Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions.

(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine's metabolism in the AD actions of the drug, we evaluated the effects of inhibiting hepatic cytochrome P450 enzymes on AD responses. We assessed whether pre-treatment with fluconazole (10 and 20 mg/kg, i. p.) 1 h prior to ketamine or HNKs (10 mg/kg, i. p.) administration would alter behavioral and neurochemical actions of the drugs in male BALB/cJ mice with a highly anxious phenotype. Extracellular microdialysate levels of glutamate and GABA (Gluext, GABAext) were also measured in the medial prefrontal cortex (mPFC). Pre-treatment with fluconazole altered the pharmacokinetic profile of ketamine, by increasing both plasma and brain levels of ketamine and (R,S)-norketamine, while robustly reducing those of (6)-HNKs. At 24 h post-injection (t24 h), fluconazole prevented the sustained AD-like response of ketamine responses in the forced swim test and splash test, as well as the enhanced cortical GABA levels produced by ketamine. A single (2R,6R)-HNK administration resulted in prevention of the effects of fluconazole on the antidepressant-like activity of ketamine in mice. Overall, these findings are consistent with an essential contribution of (6)-HNK to the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients.

Sin in the Digital Flesh? Religiosity and the Sexting Behavior of Women and Men in the United States.

Scholars have noted a rise in sexting behavior in the aftermath of the COVID-19 pandemic. Although the association between religion and sexual behavior has been widely studied, researchers have yet to consider whether sexting behavior might vary according to levels of religiosity. Building on prior research, this study uses national survey data to formally test whether several dimensions of religiosity (religious attendance, divine control, and religious/spiritual struggles) are associated with the sexting behavior of women (n = 619, Mage = 40.28, SD = 11.50) and men (n = 548, Mage = 40.04, SD = 11.51). Results suggest that the odds of sexting are lower among women who report higher levels of in-person religious attendance (not virtual attendance) and greater perceptions of divine control. Among women and men, the odds of sexting are higher among those who report more religious/spiritual struggles. This study is among the first to show how various dimensions of religiosity might influence sexting behavior in different ways for women and men during the COVID-19 pandemic. It is important for future research to replicate our findings and to consider whether other dimensions of religiosity might also contribute to the likelihood of sexting in an increasingly digital world.

Group decision-making algorithm with sine trigonometric r,s,t-spherical fuzzy aggregation operators and their application.

r, s, t-spherical fuzzy (r, s, t-SPF) sets provide a robust framework for managing uncertainties in decision-making, surpassing other fuzzy sets in their ability to accommodate diverse uncertainties through the incorporation of flexible parameters r, s, and t. Considering these characteristics, this article explores sine trigonometric laws to enhance the applicability and theoretical foundation for r, s, t-SPF setting. Following these laws, several aggregation operators (AOs) are designed for aggregation of the r, s, t-SPF data. Meanwhile, the desired characteristics and relationships of these operators are studied under sine trigonometric functions. Furthermore, we build a group decision-making algorithm for addressing multiple attribute group decision-making (MAGDM) problems using the developed AOs. To exemplify the applicability of the proposed algorithm, we address a practical example regarding laptop selection. Finally, parameter analysis and a comprehensive comparison with existing operators are conducted to uncover the superiority and validity of the presented AOs.

A New Approach in Lipase-Octyl-Agarose Biocatalysis of 2-Arylpropionic Acid Derivatives.

The use of lipase immobilized on an octyl-agarose support to obtain the optically pure enantiomers of chiral drugs in reactions carried out in organic solvents is a great challenge for chemical and pharmaceutical sciences. Therefore, it is extremely important to develop optimal procedures to achieve a high enantioselectivity of the biocatalysts in the organic medium. Our paper describes a new approach to biocatalysis performed in an organic solvent with the use of CALB-octyl-agarose support including the application of a polypropylene reactor, an appropriate buffer for immobilization (Tris base-pH 9, 100 mM), a drying step, and then the storage of immobilized lipases in a climatic chamber or a refrigerator. An immobilized lipase B from Candida antarctica (CALB) was used in the kinetic resolution of (R,S)-flurbiprofen by enantioselective esterification with methanol, reaching a high enantiomeric excess (eep = 89.6 ± 2.0%). As part of the immobilization optimization, the influence of different buffers was investigated. The effect of the reactor material and the reaction medium on the lipase activity was also studied. Moreover, the stability of the immobilized lipases: lipase from Candida rugosa (CRL) and CALB during storage in various temperature and humidity conditions (climatic chamber and refrigerator) was tested. The application of the immobilized CALB in a polypropylene reactor allowed for receiving over 9-fold higher conversion values compared to the results achieved when conducting the reaction in a glass reactor, as well as approximately 30-fold higher conversion values in comparison with free lipase. The good stability of the CALB-octyl-agarose support was demonstrated. After 7 days of storage in a climatic chamber or refrigerator (with protection from humidity) approximately 60% higher conversion values were obtained compared to the results observed for the immobilized form that had not been stored. The new approach involving the application of the CALB-octyl-agarose support for reactions performed in organic solvents indicates a significant role of the polymer reactor material being used in achieving high catalytic activity.

Religious/spiritual struggles and whole person functioning among Colombian university students: Longitudinal evidence of mutual influence.

This prospective study examined the primary, secondary and complex conceptual models of religious/spiritual struggles with 18 indicators of whole person functioning across five domains: psychological well-being, psychological distress, social well-being, physical well-being and character. We used three waves of longitudinal data (Wave 1: August/September 2021, Wave 2: October/November 2021, Wave 3: February 2022) from Colombian university students (N = 2878, Mage = 20.88 ± 4.05 years). Adjusting for covariates assessed in Wave 1, our primary analysis applied the analytic templates for outcome-wide and lagged exposure-wide designs to estimate two sets of lagged linear regression models. Religious/spiritual struggles in Wave 2 were associated with a small-to-medium-sized decline in subsequent functioning on 17/18 indicators in Wave 3, and worse functioning on 16/18 indicators in Wave 2 was associated with very small-to-medium-sized increases in subsequent religious/spiritual struggles in Wave 3. The results provided evidence in favour of the complex conceptual model for 16/18 indicators of whole person functioning. Our findings extend existing evidence on the reciprocal association between religious/spiritual struggles and individual functioning to a wide range of indicators, reinforcing the need for practitioners to consider the dynamic interplay between religious/spiritual struggles and individual functioning as they work with younger populations.

Actively extracting kidney stones combined dusting technique can improve SFR of moderate-complexity kidney stones in fURL.

PURPOSE: To evaluate the necessity and effectiveness of actively extracting kidney stones with different complexity that have been visually dusted in flexible ureteroscopic lithotripsy (fURL). METHODS: We retrospectively reviewed the medical records of patients who underwent fURL with dusting technique in established hospitals. A total of 535 cases were divided into the dusting group or the dusting plus basketing group according to the use of stone basket. Their characteristics and operative parameters were collected and analyzed. We used the R.I.R.S. scoring system to classify the complexity of kidney stones and divided these kidney stones into three subgroups, namely, mild-, moderate-, and severe-complexity group. And then, the effectiveness of stone basket in these subgroups was analyzed. RESULTS: Although using a stone basket significantly reduced re-operation rate (17.8% in dusting group versus 10.2% in dusting plus basketing group, p = 0.013), no significant difference on stone-free rate (SFR) and overall incidence of complications were noticed between groups. After we classified the complexity of kidney stones using the R.I.R.S. scoring system, we found a stone basket was helpful to improve SFR in kidney stones with moderate-complexity that had been visually dusted in fURL (73.5% in dusting group versus 87.3% in dusting plus basketing group, p = 0.002) but had limited influence on SFR in mild (93.8% in dusting group versus 92.6% in dusting plus basketing group, p = 0.783) or severe (28.5% in dusting group versus 34.0% in dusting plus basketing group, p = 0.598)-complexity kidney stones. CONCLUSION: The use of stone basket should be encouraged in moderate-complexity kidney stones which can be visually dusted in fURL.

Traumatic Brain Injury-Induced Fear Generalization in Mice Involves Hippocampal Memory Trace Dysfunction and Is Alleviated by (R,S)-Ketamine.

BACKGROUND: Traumatic brain injury (TBI) is a debilitating neurological disorder caused by an impact to the head by an outside force. TBI results in persistent cognitive impairments, including fear generalization and the inability to distinguish between aversive and neutral stimuli. The mechanisms underlying fear generalization have not been fully elucidated, and there are no targeted therapeutics to alleviate this symptom of TBI. METHODS: To identify the neural ensembles mediating fear generalization, we utilized ArcCreERT2 × enhanced yellow fluorescent protein (EYFP) mice, which allow for activity-dependent labeling and quantification of memory traces. Mice were administered a sham surgery or the controlled cortical impact model of TBI. Mice were then administered a contextual fear discrimination paradigm and memory traces were quantified in numerous brain regions. In a separate group of mice, we tested if (R,S)-ketamine could decrease fear generalization and alter the corresponding memory traces in TBI mice. RESULTS: TBI mice exhibited increased fear generalization when compared with sham mice. This behavioral phenotype was paralleled by altered memory traces in the dentate gyrus, CA3, and amygdala, but not by alterations in inflammation or sleep. In TBI mice, (R,S)-ketamine facilitated fear discrimination, and this behavioral improvement was reflected in dentate gyrus memory trace activity. CONCLUSIONS: These data show that TBI induces fear generalization by altering fear memory traces and that this deficit can be improved with a single injection of (R,S)-ketamine. This work enhances our understanding of the neural basis of TBI-induced fear generalization and reveals potential therapeutic avenues for alleviating this symptom.

Research on the dissemination and evolution of the traditional ethnic sport culture / Investigación sobre la difusión y evolución de la cultura del deporte étnico tradicional

The basic aim of this research study is to describe the dissemination of evolution related to the traditional ethnic sport culture. This research study depends on theoretical base analysis to determine the research used different websites linked to dissemination and evolution. The data collected related to the traditional ethnic sport culture research study based on theory and some data based on primary research. For this purpose, data collected through questions for measuring the research used smart PLS software, and run results included significant analysis and smart PLS Algorithm model related to the traditional ethnic sport culture. In conclusion, sports are cultural in a variety of ways. Participating in sports enables us to have and share culture, keeping us physically fit and healthy and enhancing our reputation via success. Furthermore, Sports help us develop a sense of self and community. Even better, we can introduce people to our culture. Sports participation is one of the few ways we can interact with and learn about another culture. Recognizing this fact enables us to use sports for good.(AU)

The Influence of 5',8-Cyclo-2'-Deoxyguanosine on ds-DNA Charge Transfer Depends on Its Diastereomeric Form: A Theoretical Study.

The genetic information stored in the nucleobase sequence is continuously exposed to harmful extra- and intra-cellular factors, which can lead to different types of DNA damage, with more than 70 lesion types identified so far. In this article, the influence of a multi-damage site containing (5'R/S) 5',8-cyclo-2'-deoxyguanosine (cdG) and 7,8-dihydro-8-oxo-2'-deoxyguanosine (OXOdG) on charge transfer through ds-DNA was taken into consideration. The spatial geometries of oligo-RcdG: d[A1(5'R)cG2A3OXOG4A5]*d[T5C4T3C2T1] and oligo-ScdG: d[A1(5'S)cG2A3OXOG4A5]*d[T5C4T3C2T1] were optimized at the M06-2X/6-D95**//M06-2X/sto-3G level of theory in the aqueous phase using ONIOM methodology. For all the electronic property energies under discussion, the M06-2X/6-31++G** level of theory was used. Additionally, the non-equilibrated and equilibrated solvent-solute interactions were into consideration. The obtained results confirm the predisposition of OXOdG to radical cation formation regardless of the presence of other lesions in a ds-DNA structure. In the case of electron transfer, however, the situation is different. An excess electron migration towards (5'S)cdG was found to be preferred in the case of oligo-ScdG, while in the case of oligo-RcdG, OXOdG was favored. The above observation was confirmed by the charge transfer rate constant, vertical/adiabatic ionization potential, and electron affinity energy values, as well as the charge and spin distribution analysis. The obtained results indicate that 5',8-cyclo-2'-deoxyguanosine, depending on the C5' atom chirality, can significantly influence the charge migration process through the double helix. The above can be manifested by the slowdown of DNA lesion recognition and removal processes, which can increase the probability of mutagenesis and subsequent pathological processes. With regard to anticancer therapy (radio/chemo), the presence of (5'S)cdG in the structure of formed clustered DNA damage can lead to improvements in cancer treatment.

Integrating transformer and autoencoder techniques with spectral graph algorithms for the prediction of scarcely labeled molecular data.

In molecular and biological sciences, experiments are expensive, time-consuming, and often subject to ethical constraints. Consequently, one often faces the challenging task of predicting desirable properties from small data sets or scarcely-labeled data sets. Although transfer learning can be advantageous, it requires the existence of a related large data set. This work introduces three graph-based models incorporating Merriman-Bence-Osher (MBO) techniques to tackle this challenge. Specifically, graph-based modifications of the MBO scheme are integrated with state-of-the-art techniques, including a home-made transformer and an autoencoder, in order to deal with scarcely-labeled data sets. In addition, a consensus technique is detailed. The proposed models are validated using five benchmark data sets. We also provide a thorough comparison to other competing methods, such as support vector machines, random forests, and gradient boosting decision trees, which are known for their good performance on small data sets. The performances of various methods are analyzed using residue-similarity (R-S) scores and R-S indices. Extensive computational experiments and theoretical analysis show that the new models perform very well even when as little as 1% of the data set is used as labeled data.

Growth promoter, immune response, and histopathological change of prebiotic, probiotic and synbiotic bacteria on Nile tilapia.

This study aimed at determining the influence of prebiotic, probiotic, and synbiotic supplemented diets on Oreochromis niloticus. Fish with initial body weight (25.8 ± 1.2) g and length range from (13.5 ± 1.5) cm were collected and randomized to four dietary treatments for 60 days. Furthermore, fish were divided into three groups in triplicate; A0 control (-ve), A1 control (+ve) infected with V.anguillarium, and a third non-treated group. Moreover, the third group further separated into two groups, A and B. Group (A) was treated with prebiotic, probiotic, and symbiotic (A2, A3, and A4), while group (B) was infected with V.anguillarium then treated with prebiotic, probiotic and symbiotic (A5, A6, and A7). The results revealed that all treatments supplemented with synbiotics represented highly significant increase (p ≤ 0.05) in (SGR), BWG percentage, relative growth rate (%), lysozyme activity, IMG, SOD, and CAT. At the same time, they exhibited a significant decrease in MAD and FCR. Besides, fish that feed dietary supplementation with prebiotics, probiotics, and synbiotics revealed a significant increase in RBCs, WBCs, and Hb. In contrast, they showed a significant decrease in ALT, AST, albumin, total protein, globulin, creatinine, and urea compared with control. Additionally, high survival rates were recorded in groups that received a diet supplemented with probiotics, followed by prebiotics and synbiotics.

Chiral LC-MS/MS method for the simultaneous determination of (R,S)-ketamine, (R,S)-norketamine, and (2R,6R;2S,6S)-hydroxynorketamine in mouse plasma and brain.

A convenient LC-MS/MS assay method to simultaneously and sensitively determine (R,S)-ketamine (Ket), (R,S)-norketamine (NK), and (2R,6R;2S,6S)-hydroxynorketamine (HNK) enantiomers in plasma and brain from mice was developed. This method enables the chiral separations of these six enantiomers in one analysis by constructing a column-switching system composed of one achiral column and two chiral columns with a relatively short analysis time (17 min). The chromatography involves the separation of (2R,6R;2S,6S)-HNK from (R,S)-Ket and (R,S)-NK on an octadecyl-silica column, followed by chiral separations on a CHIRALPAK AY-RH column for (2R,6R;2S,6S)-HNK or on a CHIRALPAK AS-RH column for the other analytes. The calibration curves for plasma and brain showed a good linearity in the range of 3-1000 ng/mL and 1.5-500 ng/g, respectively. The accuracy ranged from 90.0% to 104.0% in within-run and between-run. This validated method was applicable to determine the stereoselective pharmacokinetic profiles of (R,S)-Ket, (R,S)-NK, and (2R,6R;2S,6S)-HNK in plasma and brain collected from individual mice after a single intraperitoneal dosing of racemic Ket at an antidepressant dose. It is hoped that this assay will greatly help for understanding the relationship between the antidepressant actions of (R,S)-Ket enantiomers or their metabolites and their pharmacokinetics.

"Spiritual Readiness" in the U.S. Military: A Neglected Component of Warrior Readiness.

Recent events have led to concerns about whether U.S. service members are "ready" to engage in combat operations. With most discussions now focused on military readiness, attention paid to warfighter readiness may have fallen behind. Service members typically receive extensive training in the tactical, physical, mental, social, and behavioral aspects of readiness, while the spiritual aspects are often ignored. This review examines (1) recent concerns over warfighter readiness, (2) mental health problems that are common among members of the U.S. military, (3) definitions and determinants of "spiritual readiness" (SR), (4) the impact of SR on human flourishing (HF) and warfighter readiness, (5) research on the effects of religious/spiritual involvement on HF, and (6) those responsible for building and sustaining SR in the military. An extensive body of research over the past 30 years has documented the impact of religious/spiritual (R/S) involvement on many aspects of human flourishing, thereby affecting the warfighter's readiness to perform duties at the highest level. Military chaplains, mental health professionals, and medical providers all play important roles in building and sustaining the spiritual readiness of those in the U.S. military, thereby ensuring that these individuals perform in a way that maximizes their success during combat operations.

Enantioselective resolution of (R,S)-DMPM to prepare (R)-DMPM by an adsorbed-covalent crosslinked esterase PAE07 from Pseudochrobactrum asaccharolyticum WZZ003.

(R)-N-(2,6-dimethylphenyl) aminopropionic acid methyl ester ((R)-DMPM) is an important chiral intermediate of the fungicide N-(2,6-Dimethylphenyl)-N-(methoxyacetyl)-alanine methyl ester ((R)-Metalaxyl). In this study, (1) D3520 (macroporous acrylic anion resin), selected from the ten resins, was used to immobilize the esterase from Pseudochrobactrum asaccharolyticum WZZ003 (PAE07) for resoluting the (R,S)-DMPM to obtain (R)-DMPM. (2) Up to 20 g/L PAE07 could be immobilized onto D3520 with a high enzymatic activity of 32.4 U/g. Moreover, the Km and Vmax values of 19.1 mM and 2.8 mM/min for D3520-immobilized PAE07 indicated its high activity and stereoselectivity. (3) The optimal temperature and pH for the immobilized PAE07 were 40 ℃ and 8.0, and substrate concentration was up to 0.35 M. After 15 h reaction, the conversion rate from (R,S)-DMPM to (R)-DMPM was 48.0% and the e.e.p and E values were 99.5% and 1393.0, respectively. In scale-up resolution, 200 g/L substrate and 12.5 g immobilized esterase PAE07 condition, a conversion rate from substrate to product of 48.1% and a product e.e.p of 98% were obtained within 12 h, with the activity of immobilized PAE07 retained 80.2% after 5 cycles of reactions. These results indicated that the D3520-immobilized esterase PAE07 had great potential for enzymatic resolution of (R,S)-DMPM to prepare (R)-Metalaxyl.

Weapons of stress reduction: (R,S)-ketamine and its metabolites as prophylactics for the prevention of stress-induced psychiatric disorders.

Exposure to stress is one of the greatest contributing factors to developing a psychiatric disorder, particularly in susceptible populations. Enhancing resilience to stress could be a powerful intervention to reduce the incidence of psychiatric disease and reveal insight into the pathophysiology of psychiatric disorders. (R,S)-ketamine and its metabolites have recently been shown to exert protective effects when administered before or after a variety of stressors and may be effective, tractable prophylactic compounds against psychiatric disease. Drug dosing, sex, age, and strain in preclinical rodent studies, significantly influence the prophylactic effects of (R,S)-ketamine and related compounds. Due to the broad neurobiological actions of (R,S)-ketamine, a variety of mechanisms have been proposed to contribute to the resilience-enhancing effects of this drug, including altering various transcription factors across the genome, enhancing inhibitory connections from the prefrontal cortex, and increasing synaptic plasticity in the hippocampus. Promisingly, select data have shown that (R,S)-ketamine may be an effective prophylactic against psychiatric disorders, such as postpartum depression (PPD). Overall, this review will highlight a brief history of the prophylactic effects of (R,S)-ketamine, the potential mechanisms underlying its protective actions, and possible future directions for translating prophylactic compounds to the clinic. This article is part of the Special Issue on 'Ketamine and its Metabolites'.

Designing of Drug Delivery Systems to Improve the Antimicrobial Efficacy in the Periodontal Pocket Based on Biodegradable Polyesters.

Delivery systems for biologically active substances such as proanthocyanidins (PCANs), produced in the form of electrospun nonwoven through the electrospinning method, were designed using a polymeric blend of poly(L-lactide-co-glycolide) (PLGA)and poly[(R,S)-3-hydroxybutyrate] ((R,S)-PHB). The studies involved the structural and thermal characteristics of the developed electrospun three-dimensional fibre matrices unloaded and loaded with PCANs. In the next step, the hydrolytic degradation tests of these systems were performed. The release profile of PCANs from the electrospun nonwoven was determined with the aid of UV-VIS spectroscopy. Approximately 30% of the PCANs were released from the tested electrospun nonwoven during the initial 15-20 days of incubation. The chemical structure of water-soluble oligomers that were formed after the hydrolytic degradation of the developed delivery system was identified through electrospray ionization mass spectrometry. Oligomers of lactic acid and OLAGA oligocopolyester, as well as oligo-3-hydroxybutyrate terminated with hydroxyl and carboxyl end groups, were recognized as degradation products released into the water during the incubation time. It was also demonstrated that variations in the degradation rate of individual mat components influenced the degradation pattern and the number of formed oligomers. The obtained results suggest that the incorporation of proanthocyanidins into the system slowed down the hydrolytic degradation process of the poly(L-lactide-co-glycolide)/poly[(R,S)-3-hydroxybutyrate] three-dimensional fibre matrix. In addition, in vitro cytotoxicity and antimicrobial studies advocate the use of PCANs for biomedical applications with promising antimicrobial activity.

Religion and Pandemic Weight Gain: A Refuge from the Storm?

The COVID-19 pandemic was an inherently stressful global crisis that was associated with weight gain for over 40% of the American public. Building on previous research, we draw on recently collected national survey data from the United States to examine the effects of religious attendance (both in-person and virtual), the sense of divine control, and religious/spiritual (R/S) struggles on pandemic weight gain. A series of logistic regression models were conducted. Our findings suggest that divine control and monthly in-person religious attendance were associated with a lower risk of pandemic weight gain, while R/S struggles were associated with a higher risk of weight gain. Our results reveal the complex role that religiosity can play with respect to pandemic weight gain.

Air quality assessment based on R/S-SPA composite model: A case study of the Hebei province (China).

Air pollution has been the favorite subject of pollution prevention and control measures with the aim of sustainable development. Therefore, a composite model of rescaled range (R/S) and set pair analysis (SPA) was constructed to evaluate the air pollution situation based on the data from 2013 to 2020 in the Hebei province and then predict its air quality development trend. The results show that (1) the air pollution situation is severe, but the development trend is good and (2) the main pollutants are the core factors affecting air quality, and it is necessary to focus on intervention. The innovation of this paper lies on the combination of R/S and SPA to jointly predict the development trend of air quality in the Hebei province and ensure its scientific prediction. Meanwhile, this paper does not point out the continuation cycle of development state, which is the limitation of this paper. Finally, this study deepens the understanding of air quality evaluation, and the following countermeasures are formed: adherence to the problem- and goal-oriented approach to help the transformation of low-carbon development and enhancing the awareness of energy conservation and environmental protection to practice low-carbon lifestyle.

In Planta, In Vitro and In Silico Studies of Chiral N6-Benzyladenine Derivatives: Discovery of Receptor-Specific S-Enantiomers with Cytokinin or Anticytokinin Activities.

Cytokinins, classical phytohormones, affect all stages of plant ontogenesis, but their application in agriculture is limited because of the lack of appropriate ligands, including those specific for individual cytokinin receptors. In this work, a series of chiral N6-benzyladenine derivatives were studied as potential cytokinins or anticytokinins. All compounds contained a methyl group at the α-carbon atom of the benzyl moiety, making them R- or S-enantiomers. Four pairs of chiral nucleobases and corresponding ribonucleosides containing various substituents at the C2 position of adenine heterocycle were synthesized. A nucleophilic substitution reaction by secondary optically active amines was used. A strong influence of the chirality of studied compounds on their interaction with individual cytokinin receptors of Arabidopsis thaliana was uncovered in in vivo and in vitro assays. The AHK2 and CRE1/AHK4 receptors were shown to have low affinity for the studied S-nucleobases while the AHK3 receptor exhibited significant affinity for most of them. Thereby, three synthetic AHK3-specific cytokinins were discovered: N6-((S)-α-methylbenzyl)adenine (S-MBA), 2-fluoro,N6-((S)-α-methylbenzyl)adenine (S-FMBA) and 2-chloro,N6-((S)-α-methylbenzyl)adenine (S-CMBA). Interaction patterns between individual receptors and specific enantiomers were rationalized by structure analysis and molecular docking. Two other S-enantiomers (N6-((S)-α-methylbenzyl)adenosine, 2-amino,N6-((S)-α-methylbenzyl)adenosine) were found to exhibit receptor-specific and chirality-dependent anticytokinin properties.

Dose-dependent suppression of hippocampal contextual memory formation, place cells, and spatial engrams by the NMDAR antagonist (R)-CPP.

We recently reported that the competitive NMDAR antagonist (R,S)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) does not suppress NMDAR-mediated field EPSPs (fEPSPNMDA) or long-term potentiation (LTP) in vitro at concentrations that block contextual conditioning in vivo. Here we tested one possible explanation for the mismatch - that the hippocampus is relatively resistant to CPP compared to other brain structures engaged in contextual fear conditioning. Using the context pre-exposure facilitation effect (CPFE) paradigm to separate the hippocampal and extra-hippocampal components of contextual learning, we found that the active enantiomer (R)-CPP suppressed the hippocampal component with an IC50 of 3.1 mg/kg, a dose that produces brain concentrations below those required to block fEPSPNMDA or LTP. Moreover, using in-vivo calcium imaging of place cells and spatial engrams to directly assess hippocampal spatial coding, we found that (R)-CPP dose-dependently reduced the development of place cells and interfered with the formation of stable spatial engrams when it was administered prior to exposing mice to a novel context. Both effects occurred at doses that interfered with freezing to context in CPFE experiments. We conclude that (R)-CPP blocks memory formation by interfering with hippocampal function, but that it does so by modulating NMDARs at sites that are not engaged in vitro in the same manner that they are in vivo - perhaps through interneuron circuits that do not contribute to fEPSPs and are not required to elicit LTP using standard induction protocols in vitro, but are essential for successful mnemonic function in vivo.