Clozapine-N-oxide protects dopaminergic neurons against rotenone-induced neurotoxicity by preventing ferritinophagy-mediated ferroptosis.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, yet treatment options are limited. Clozapine (CLZ), an antipsychotic used for schizophrenia, has potential as a PD treatment. CLZ and its metabolite, Clozapine-N-Oxide (CNO), show neuroprotective effects on dopaminergic neurons, with mechanisms needing further investigation. This study aimed to confirm the neuroprotective effects of CLZ and CNO in a rotenone-induced mouse model and further explore the underlying mechanisms of CNO-afforded protection. Gait pattern and rotarod activity evaluations showed motor impairments in rotenone-exposed mice, with CLZ or CNO administration ameliorating behavioral deficits. Cell counts and biochemical analysis demonstrated CLZ and CNO's effectiveness in reducing rotenone-induced neurodegeneration of dopaminergic neurons in the nigrostriatal system in mice. Mechanistic investigations revealed that CNO suppressed rotenone-induced ferroptosis of dopaminergic neurons by rectifying iron imbalances, curtailing lipid peroxidation, and mitigating mitochondrial morphological changes. CNO also reversed autolysosome and ferritinophagic activation in rotenone-exposed mice. SH-SY5Y cell cultures validated these findings, indicating ferritinophage involvement, where CNO-afforded protection was diminished by ferritinophagy enhancers. Furthermore, knockdown of NCOA4, a crucial cargo receptor for ferritin degradation in ferritinophagy, hampered rotenone-induced ferroptosis and NCOA4 overexpression countered the anti-ferroptotic effects of CNO. Whereas, iron-chelating agents and ferroptosis enhancers had no effect on the anti-ferritinophagic effects of CNO in rotenone-treated cells. In summary, CNO shielded dopaminergic neurons in the rotenone-induced PD model by modulating NCOA4-mediated ferritinophagy, highlighting a potential therapeutic pathway for PD treatment. This research provided insights into the role of NCOA4 in ferroptosis and suggested new approaches for PD therapy.

High-resolution fiber grating pressure sensor with in-situ calibration for deep sea exploration.

A high-resolution and wide-range pressure sensor based on π phase-shifted fiber Bragg grating (π-FBG) encapsulated with metal thin-walled cylinder is reported. The sensor has been tested with a wavelength-sweeping distributed feedback laser, photodetector and a H13C14N gas cell. To perceive temperature and pressure synchronously, a pair of π-FBGs are glued on the outer wall of the thin-walled cylinder along the circumferential direction with different angles. The interference of temperature is effectively corrected by a high-precision calibration algorithm. The reported sensor has a sensitivity of 4.42 pm/MPa, a resolution of 0.036% full scale (F.S.), and a repeatability error of 0.045% F.S. in the range of 0-110 MPa that corresponds to an ocean depth resolution of 5 m and a measurement range of eleven thousand meters to cover the deepest trench of the Ocean. The sensor features simplicity, good repeatability, and practicability.

Resonant fiber-optic thermometry with high resolution and wide range.

We report a high-resolution and wide-range thermometer using a fiber Bragg grating Fabry-Perot cavity (FBG-FP) combined with beat frequency interrogation. Two distributed feedback (DFB) lasers are locked to the FBG-FP sensing head and a hydrogen cyanide H13C14N (HCN) gas cell, respectively, both using the Pound-Drever-Hall (PDH) technique. The light beams from two lasers are brought together to interfere on a photodetector producing a beat frequency signal which provides a measure of the temperature change. Our sensor exhibits a dynamic range of ∼109 °C, a high resolution of 2×10-4 °C with an averaging time of 1 s. By introducing the reference frequency, the sensor has demonstrated good long-term stability. This sensor provides a useful tool for those fields where resolving slight temperature changes is crucial, such as deep ocean temperature measurement.

Organic anion transporter 3 (OAT3)-mediated transport of dicaffeoylquinic acids and prediction of potential drug-drug interaction.

Dicaffeoylquinic acids (DCQAs) are widely distributed in daily food and herb medicine (such as Dengzhanxiyin injection) with multiple health benefits and pharmacological activities. However, drug-drug Interactions (DDIs) between DCQAs and possible concomitant drugs were not fully understood in clinic. The purpose of present study was to investigate the role of organic anion transporters (OATs) in the transport of DCQAs and to explore the potential clinical DDIs using in vitro transporter assays. Uptake study using hOAT1/hOAT3-transfected HEK293 cells revealed that none of DCQAs was OAT1 substrate, while 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA were substrates of OAT3 with Km values of 119.7 ±â€¯28.8, 269.3 ±â€¯129.5 and 53.2 ±â€¯32.1 µM, respectively. The docking analysis revealed that 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA were effectively embedded in the active site of OAT3 and fitted well with the cavity in three-dimensional space. Moreover, the classical substrates/inhibitors of OAT decreased the accumulation of 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA in kidney slices, suggesting potential DDI risks with co-administration of substrate drugs of OAT. In fact, antivirals, antibiotics, neuroprotective agents, and PPIs (proton pump inhibitors) all showed varying degrees of inhibition of OAT3-mediated uptake of 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA in vitro. For cefaclor, ceftizoxime, pantoprazole, and zidovudine, in particular, their IC50 values were <10 times the maximal free plasma concentration, indicating potential clinically relevant DDIs when used together with DCQAs. These findings provided useful information for the prediction of DDIs between DCQAs and OAT3 inhibitors, and rational application of herbal medicines containing DCQAs in clinic.

Intermittent low-level vagosympathetic nerve trunk stimulation inhibits ganglionated plexi activity to prevent atrial fibrillation.

BACKGROUND: The cardiac autonomic nervous system (CANS) plays a role in the occurrence and persistence of atrial fibrillation (AF). Low-level vagosympathetic nerve stimulation (LL-VNS) has been shown to inhibit the occurrence of AF. OBJECTIVE: The novel objective of this study was to compare the effects of intermittent low- level vagosympathetic nerve stimulation (I-VNS) and continuous low-level vagosympathetic nerve stimulation (C-VNS). METHODS: 19 beagles were randomly divided into 3 groups: Group A, rapid left atrial appendage pacing for 6 hours; Group B, rapid atrial pacing (RAP) for 6 hours and C-VNS (20 Hz, interval 0.1 ms, square wave) with 50% threshold voltage strength; Group C, RAP for 6 hours and I-VNS (continuously recurring cycles of 30-second ON, 30-second OFF). The atrial monophasic action potential (MAP) and the effective refractory periods (ERP) of the atrium and the pulmonary veins were measured at baseline, 1 hour, 3 hours and 6 hours after the experiment began. After the experiment, tyrosine hydroxylase (TH) and choline acetyl transferase (CHAT) expression levels in the anterior right ganglionated plexi (ARGP) from each group were measured. RESULTS: Inter-group comparisons of MAP and ERP demonstrated that Group A was significantly different from Groups B and C (P < 0.05), while the difference between Groups B and C was not significant (P > 0.05). The MAP and ERP in Group A gradually decreased, reaching a minimum at 6 hours, but no significant changes were observed in Groups B and C. When compared to Group A, both Groups B and C had reduced TH and CHAT expression. CONCLUSIONS: During the occurrence and development of AF, I-VNS could protect the cardiovascular system, possibly replacing C-VNS. Additionally, both I-VNS and C-VNS inhibited ganglionated plexus (GP) activity during the AF prevention.

[Effects of planting density on the grain yield and source-sink characteristics of summer maize].

Taking high-yielding summer maize cultivars Zhengdan 958 (ZD 958) and Denghai 661 (DH 661) as test materials, this paper studied the effects of different planting density (22500, 45000, 67500, 90000, and 112500 plant x hm(-2)) on the grain yield and source-sink characteristics of the cultivars in four regions, i.e., Shandong Agricultural University, Wenkou, Yanzhou, and Laizhou. At the planting density 112500 plant x hm(-2), the grain yield and the biomass of the cultivars were the highest, being 19132 and 36965 kg x hm(-2), respectively. Comparing with those at the planting densities 22500 and 67500 plant x hm(-2), the grain yield at the planting density 112500 plant x hm(-2) was increased by 72% and 48%, and the biomass was increased by 152% and 112%, respectively. With the increase of planting density, the leaf area index (LAI) increased significantly, while the leaf area per plant (LA), the maximum number of filaments, the grains per ear, and the 1000-grain weight all decreased. The harvest index and the grain-leaf ratio decreased with increasing planting density, but no significant change was observed when the planting density was higher than 67500 plant x hm(-2), suggesting that at higher planting densities, summer maize could improve their grain yield via increasing population sink.

Trustworthy data collection from implantable medical devices via high-speed security implementation based on IEEE 1363.

Implantable medical devices (IMDs) have played an important role in many medical fields. Any failure in IMDs operations could cause serious consequences and it is important to protect the IMDs access from unauthenticated access. This study investigates secure IMD data collection within a telehealthcare [mobile health (m-health)] network. We use medical sensors carried by patients to securely access IMD data and perform secure sensor-to-sensor communications between patients to relay the IMD data to a remote doctor's server. To meet the requirements on low computational complexity, we choose N-th degree truncated polynomial ring (NTRU)-based encryption/decryption to secure IMD-sensor and sensor-sensor communications. An extended matryoshkas model is developed to estimate direct/indirect trust relationship among sensors. An NTRU hardware implementation in very large integrated circuit hardware description language is studied based on industry Standard IEEE 1363 to increase the speed of key generation. The performance analysis results demonstrate the security robustness of the proposed IMD data access trust model.