Several findings propose the altered tau protein network as an important target for Alzheimer's disease (AD). Particularly, two points of pharmacological intervention can be envisaged: inhibition of phosphorylating tau kinase GSK-3β and tau aggregation process. On the basis of this consideration and on our interest in multitarget paradigms in AD, we report on the discovery of 2,4-thiazolidinedione derivatives endowed with such a profile. 28 and 30 displayed micromolar IC values toward GSK-3β, together with the capacity of inhibiting AcPHF6 aggregation of 60% and 80% at 10 μM, respectively. In addition, they showed PAMPA-BBB permeability, together with a suitable cellular safety profile. 30 also displayed inhibition of both K18 and full-length tau aggregations. Finally, both compounds were able to improve cell viability in an okadaic acid-induced neurodegeneration cell model. To the best of our knowledge, 28 and 30 are the first balanced, nontoxic, dual-acting compounds hitting tau cascade at two different hubs.

The dysregulation of the concentration of individual circulating microRNAs or small sets of them has been recognized as a marker of disease. For example, an increase of the concentration of circulating miR-17 has been linked to lung cancer and metastatic breast cancer, while its decrease has been found in multiple sclerosis and gastric cancer. Consequently, techniques for the fast, specific and simple quantitation of microRNAs are becoming crucial enablers of early diagnosis and therapeutic follow-up. DNA based biosensors can serve this purpose, overcoming some of the drawbacks of conventional lab-based techniques. Herein, we report a cost-effective, simple and robust biosensor based on localized surface plasmon resonance and hybridization chain reaction. Immobilized gold nanoparticles are used for the detection of miR-17. Specificity of the detection was achieved by the use of hairpin surface-tethered probes and the hybridization chain reaction was used to amplify the detection signal and thus extend the dynamic range of the quantitation. Less than 1 h is needed for the entire procedure that achieved a limit of detection of about 1 pM or 50 amol/measurement, well within the reported useful range for diagnostic applications. We suggest that this technology could be a promising substitute of traditional lab-based techniques for the detection and quantification of miRNAs after these are extracted from diagnostic specimens and their analysis is thus made possible.

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We investigated the dewetting process on flat and chemically patterned surfaces of ultrathin films (thickness between 2 and 15 nm) of a cylinder forming polystyrene- block-poly(methyl methacrylate) (PS- b-PMMA) spin coated on poly(styrene- r-methyl methacrylate) random copolymers (RCPs). When the PS- b-PMMA film dewets on a 2 nm-thick RCP layer, the ordering of the hexagonally packed PMMA cylinders in the dewetted structures extends over distances far exceeding the correlation length obtained in continuous block copolymer (BCP) films. As a result, micrometer-sized circular droplets featuring defectless single grains of self-assembled PS- b-PMMA with PMMA cylinders perpendicularly oriented with respect to the substrate are generated and randomly distributed on the substrate. Additionally, alignment of the droplets along micrometric lines was achieved by performing the dewetting process on large-scale chemically patterned stripes of 2 nm thick RCP films by laser lithography. By properly adjusting the periodicity of the chemical pattern, it was possible to tune and select the geometrical characteristics of the dewetted droplets in terms of maximum thickness, contact angle and diameter while maintaining the defectless single grain perpendicular cylinder morphology of the circular droplets.