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Disturbance of the cholinergic system plays a crucial role in the pathological progression of neurological diseases that cause dyskinesia-like behaviors. However, the molecular mechanisms underlying this disturbance remain elusive. Here, we showed that cyclin-dependent kinase 5 (Cdk5) was reduced in cholinergic neurons of midbrain according to the single-nucleus RNA sequencing analysis. Serum levels of CDK5 also decreased in patients with Parkinson’s disease accompanied by motor symptoms. Moreover, Cdk5 deficiency in cholinergic neurons triggered paw tremors, abnormal motor coordination, and motor balance deficits in mice. These symptoms occurred along with cholinergic neuron hyperexcitability and increases in the current density of large-conductance Ca2+-activated K+ channels (BK channels). Pharmacological inhibition of BK channels restrained the excessive intrinsic excitability of striatal cholinergic neurons in Cdk5-deficient mice. Furthermore, CDK5 interacted with BK channels and negatively regulated BK channel activity via phosphorylation of threonine-908. Restoration of CDK5 expression in striatal cholinergic neurons reduced dyskinesia-like behaviors in ChAT-Cre;Cdk5f/f mice. Together, these findings indicate that CDK5-induced phosphorylation of BK channels involves in cholinergic-neuron-mediated motor function, providing a potential new therapeutic target for treating dyskinesia-like behaviors arising from neurological diseases.

In this paper, a direct numerical simulation (DNS) of dielectric fluid flow subjected to unipolar injection under an alternating current (AC) electric field is carried out. The effect of frequency f of pulsed direct current (PDC) and AC on the transient evolution of electroconvection and their subcritical bifurcations are investigated in details. Electroconvection under PDC or AC tends to exhibit oscillating flow due to the periodic boundary condition of charge density and potential compared to the direct current (DC) case. The results demonstrate that under the PDC field, the linear criterion Tc decreases with increasing frequency, while the nonlinear stability criterion Tf is hardly affected. Under the AC field, a critical frequency fc = 0.0316 is found, which separates electroconvection into two typical flow regimes—periodic flow regime (f

DNA G-quadruplexes occur in oncologically relevant regions, thus are interesting targets for cancer research and treatment. Here, the authors solved the 1:1 and 4:2 (ligand/DNA) NMR structures of human telomeric DNA in complex with platinum(II)-tripod ligand and show that the binding is dynamic.

To prospectively evaluate the feasibility, safety and efficacy of the percutaneous pedicle screw fixation through the pedicle of fractured vertebra in the treatment of type A thoracolumbar fractures using Sextant system in the retrospective non- randomized case-control study.

An active fault-tolerant pulse-width-modulated tracker using the nonlinear autoregressive moving average with exogenous inputs model-based state-space self-tuning control is proposed for continuous-time multivariable nonlinear stochastic systems with unknown system parameters, plant noises, measurement noises, and inaccessible system states. Through observer/Kalman filter identification method, a good initial guess of the unknown parameters of the chosen model is obtained so as to reduce the identification process time and enhance the system performances. Besides, by modifying the conventional self-tuning control, a fault-tolerant control scheme is also developed. For the detection of fault occurrence, a quantitative criterion is exploited by comparing the innovation process errors estimated by the Kalman filter estimation algorithm. In addition, the weighting matrix resetting technique is presented by adjusting and resetting the covariance matrix of parameter estimates to improve the parameter estimation for faulty system recovery. The technique can effectively cope with partially abrupt and/or gradual system faults and/or input failures with fault detection.