Correction: UHPLC-MS/MS combined with microdialysis for simultaneous determination of nicotine and neurotransmitter metabolites in the rat hippocampal brain region: application to pharmacokinetic and pharmacodynamic study.

Correction for 'UHPLC-MS/MS combined with microdialysis for simultaneous determination of nicotine and neurotransmitter metabolites in the rat hippocampal brain region: application to pharmacokinetic and pharmacodynamic study' by Mingyu Zhu et al., Anal. Methods, 2024, https://doi.org/10.1039/d4ay00522h.

UHPLC-MS/MS combined with microdialysis for simultaneous determination of nicotine and neurotransmitter metabolites in the rat hippocampal brain region: application to pharmacokinetic and pharmacodynamic study.

Nicotine crosses the blood-brain barrier and interacts with nicotinic acetylcholine receptors, initiating a cascade of neurotransmitter effects with potential therapeutic implications for neurodegenerative conditions such as Alzheimer's and Parkinson's disease. The hippocampus, pivotal for cognitive processes, plays a crucial role in nicotine-mediated cognitive enhancement due to its abundant expression of nicotinic acetylcholine receptors, particularly the α7 subtype, which is heavily implicated in hippocampus-related behavioral functions and dysfunctions. However, the intricate process of nicotine metabolism within the hippocampus remains poorly understood, impeding our comprehension of how nicotine and its metabolites modulate neurotransmitter dynamics. To address this gap, we have developed and validated a novel methodology combining microdialysis with UHPLC-MS/MS, enabling simultaneous detection of 12 neurotransmitters, nicotine, and its seven metabolites within the rat hippocampus. The linearity range of the targeted compounds is satisfactory (R2 > 0.9970), with intra-day and inter-day precision not exceeding 12.7%, and accuracy ranging from -12.4% to 13.7%. Our findings reveal differential pharmacokinetics of nicotine and its metabolites in the α7KO group compared to the control group, characterized by heightened nicotine absorption and slower elimination and distribution in the former. Notably, the pharmacokinetic parameters of cotinine exhibit similarity across both groups. Studies investigating the impact of nicotine on monoamine neurotransmitters have elucidated its capacity to augment the release of dopamine, serotonin, norepinephrine, glutamate, and acetylcholine in the rat hippocampus. This integrated approach facilitates a comprehensive analysis of neurotransmitter alterations within the hippocampal region following nicotine administration, thereby providing robust technical support and scientific rationale for understanding the neurochemical effects of nicotine and its metabolites. Further exploration into the pharmacokinetics and pharmacodynamics of nicotine holds promise for uncovering novel therapeutic avenues in the management of neurodegenerative diseases such as Alzheimer's.

Simulation and Optimization of Surface Gas Injection Systems for Underground Gas Storage.

With the rapid development and popularization of sensing technology and information technology, the demand for intelligence in the oil and gas industry and gas storage has increased. The optimized operation of surface engineering is an important part of intelligence. To master the operation law of the surface engineering of gas storage, improve the production management level, and reduce the cost of gas injection, we investigated the simulation and optimization of a surface gas injection system for practical underground gas storage. We propose calculation formulas for gas injection well pressure separately according to the ideal gas equation of state, the van der Waals equation, and the R-K equation and verify them using actual data. By comparing the calculation error of the data and the complexities for both the equation and the calculation process, we finally choose the formula derived from the ideal gas equation of state as the constraint condition for our research. Moreover, we model the surface gas injection system by using the Aspen HYSYS simulation software. From the variation in the compressor power, we determine that the equalizing pressure injection pattern is the optimal injection pattern and the optimal number of injection wells is three. In addition, we examine the relationship between injection flow and well pressure with injection time under the optimal injection pattern. Finally, we obtain the functional formula of well pressure and injection flow with injection time. The results can provide not only a basis for the gas injection decision making of production systems but also a basic guarantee for the digital transformation and intelligent operation of enterprises.

Do tau-synaptic long-term depression interactions in the hippocampus play a pivotal role in the progression of Alzheimer's disease?

Cognitive decline in Alzheimer's disease correlates with the extent of tau pathology, in particular tau hyperphosphorylation that initially appears in the transentorhinal and related regions of the brain including the hippocampus. Recent evidence indicates that tau hyperphosphorylation caused by either amyloid-ß or long-term depression, a form of synaptic weakening involved in learning and memory, share similar mechanisms. Studies from our group and others demonstrate that long-term depression-inducing low-frequency stimulation triggers tau phosphorylation at different residues in the hippocampus under different experimental conditions including aging. Conversely, certain forms of long-term depression at hippocampal glutamatergic synapses require endogenous tau, in particular, phosphorylation at residue Ser396. Elucidating the exact mechanisms of interaction between tau and long-term depression may help our understanding of the physiological and pathological functions of tau/tau (hyper)phosphorylation. We first summarize experimental evidence regarding tau-long-term depression interactions, followed by a discussion of possible mechanisms by which this interplay may influence the pathogenesis of Alzheimer's disease. Finally, we conclude with some thoughts and perspectives on future research about these interactions.

Pharmacokinetics of freebase nicotine and nicotine salts following subcutaneous administration in male rats.

Nicotine lactate, nicotine tartrate, nicotine benzoate, and freebase nicotine (FBN) are four forms of nicotine salt systems that are present in tobacco products. However, few in vivo studies have compared their pharmacological (pK) efficacies, which are important for understanding their roles in the addiction and abuse of tobacco and nicotine products. In this work, the pK of the above nicotine salt systems was studied by subcutaneously injecting their aqueous solutions in rats and obtaining blood samples from the jugular vein. Nicotine levels in the blood were analyzed by LC-MS/MS. The results demonstrated that rapid nicotine absorption occurred in all nicotine systems. Of them, NB had the smallest Tmax , while FBN had the largest Tmax . The nicotine metabolic rate and clearance decreased for FBN, indicating that nicotine retention in the body was higher than for the other three salt-based systems. Compared with nicotine salts, FBN could reach and maintain a higher concentration in the animal model. Additionally, as the benzoic acid ratios increased, the Cmax of the nicotine benzoate (NB) in the plasma decreased. This indicates that the lower the pH, the lower the Cmax . When different concentrations of NB were used, the higher the NB concentration, the greater the Cmax and AUC(0-t) . These results demonstrate that nicotine adsorption by NB in the animal model depended on both pH and concentration. This baseline information could be used to explain different clinical pharmacological observations in humans, though this study only considered the effects of nicotine on pharmacokinetics in vivo.

Pharmacokinetic differences in nicotine and nicotine salts mediate reinforcement-related behavior: an animal model study.

Since their introduction in the United States and Europe in 2007, electronic cigarettes (E-Cigs) have become increasingly popular among smokers. Nicotine, a key component in both tobacco and e-cigarettes, can exist in two forms: nicotine-freebase (FBN) and nicotine salts (NS). While nicotine salt is becoming more popular in e-cigarettes, the effect of nicotine salts on reinforcement-related behaviors remains poorly understood. This study aimed to compare the reinforcing effects of nicotine and nicotine salts in animal models of drug self-administration and explore potential mechanisms that may contribute to these differences. The results demonstrated that three nicotine salts (nicotine benzoate, nicotine lactate, and nicotine tartrate) resulted in greater reinforcement-related behaviors in rats compared to nicotine-freebase. Moreover, withdrawal-induced anxiety symptoms were lower in the three nicotine salt groups than in the nicotine-freebase group. The study suggested that differences in the pharmacokinetics of nicotine-freebase and nicotine salts in vivo may explain the observed behavioral differences. Overall, this study provides valuable insights into the reinforcing effects of nicotine as well as potential differences between nicotine-freebase and nicotine salts.

Inhibition of the ISR abrogates mGluR5-dependent long-term depression and spatial memory deficits in a rat model of Alzheimer's disease.

Soluble amyloid-ß-protein (Aß) oligomers, a major hallmark of AD, trigger the integrated stress response (ISR) via multiple pathologies including neuronal hyperactivation, microvascular hypoxia, and neuroinflammation. Increasing eIF2α phosphorylation, the core event of ISR, facilitates metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), and suppressing its phosphorylation has the opposite effect. Having found the facilitation of mGluR5-LTD by Aß in live rats, we wondered if suppressing eIF2α phosphorylation cascade would protect against the synaptic plasticity and cognitive disrupting effects of Aß. We demonstrate here that the facilitation of mGluR5-LTD in a delayed rat model by single i.c.v. injection of synthetic Aß1-42. Systemic administration of the small-molecule inhibitor of the ISR called ISRIB (trans-isomer) prevents Aß-facilitated LTD and abrogates spatial learning and memory deficits in the hippocampus in exogenous synthetic Aß-injected rats. Moreover, ex vivo evidence indicates that ISRIB normalizes protein synthesis in the hippocampus. Targeting the ISR by suppressing the eIF2α phosphorylation cascade with the eIF2B activator ISRIB may provide protective effects against the synaptic and cognitive disruptive effects of Aß which likely mediate the early stage of sporadic AD.

Long-Term Depression-Inducing Low Frequency Stimulation Enhances p-Tau181 and p-Tau217 in an Age-Dependent Manner in Live Rats.

BACKGROUND: Cognitive decline in Alzheimer's disease (AD) correlates with the extent of tau pathology, in particular tau hyperphosphorylation, which is strongly age-associated. Although elevation of cerebrospinal fluid or blood levels of phosphorylated tau (p-Tau) at residues Thr181 (p-Tau181), Thr217 (p-Tau217), and Thr231 (p-Tau231) are proposed to be particularly sensitive markers of preclinical AD, the generation of p-Tau during brain activity is poorly understood. OBJECTIVE: To study whether the expression levels of p-Tau181, p-Tau217, and p-Tau231 can be enhanced by physiological synaptic long-term depression (LTD) which has been linked to the enhancement of p-Tau in hippocampus. METHODS: In vivo electrophysiology was performed in urethane anesthetized young adult and aged male rats. Low frequency electrical stimulation (LFS) was used to induce LTD at CA3 to CA1 synapses. The expression level of p-Tau and total tau was measured in dorsal hippocampus using immunofluorescent staining and/or western blotting. RESULTS: We found that LFS enhanced p-Tau181 and p-Tau217 in an age-dependent manner in the hippocampus of live rats. In contrast, phosphorylation at residues Thr231, Ser202/Thr205, and Ser396 appeared less sensitive to LFS. Pharmacological antagonism of either N-methyl-D-aspartate or metabotropic glutamate 5 receptors inhibited the elevation of both p-Tau181 and p-Tau217. Targeting the integrated stress response, which increases with aging, using a small molecule inhibitor ISRIB, prevented the enhancement of p-Tau by LFS in aged rats. CONCLUSION: Together, our data provide a novel in vivo means to uncover brain plasticity-related cellular and molecular processes of tau phosphorylation at key sites in health and aging.

Transfer matrix modeling on a longitudinal-bending coupled piezoelectric transducer with single-phase excitation: Analysis and verification.

Surface-bonded type piezoelectric transducers have the advantages of simple structure, easy miniaturization, and flexible design and have been widely employed as the stator of ultrasonic motors. In order to simplify the control system, a surface-bonded type single-phase excited piezoelectric transducer operating in the longitudinal-bending coupling vibration is proposed, modeled, and validated in this study. Using the asymmetrical excitation effect, the longitudinal-bending coupled vibration is generated in the proposed piezoelectric transducer only applied with a single-phase electrical signal, leading to the production of the elliptical motion at its driving tip. The proposed transducer holds the advantages of compact structure, simple control system, and low manufacturing costs. The transfer matrix method, which is an efficient and fast semi-analytic computation solution, is employed to develop a dynamic model for the proposed transducer in this study in order to provide a general modeling method for surface-bonded type piezoelectric transducers operating with the longitudinal-bending coupled vibration. A novel longitudinal-bending coupled vibration transfer matrix is created first for surface-bonded type piezoelectric composite element. Then, a general semi-analytical electromechanical coupling model is developed to analyze dynamic behaviors of the proposed piezoelectric transducer. Finally, experimental validation is carried out on the prototype of the proposed piezoelectric transducer and compared with the calculation results using the developed transfer matrix model. Experimental results matched well with the calculation results, which confirmed the correctness of the transducer design and verified the feasibility of the developed transfer matrix model. The proposed piezoelectric transducer presents the potential application for linear ultrasonic motors.

A novel ring-beam piezoelectric actuator for small-size and high-precision manipulator.

A new type of ring (joint)-beam (arm) element based on piezoelectric actuator is designed in this paper. By using piezoelectric ceramics, the vibration modes of two parallel beams are excited and coupled to form in-plane waves on the ring. As the piezoelectric actuator has the dual effect of acting as the power source and the main body structure of the arm joint, compared with the rotating joint using DC motor as the power source, the actuator does not need additional space to install the motor, which makes joint mechanism have the advantages of simple structure and small volume. Furthermore, the micro-displacement control of joints can be achieved by the characteristics of fast response and power self-locking based on the friction driving principle. A two-degree-of-freedom three-arm prototype of the joint mechanism is designed to obtain the parameters of the piezoelectric actuator and carry out related experiments. The prototype of the mechanism is 72 g in weight and 105 mm in length, and the maximum rotation angle of each joint is 210 deg. The experimental results indicate that, when driving frequency is 58.6 kHz and the driving voltage is 300 Vpp, the angular speed of the prototype reaches 45.9 deg/s, the resolution is 0.015 deg and the startup and shutdown response time are 35 ms and 21 ms, respectively. Due to its simple and compact structure, the manipulator have strong growth potential for meeting the requirements of wet hyperbaric environment. The characteristics of fast response time and high resolution enable good mobility and high precision.

Association of polymorphisms in HTR2A, TPH1, and TPH2 genes with attempted suicide in rural China.

OBJECTIVE: We aimed to test the association of polymorphisms in HTR2A, TPH1, and TPH2 genes with attempted suicide in rural China. PARTICIPANTS AND METHODS: On the basis of a case-control study, we recruited 1200 pairs of participants from Shandong Province, China. The blood samples of 712 suicide attempters and 739 nonsuicide attempters were collected finally. We tested seven single nucleotide polymorphisms: rs6313 and rs6311 in HTR2A, rs4537731, rs1800532, and rs1799913 in TPH1, and rs4448731 and rs4641527 in TPH2. RESULTS: In univariate analysis, allele C of rs4537731 was associated negatively with attempted suicide among total and male samples; however, the association was not statistically significant in multivariate analysis after adjusting for other potential confounding factors. No association between other six single nucleotide polymorphisms and attempted suicide was found in the total, male, or female samples. CONCLUSION: This study did not support the effect of these seven serotonergic gene polymorphisms on attempted suicide in rural China.

Associations between depression, anxiety, stress, hopelessness, subjective well-being, coping styles and suicide in Chinese university students.

Suicide is a major public health concern worldwide. This study aimed to predict the suicidal behavior of Chinese university students by studying psychological measures such as hopelessness, orientation to happiness, meaning in life, depression, anxiety, stress, and coping styles. In November 2016, a stratified-clustered-random sampling approach was utilized to select subjects from two large public medical-related universities in Shandong province, China. This sample consisted of 2,074 undergraduate students (706 males, 1,368 females; mean age = 19.79±1.39 years). The students' major risk factors for suicide were depression, anxiety, stress, and hopelessness, and the students' minor risk factors included orientation to happiness and coping styles (including self-distraction, self-blame and substance use). Notably, the presence of meaning in life had a positive effect on preventing suicide and acted as a protective factor, which suggests that it is important to identify risk factors as well as protective factors relevant to the target population group in order to increase the effectiveness of counseling and suicide prevention programs.

The AAA protein spastin possesses two levels of basal ATPase activity.

The AAA ATPase spastin is a microtubule-severing enzyme that plays important roles in various cellular events including axon regeneration. Herein, we found that the basal ATPase activity of spastin is negatively regulated by spastin concentration. By determining a spastin crystal structure, we demonstrate the necessity of intersubunit interactions between spastin AAA domains. Neutralization of the positive charges in the microtubule-binding domain (MTBD) of spastin dramatically decreases the ATPase activity at low concentration, although the ATP-hydrolyzing potential is not affected. These results demonstrate that, in addition to the AAA domain, the MTBD region of spastin is also involved in regulating ATPase activity, making interactions between spastin protomers more complicated than expected.