally consistent semirealistic type I string vacua on an elliptically fibered manifold where the zero modes of the Euclidean D1-instanton sector allow for the generation of nonperturbative Majorana masses of an intermediate scale. In another class of global models, a D1-brane instanton can generate a Polonyi-type superpotential breaking supersymmetry at an exponentially suppressed scale.     

Testing for a $$\delta $$ -neighborhood of a generalized Pareto copula

Annals of the Institute of Statistical Mathematics - A multivariate distribution function F is in the max-domain of attraction of an extreme value distribution if and only if this is true for the...     

Targeted Photodynamic Therapy of Human Head and Neck Squamous Cell Carcinoma with Anti-epidermal Growth Factor Receptor Antibody Cetuximab and Photosensitizer IR700DX in the Mouse Skin-fold Window Chamber Model

Targeted photodynamic therapy (PDT) in head/neck cancer patients with a conjugate of the anti-epidermal growth factor receptor (EGFR) antibody, Cetuximab and a phthalocyanine photosensitizer IR700DX is under way, but the exact mechanisms of action are still not fully understood. In this study, the EGFR-overexpressing human head/neck OSC-19-luc2-cGFP tumor with transfected GFP gene was used in a skin-fold window chamber model in BALB/c nude mice. The uptake and localization of the conjugate in the tumor and its surrounding normal tissues were studied by an intravital confocal laser scanning microscopy with image analyses. The tumor was also irradiated with 690 nm laser light 24 h after conjugate administration. The vascular and tumor responses were examined by morphological evaluation and immunohistochemistry (IHC). The amount of conjugate in the tumor peaked at 24–48 h after injection. Image analyses of colocalization correlation parameters demonstrated a high fraction of the conjugate IR700DX colocalized in the GFP-expressing tumor cells. PDT-treated tumors showed extensive necrotic/apoptotic destruction with little vascular damage, while IHC showed no HIF-1α expression and decreased EGFR and Ki67 expression with activated caspase-3 overexpression, indicating a direct killing of tumor cells through both necrotic and apoptotic cell death.