α-Synuclein Aggregates in the Nigro-Striatal Dopaminergic Pathway Impair Fine Movement: Partial Reversal by the Adenosine A2A Receptor Antagonist.

Parkinson's disease (PD) is characterized pathologically by abnormal aggregation of alpha-synuclein (α-Syn) in the brain and clinically by fine movement deficits at the early stage, but the roles of α-Syn and associated neural circuits and neuromodulator bases in the development of fine movement deficits in PD are poorly understood, in part due to the lack of appropriate behavioral testing paradigms and PD models without motor confounding effects. Here, we coupled two unique behavioral paradigms with two PD models to reveal the following: (i) Focally injecting α-Syn fibrils into the dorsolateral striatum (DLS) and the transgenic expression of A53T-α-Syn in the dopaminergic neurons in the substantia nigra (SN, PITX3-IRES2-tTA/tetO-A53T mice) selectively impaired forelimb fine movements induced by the single-pellet reaching task. (ii) Injecting α-Syn fibers into the SN suppressed the coordination of cranial and forelimb fine movements induced by the sunflower seed opening test. (iii) Treatments with the adenosine A2A receptor (A2AR) antagonist KW6002 reversed the impairment of forelimb and cranial fine movements induced by α-Syn aggregates in the SN. These findings established a causal role of α-Syn in the SNc-DLS dopaminergic pathway in the development of forelimb and cranial fine movement deficits and suggest a novel therapeutic strategy to improve fine movements in PD by A2AR antagonists.

Effects of AC frequency on the capacitance measurement of hybrid response pressure sensors.

E-skins consisting of soft pressure sensors are enabling technology for soft robots, bio-integrated devices, and deformable touch panels. A well-known bottleneck of capacitive pressure sensors (CPS) is the drastic decay in sensitivity with increasing pressure. To overcome this challenge, we have invented a hybrid-response pressure sensor (HRPS) that exhibits both the piezoresistive and piezocapacitive effects intrinsic to a highly porous nanocomposite (PNC) with carbon nanotube (CNT) dopants. The HRPS is constructed with two conductive electrodes sandwiching a laminated PNC and a stiff dielectric layer. We have simplified the hybrid response into a parallel resistor-capacitor circuit, whose output depends on the AC (alternating current) frequency used for the capacitance measurement. Herein, through theoretical analysis, we discover a dimensionless parameter that governs the frequency responses of the HRPS. The master curve is validated through experiments on the HRPS with various doping ratios, subject to different compressive strains, under diverse AC frequencies. In addition, the relative contribution of piezoresistive and piezocapacitive mechanisms are also found to vary with the three parameters. Based on this experimentally validated theory, we establish a very practical guideline for selecting the optimal AC frequency for the capacitance measurement of HRPSs.

Voltammetric determination of DNA based on regulation of DNA strand displacement using an allosteric DNA toehold.

An electrochemical biosensor for determination of DNA is described that is based on the reaction of regulated DNA (reg-DNA) first with substrated DNA (subs-DNA) to form a reaction intermediate. The intermediate binds target DNA (T) by hybridization and initiates a branch migration leading to the production of complex of substrated DNA and target DNA (TC). Once TC is produced, it reacts with assisted DNA (ass-DNA) through a toehold exchange mechanism, yielding the product complex of substrated DNA and assisted DNA (CS). The target is then released back into the solution and and catalyzes the next cycle of toehold-exchange with the reaction intermediate of substrated DNA and regulated DNA (CPR). Unlike in a conventional DNA toehold that is hardwired with the branch migration domain, the allosteric DNA toehold is designed into a reg-DNA which is independent of the branch migration domain. Under the optimal experimental conditions and at a working potential as low as 0.18 V, response to DNA is linear in the 1 fM to 1000 pM concentration range, and the detection limit is 0.83 fM. The assay is highly specific and can discriminate target DNA even from a single-base mismatch. It was applied to the analysis of DNA spiked plasma samples. Graphical abstract Schematic illustration of the electrochemical strategy for target DNA detection based on regulation of DNA strand displacement using an allosteric DNA toehold strategy. It can be used to analyze DNA-spiked plasma samples and has a low detection limit of 0.83 fM.

Single-step and ultrasensitive detection of carcinoembryonic antigen based on an aptamer transduction-mediated exonuclease III-assisted dual-amplification strategy.

Herein, a single-step, rapid and homogenous fluorescence approach for highly sensitive and specific detection of CEA was successfully constructed for the first time using an aptamer binding-induced exonuclease III (Exo III)-mediated dual-amplification strategy. When present, CEA can specifically combine with the aptamer region in H1, resulting in a conformational change of H1 and the exposure of the occluded DNA fragment in the stem regions. Successively, the exposed DNA fragment partially hybridizes with H2 to initiate Exo III-assisted cycling cleavage to release another DNA fragment, which can in turn activate the cycling cleavage of the DNA fluorescence substrate (FS). Therefore, many fluorophore fragments are liberated to produce a significantly amplified fluorescence signal toward CEA detection. By virtue of the Exo III-assisted dual-amplification strategy, this method allows the detection of CEA at the fg mL-1 level with excellent selectivity. Compared with other reported strategies for CEA detection, the Exo III-assisted dual-amplification homogeneous platform only requires a one-step reaction, offering a very simple and low-cost detection. The practical ability of the developed strategy is demonstrated by the detection of CEA in human serum with satisfactory results. Thus, this method shows great potential in assays of many other biological analytes in clinical diagnosis.