A brain-targeting lipidated peptide for neutralizing RNA-mediated toxicity in Polyglutamine Diseases

Abstract Polyglutamine (PolyQ) diseases are progressive neurodegenerative disorders caused by both protein- and RNA-mediated toxicities. We previously showed that a peptidyl inhibitor, P3, which binds directly to expanded CAG RNA can inhibit RNA-induced nucleolar stress and suppress RNA-induced neurotoxicity. Here we report a N-acetylated and C-amidated derivative of P3, P3V8, that showed a more than 20-fold increase in its affinity for expanded CAG RNA. The P3V8 peptide also more potently alleviated expanded RNA-induced cytotoxicity in vitro, and suppressed polyQ neurodegeneration in Drosophila with no observed toxic effects. Further N-palmitoylation of P3V8 (L1P3V8) not only significantly improved its cellular uptake and stability, but also facilitated its systemic exposure and brain uptake in rats via intranasal administration. Our findings demonstrate that concomitant N-acetylation, C-amidation and palmitoylation of P3 significantly improve both its bioactivity and pharmacological profile. L1P3V8 possesses drug/lead-like properties that can be further developed into a lead inhibitor for the treatment of polyQ diseases

Dictionary Learning-Cooperated Matrix Decomposition for Hyperspectral Target Detection

Hyperspectral target detection is one of the most challenging tasks in remote sensing due to limited spectral information. Many algorithms based on matrix decomposition (MD) are proposed to promote the separation of the background and targets, but they suffer from two problems: (1) Targets are detected with the criterion of reconstruction residuals, and the imbalanced number of background and target atoms in union dictionary may lead to misclassification of targets. (2) The detection results are susceptible to the quality of the apriori target spectra, thus obtaining inferior performance because of the inevitable spectral variability. In this paper, we propose a matrix decomposition-based detector named dictionary learning-cooperated matrix decomposition (DLcMD) for hyperspectral target detection. The procedure of DLcMD is two-fold. First, the low rank and sparse matrix decomposition (LRaSMD) is exploited to separate targets from the background due to its insensitivity to the imbalanced number of background and target atoms, which can reduce the misclassification of targets. Inspired by dictionary learning, the target atoms are updated during LRaSMD to alleviate the impact of spectral variability. After that, a binary hypothesis model specifically designed for LRaSMD is proposed, and a generalized likelihood ratio test (GLRT) is performed to obtain the final detection result. Experimental results on five datasets have shown the reliability of the proposed method. Especially in the Los Angeles-II dataset, the area under the curve (AUC) value is nearly 16% higher than the average value of the other seven detectors, which reveals the superiority of DLcMD in hyperspectral target detection

Dual Modification of Stainless Steel by Small Molecule Oxalic Acid for Oxygen Evolution Reaction

A electrocatalyst with low cost and high performance is the key to achieve the industrial application of hydrogen energy. In this work, inexpensive commercial stainless steel is modified by a simple hydrothermal method. For the first time, surface corrosion modification and active substance loading are realized simultaneously with small-molecule oxalic acid. Compared with 304-type stainless steel mesh (SSM-304), the overpotential of the sample after two-step treatment (noted as OESSM) is largely decreased (125 mV), and exceptional stability (48 h) is achieved. In acidic hydrothermal corrosion, the metal on the surface of stainless steel is eroded into the solution. Then, the C2O42– recomplexes with the dissolved metal ions, and the oxalate is grown on the surface. The excellent catalytic activity and stability come from the unique framework structure of the metal oxalate crystals. Oxalic acid is widely available and with double carboxyl group in C2O42–. The electrons enriched in CO can enhance the adsorption energy on the catalyst surface and induce the production of active catalytic sites *OOH. In addition, the oxalate crystal framework provides critical support for maintaining positive catalytic activity and stability. This work creates the possibility of realizing the large-scale application of stainless steel-based electrocatalysts in actual production

Self-Powered and Autonomous Vibrational Wake-Up System Based on Triboelectric Nanogenerators and MEMS Switch

With the extensive application of wireless sensing nodes, the demand for sustainable energy in unattended environments is increasing. Here, we report a self-powered and autonomous vibrational wake-up system (SAVWS) based on triboelectric nanogenerators and micro-electromechanical system (MEMS) switches. The energy triboelectric nanogenerator (E-TENG) harvests vibration energy to power the wireless transmitter through a MEMS switch. The signal triboelectric nanogenerator (S-TENG) controls the state of the MEMS switch as a self-powered accelerometer and shows good linearity in the acceleration range of 1–4.5 m/s2 at 30 Hz with a sensitivity of about 14.6 V/(m/s2). When the acceleration increases, the S-TENG turns on the MEMS switch, and the wireless transmitter transmits an alarm signal with the energy from E-TENG, using only 0.64 mJ. Using TENGs simultaneously as an energy source and a sensor, the SAVWS provides a self-powered vibration monitoring solution for unattended environments and shows extensive applications and great promise in smart factories, autonomous driving, and the Internet of Things

Brain-Targeting Delivery of Two Peptidylic Inhibitors for Their Combination Therapy in Transgenic Polyglutamine Disease Mice via Intranasal Administration

Polyglutamine diseases are a set of progressive neurodegenerative disorders caused by misfolding and aggregation of mutant CAG RNA and polyglutamin protein. To date, there is a lack of effective therapeutics that can counteract the polyglutamine neurotoxicity. Two peptidylic inhibitors, QBP1 and P3, targeting the protein and RNA toxicities, respectively, have been previously demonstrated by us with combinational therapeutic effects on the Drosophila polyglutamine disease model. However, their therapeutic efficacy has never been investigated in vivo in mammals. The current study aims to (a) develop a brain-targeting delivery system for both QBP1 and L1P3V8 (a lipidated variant of P3 with improved stability) and (b) evaluate their therapeutic effects on the R6/2 transgenic mouse model of polyglutamine disease. Compared with intravenous administration, intranasal administration of QBP1 significantly increased its brain-to-plasma ratio. In addition, employment of a chitosan-containing in situ gel for the intranasal administration of QBP1 notably improved its brain concentration for up to 10-fold. Further study on intranasal cotreatment with the optimized formulation of QBP1 and L1P3V8 in mice found no interference on the brain uptake of each other. Subsequent efficacy evaluation of 4-week daily QBP1 (16 μmol/kg) and L1P3V8 (6 μmol/kg) intranasal cotreatment in the R6/2 mice demonstrated a significant improvement on the motor coordination and explorative behavior of the disease mice, together with a full suppression on the RNA- and protein-toxicity markers in their brains. In summary, the current study developed an efficient intranasal cotreatment of the two peptidylic inhibitors, QBP1 and L1P3V8, for their brain-targeting, and such a novel therapeutic strategy was found to be effective on a transgenic polyglutamine disease mouse model